WO2012166700A2

WO2012166700A2 - Molecular profiling of a lethal tumor microenvironment

Info

Publication number: WO2012166700A2
Application number: PCT/US2012/039814
Authority: WO
Inventors: Michael P. Lisanti; Federica Sotgia
Original assignee: Individual
Current assignee: Individual
Priority date: 2011-05-29
Filing date: 2012-05-29
Publication date: 2012-12-06
Anticipated expiration: 2013-11-29
Also published as: WO2012166700A3

Abstract

Presented herein are useful biological markers related to cancers with stromal components. These newly identified biological markers are useful as prognostic signatures for assessing cancer prognosis in subject having cancer (e.g., risk of cancer recurrence, progression of a cancer in a cancer subject, overall survival of cancer by a cancer patient). They can also be implemented as a method of monitoring progression of breast cancer in subjects undergoing treatment for cancer or as a method of stratifying a subject or a group of subjects having a cancer tumor for a clinical trial.

Description

MOLECULAR PROFILING OF A LETHAL TUMOR MICROENVIRONMENT

FIELD OF THE INVENTION.

[0001] The present invention relates to the biological markers that are useful in the course of detection and/or treatment of cancer. BACKGROUND OF THE FNVENTION

[0002] Cancer is one of the most significant diseases confronting mankind, and even though progress has been made in cancer treatment, particularly in the medical therapy of cancer, many challenges remain. In medical therapy of cancer, for example, the various anticancer agents for suppressing the growth of cancer cells that have been developed suppress the growth of not only cancer cells, but also normal cells, causing various side effects including nausea and vomiting, hair loss, myelosuppression, kidney damage, and nerve damage. Consequently, understanding the origins of these malignancies and their microenvironments will facilitate development of more precise diagnostic tools and more effective therapeutic strategies that minimize maximize therapeutic benefits and minimize toxicity for the patients undergoing treatment for cancer. [0003] Some research suggests that the environment around a cancer, for example, interstitial tissue which includes blood vessels, extracellular matrix (ECM), and fibroblasts, may play a role in the onset and progression of cancer. For example, Camps et al. (Proc. Natl. Acad. Sci. USA 1990, 87(1), 75-79) reported that when an athymic nude mouse was inoculated with tumor cells that do not form a tumor on their own or for which the tumor formation rate is low, together with tumorigenic fibroblasts, rapid and marked formation of a tumor was observed, and Olumi et al. (Cancer Res. 1999, 59(19), 5002-5011) reported that when peritumoral fibroblasts (i.e., cancer- associated fibroblasts or CAFs) from a prostate tumor patient were grafted on an athymic animal together with human prostate cells, neoplastic growth thereof was markedly accelerated.

Furthermore, it has been clarified that a bioactive substance such as PDGF (platelet-derived growth factor), TGF-β (transforming growth factor-β), HGF (hepatocyte growth factor), or SDF- 1 (stromal cell-derived factor- 1) produced in the interstitium is involved in such growth of a tumor (Micke et al, Expert Opin Ther Targets. 2005, 9(6), 1217-1233).

[0004] Despite these findings, many questions remain unanswered with respect to regulation of gene expression in the cancer microenvironment, innate and adaptive immunity in the cancer microenvironment, inflammation and cancer, tumor-associated stroma and extracellular matrix, tumor-endothelium interactions (angiogenesis, extravasation), cancer stem cells, the metastatic niche, and effective targeting of the tumor microenvironment both in preclinical and clinical trials. As a result, most treatments of cancers, including surgical and adjuvant therapies of patients with conventional chemotherapeutic agents, remain largely empirical, guided mostly by measured histological tumor parameters in the absence of specific mechanistic understanding. [0005] Previously, it has been shown that a loss of stromal caveolin-1 can be a useful biomarker of a "lethal" tumor microenvironment. In triple negative breast cancers, for example, a loss of stromal Cav-1 was associated with a five-year survival rate of less than 10%. By contrast, triple negative patients from the same cohort, but having high stromal Cav-1 levels, had a twelve-year survival rate of greater than 75%. In ductal carcinoma in situ (DCIS) patients, a loss of stromal Cav-1 was predictive of disease recurrence and progression to invasive breast cancer. In this particular study, all of the DCIS patients with a loss of stromal Cav-1 were reported to have undergone disease recurrence and 80%> of them were reported to have progressed from DCIS to invasive disease. In prostate cancer, a loss of stromal Cav-1 was predictive of advanced prostate cancer, with a high Gleason score, and was also associated with lymph-node or bone metastasis, (see: Sloan E.K. et al., "Stromal Cell Expression of Caveolin-1 Predicts Outcome in Breast Cancer" Am J. Pathol. 2009, 174, 2035-43; Witkiewicz A.K., "Towards a new "stromal-based" classification system for human breast cancer prognosis and therapy" Cell Cycle 2009, 8, 1654-8; Witkiewicz A.K, "Stromal caveolin-1 levels predict early DCIS progression to invasive breast cancer" Cancer Biol. Ther. 2009, 8, 1167-75; Witkiewicz A.K., "Loss of Stromal Caveolin-1 Expression Predicts Poor Clinical Outcome in Triple Negative and Basal-like Breast Cancers" Cancer Biology & Therapy 2010, 10,135-43; and Witkiewicz A.K., "An Absence of Stromal Caveolin-1 Expression Predicts Early Tumor Recurrence and Poor Clinical Outcome in Human Breast Cancers" Am. J. Pathol. 2009, 174, 2023-34). Taken together, these reports suggest that a loss of stromal Cav-1 portends rapid disease progression and death for a broad spectrum of epithelial tumor types. However, many questions remain as to why a loss of stromal Cav-1 should significantly influence patients' prognosis and cancer progression.

[0006] Accordingly, there is an urgent need in the medical field for better diagnostic and prognostic indicators and better mechanistic understanding of tumor microenvironment to guide the vigor and extent of surgical and adjuvant therapies of patients, especially those with early stage cancer. BRIEF SUMMARY OF THE INVENTION

[0007] In one aspect, the present disclosure provides a prognostic signature (also referred to herein as a biological marker or biomarker) for assessing cancer prognosis in a subject, comprising a set of one or more genes (or gene products) derived from a genome -wide transcriptional profiling of a cancer tumor stroma. In an embodiment, the prognostic signature is a Cav-1 -deficient tumor stromal signature and comprises a set of at least one or more gene transcripts selected from the gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combinations thereof. In another embodiment, the Cav-1 -deficient tumor stromal signature comprises a first set of one or more gene transcripts that are up-regulated in the tumor stromal material and/or a second set of one or more gene transcripts that is down- regulated in the tumor stromal material. In another embodiment, said tumor stromal signature comprises a set of one or more gene transcripts that is up-regulated in the tumor stromal material, wherein said set of at least one or more up-regulated gene transcripts is selected from the up- regulated gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combinations thereof. In another embodiment, said tumor stromal signature comprises a set of one or more gene transcripts that is down-regulated in the tumor stromal material, wherein said set of at least one or more down-regulated gene transcripts is selected from down-regulated gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combinations thereof. [0008] In another embodiment, said tumor stromal signature comprises a first set of one or more gene transcripts that is up-regulated in the tumor stromal material, wherein said first set of at least one or more up-regulated gene transcripts is selected from the up-regulated gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combinations thereof; and a second set of one or more gene transcripts that is down-regulated in the tumor stromal material, wherein said second set of at least one or more down-regulated gene transcripts is selected from down-regulated gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combinations thereof.

[0009] In another embodiment, the Cav-1 -deficient tumor stromal signature is derived from a breast cancer tumor stroma. In another embodiment, the Cav-1 -deficient tumor stromal signature is derived from a breast cancer stroma, wherein the breast cancer is of a subtype selected from the group consisting of ER positive (or ER(+) ), ER negative (or ER(-), and HER2 positive (or HER2(+)). [0010] In another aspect, the present disclosure provides a method of assessing cancer prognosis, wherein the method comprises: (a) determining a genome-wide transcriptional profile of a first stromal material, wherein the first stromal material is derived from a biological sample obtained from a subject afflicted with cancer or suspected of having cancer; (b) comparing the genome-wide transcriptional profile (or a set of gene transcripts subgenome -transcriptional profile derived therefrom) to a Cav-1 -deficient tumor stromal signature, wherein the Cav-1 - deficient tumor stromal signature comprises a set of at least one or more gene transcripts selected from the gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combintinations thereof, whereby an overlap of from about 25% to about 75% between the genome -wide transcriptional profile (or a subgenome-transcriptional profile derived therefrom) and the Cav-1 -deficient tumor stromal signature indicates a poor prognosis (e.g., risk of recurrence the cancer, decreased overall survival of the cancer, increased risk of progression of the cancer, increased risk of metastasis of the cancer).

[0011] In one embodiment, the method of assessing cancer prognosis, comprises: (a) determining a genome-wide transcriptional profile of a biological sample, wherein the biological sample is obtained from a subject afflicted with cancer or suspected of having cancer; (b) comparing the genome-wide transcriptional profile (or a set one or more gene transcripts comprising gene transcripts up-regulated and/or gene transcripts down-regulated or both gene transcriipts up-regulated and gene transcripts down-regulated in the biological sample) to a Cav- 1 -deficient tumor stromal signature, wherein the Cav-1 -deficient tumor stromal signature comprises at least a set of one or more gene transcripts selected from the gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combintinations thereof, whereby an overlap of from about 25% to about 75% between the genome -wide transcriptional profile and the Cav-1 -deficient tumor stromal signature indicates a poor prognosis (e.g., risk of recurrence the cancer, decreased overall survival of the cancer, increased risk of progression of the cancer, increased risk of metastasis of the cancer).

[0012] In yet another aspect, the present disclosure provides a method of monitoring progression of cancer, including breast cancer, in a subject, the method comprising: (a) obtaining a first sample from a subject at a first time point and a second sample from said subject at a second time point; (b) determining a genome-wide transcriptional profile of said first and second samples; (c) comparing the genome-wide transcriptional profile of said first sample to the genome-wide transcriptional profile of said second sample; and (d) thereafter, comparing any difference in transcriptional profile between the genome -wide transcriptional profile of said first sample and the genome-wide transcriptional profile of said second sample to a Cav-1 -deficient tumor stromal signature, wherein the Cav-1 -deficient tumor stromal signature comprises a set of at least one or more gene transcripts having gene names and/or gene symbols listed in

Supplemental Tables 1, 3, or combintinations thereof, whereby an overlap of from about 25% to about 75%o is indicative of a poor clinical outcome (e.g., recurrence of the cancer in said subject, or decreased overall survival of the cancer by the subject, or is an indication that the cancer has progressed in said subject, or is an indication that the cancer has metastasized in said subject).

[0013] In another aspect, the present disclosure provides a method of stratifying a subject or a group of subjects having a cancer tumor for a clinical trial. In an embodiment, the method comprises: (a) roviding a stromal material, wherein first stromal material is derived from a biological sample obtained from a subject having a cancer tumor; (b) determining a genome-wide transcriptional profile of the stromal material; (c) comparing the genome-wide transcriptional profile of said stromal material to a Cav-1 -deficient tumor stromal signature, wherein the Cav-1 - deficient tumor stromal signature comprises at least a set one or more gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combintinations thereof; and (c) stratifying the subject for a clinical trial based on the results of the comparison step (c). In another embodiment an overlap of from about 25% to about 75% is indicative of stratification class of the subjects.

[0014] In one embodiment, the method of stratifying a subject or a group of subjects having a cancer tumor for a clinical trial comprises: (a) roviding a biological sample, wherein biological sample is obtained from a subject having a cancer tumor; (b) determining a genome-wide transcriptional profile of the biological sample; (c) comparing the genome -wide transcriptional profile of said said biological sample to a Cav-1 -deficient tumor stromal signature, wherein the Cav-1 -deficient tumor stromal signature comprises at least one or more gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combintinations thereof; and (c) stratifying the subject for a clinical trial based on the results of the comparison step (c). In one embodiment, overlap of from about 25% to about 75% is indicative of the stratification class of the subjects.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 illustrates that stromal Cav-1 can be used to stratify human breast cancer patients into two transcriptionally distinct patient populations (comparison of the transcriptional profiles of Cav-1 -positive (+) tumor stroma (N = 4) versus Cav-1 -negative tumor stroma (N = [0016] Figure 2 illustrates heatmaps of gene transcripts associated with myofibroblast differentiation, autophagy, lysosomal degradation, and glycolysis;

[0017] Figure 3 illustrates heatmaps of gene transcripts associated with the response to hypoxia and mitochondria;

[0018] Figure 4 illustrates heatmaps of gene transcripts associated with inflammation and redox/stress signaling;

[0019] Figure 5 illustrates heatmaps of gene transcripts associated with dna damage and repair;

[0020] Figure 6 illustrates heatmaps of gene transcripts associated with aging, apoptosis, and brca 1 -mutation positive breast cancer patients;

[0021] Figure 7 illustrates heatmaps of gene transcripts associated with ER-negative breast cancers;

[0022] Figure 8 illustrates heatmaps of gene transcripts associated with neural stem cells;

[0023] Figure 9 illustrates Venn diagrams for the intersection of the cav-1 -deficient stromal gene signature with other breast cancer tumor stromal gene sets;

[0024] Figure 10 illustrates the Cav-1 -deficient stromal gene signature is up-regulated in breast cancer and is associated with tumor recurrence;

[0025] Figure 11 illustrates the Cav-1 -deficient stromal gene signature is associated with tumor recurrence and poor survival in ER(+) and luminal A breast cancer patients; and

[0001] Figure 12 illustrates understanding the hierarchy of the cellular processes associated with a Cav-1 -deficient tumor microenvironment.

[0026] LIST OF TABLES

[0027] All tables referenced in this application and listed below are provided in Appendix A which is attached herewith.

[0028] Table 1: Cellular Processes that are Associated with a Lethal Tumor Micro- Environment in Human Breast Cancer (Cav-1 Deficient Stroma); [0029] Supplemental Table 1 : Comparison of the transcriptional profiles of Cav- 1 -positive (+) tumor stroma (N = 4) versus Cav-1 -negative tumor stroma (N = 7) revealed 238 gene transcripts that were up-regulated and 232 gene transcripts that were down-regulated in the stroma of tumors showing a loss of Cav-1 expression; [0030] Supplemental Table 4: Intersection with Myofibroblast and Muscle-Related Proteins;

[0031] Supplemental Table 5: Intersection with Autophagy and Lysosome Associated Gene Products;

[0032] Supplemental Table 6: Intersection with the Immune Response and TNF/NFkB Signaling;

[0033] Supplemental Table 7: Intersection with Breast Tumors Derived from BRCA 1 - positive Patients;

[0034] Supplemental Table 7: Intersection with Breast Tumors Derived from BRCA1 - positive Patients; [0035] Supplemental Table 8: Intersection with Breast Tumors Derived from ER-negative Patients;

[0036] Supplemental Table 9: Intersection with Key Regulators of Apoptosis;

[0037] Supplemental Table 10: Intersection with Glycolysis, Hypoxia, and Oxidative Stress; [0038] Supplemental Table 11: Intersection with Genes Upregulated During DNA Damage and Repair;

[0039] Supplemental Table 12: Intersection with Mitochondrial Associated Proteins;

[0040] Table 13: Intersection with Neural Stem Cell Associated Genes;

[0041] Supplemental Table 14: Intersection with Aging Associated Genes; [0042] Supplemental Table 15: contains the 3,459 unique genes that were up-regulated in the stroma of tumors showing a loss of stromal Cav-1 expression; and [0043] Supplemental Table 16 contains the 1 ,297 unique genes that were up-regulated in the stroma of tumors showing a loss of stromal Cav-1 expression.

DETAILED DESCRIPTION OF THE INVENTION

[0044] Transcriptional profiling, among other things, includes analysis of the relative abundance of messenger RNA transcribed from different genes. Transcriptional profiling can be used to facilitate the understanding of patterns of gene expression that are associated with all biological processes, including development, differentiation, response to environmental stresses, and other cellular and organismal functions of interest. The ability to analyze patterns of gene expression can lead to discovery of new genes associated with biological processes. A detailed understanding of gene regulation at the transcriptional level is also a premier concern of the pharmaceutical industry, enabling identification of genetic targets for drug development and leading to the understanding of the well known heterogenity in the way different individuals respond to pharmaceutical interventions. Transcriptional profiling may be conducted by the techniques of "differential display" (see, for example, Liang, P. and Pardee, A. B. Science 1992, 257, 967-971; Liang, et al, Nucl. Acids Res. 1994, 22, 5763-5764; Prashar, Y. and Weissman, S. M. Proc. Nat'l. Acad. Sci., U.S.A. 1996, 93, 659-663.) and "representational difference analysis" (see, for example, Hubank, M. and Schatz, D. G. Nucl. Acids Res. 1994, 22, 5640-5648; Lisitsyn, N. A. Trends Genet. 1995, 11, 303-307), both of which involve PCR, and gel electrophoretic analysis of DNA fragments. However, it would be appreciated by those skill in the art that other techniques exist that enable quantitation of a very large number of gene transcripts.

[0045] Accordingly, in one aspect, the present disclosure provides new transcriptional gene signatures that can effectively be used for prognostic and therapeutic stratification of cancer tumors: According to exemplary embodiments of the present invention, said transcriptional gene signatures comprise at least a set of one or more gene transcripts, wherein the set of one or more gene transcripts is selected from the group consisting of gene transcripts having gene names and/or gene symbols listed in Table 1, or any one of Supplementary Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 or combintinations thereof. The sequence listings associated with the accession numbers, Entrez gene Id, Unigene Id, gene symbols, gene names, alias gene symbols, and Target Acc set forth in any one of Table 1 and Supplementary Tables 1-16 are hereby incorporated by reference as if set forth fully herein.

[0046] In one embodiment, transcriptional gene signatures are used to unambiguously stratify patients based on their stromal Cav-1 status, into Cav-1 (+) and Cav-1 (-) sub-groups, thus, greatly facilitating prediction of their prognosis. In another embodiment, the transcriptional gene signatures of the present invention are used in therapeutic stratification of cancer patients. The present inventors have used transcriptional profiling of cancer patients to facilitate the

understanding of patterns of gene expression that are associated with biological processes that are activated in cancer tumor cells in the presence and absence of Cav-1 in the cancer tumor stroma, thereby delineating novel mechanistic insights into how the the status of Cav-1 in the cancer tumor stroma modulates cancer tumor progression, recurrence of cancer tumor and/or metastasis of cancer. In one embodiment, mechanistic insights into how the status of Cav-1 in the breast cancer tumor stroma modulates the breast cancer tumor progression, recurrence of cancer tumor and/or metastasis of the breast cancer is provided.

[0047] The present inventors isolated tumor stroma from breast cancer patients with a loss of stromal Cav-1 and patients with high stromal Cav-1, for direct comparison and demonstrated that the Cav-1 deficient tumor stroma from human breast cancer patients shows transcriptional evidence for the same biological processes that have been implicated in the "Autophagic Tumor Stroma Model of Cancer". These biological processes include oxidative stress/aging, hypoxia, a compensatory increase in mitochondria-associated genes, NFkB -activation, inflammation, DNA damage, aerobic glycolysis, autophagy/apoptosis, lysosomal degradation, and "sternness" (summarized in Figure 12). These same biological processes are also transcriptionally activated in mesenchymal stromal cells derived from the bone marrow of Cav-1 (-/-) null mice ¹⁶' ³¹' ³² , and reflect oxidative stress and mitochondrial dys-function, leading to a glycolytic phenotype.

[0048] The present inventors also observed strong association between Cav-1 deficient tumor stroma and ER(-) breast cancer. In particular, gene profiles from Cav-1 deficient tumor stroma were elevated in all breast cancers, relative to normal healthy breast tissue. However, there was a stronger association with ER(-) negative breast cancers, that were identified either by ER IHC or via ESR1 transcriptional analysis (summarized in Figure 10). Furthermore, an association was observed with an ER(-) gene signature via gene set enrichment analysis (GSEA) (summarized in Figure 7), as well as hereditary breast cancer patients that harbor BRCA1 -mutations

(summarized in Figure 6). Importantly, these associations were all made with existing gene set data that were derived from whole breast tumors that were not laser-captured to isolate their stroma. Thus, these results demonstrate that the presently disclosed stromal signatures can be used effectively in conjunction with gene profiling data obtained from whole or portions of breast tumors. [0049] Accordingly, one aspect of the present invention relates to use of the stromal Cav-1 deficient gene signature disclosed herein to predict clinical outcome in cancer patients, including breast cancer patients. In one embodiment, the stromal Cav-1 deficient gene signature in accordance with the present invention is used to predict recurrence of cancer, or progression of cancer and/or decreased overall survival in cancer patients, including ER(+) and luminal A breast cancer patients. In an exemplary embodiment, the present inventors have shown that the Cav-1 - deficient stromal signature of the present invention is strongly associated with increased recurrence and decreased overall survival in ER(+) and luminal A breast cancer patients, despite the fact that these breast cancer-derived tumors were not subjected to laser capture

microdissection prior to the transcriptional profiling. Thus, the tumor stromal signatures of the present invention can be used either alone or in conjunction with other diagnostic tests, including immuno-histochemical (IHC) staining.

[0050] Tumors with a "fibrotic focus" or "central scar" are reportedly associated with a poor prognosis ³⁶' ³⁷. In accordance with this notion, it was observed that keloid fibroblasts (derived from non-tumorous "scarred skin") show many of the same characteristics as Cav-1 deficient tumor stroma, with activation of HIF1 -alpha and NFkB, as well as a shift towards aerobic

27 38 39

glycolysis ' ' , thus, suggesting a mechanistic connection between loss of Cav-1 as a driver of tissue fibrosis, tumor progression, and metastasis ⁴⁰. Consistent with this notion, a fibrotic focus in breast cancers is thought to be a surrogate marker for hypoxia ³⁶' ³⁷. Similarly, a loss of Cav-1 drives activation of TGF-beta signaling in fibroblasts ¹⁹' ^41-43 , and treatment of fibroblasts with the TGF-beta ligand is sufficient to induce autophagy ⁴⁴ and aerobic glycolysis ⁴⁵ , possibly explaining the association of tumor fibrosis with a poor prognosis in cancer patients.

[0051] It has been discovered that gene set enrichment analysis (GSEA) of the tumor stroma of breast cancer patients with a loss of stromal Cav-1 showed the dramatic the up-regulation of gene transcripts normally associated with DNA damage and repair (summarized in Figure 5) and breast tumors with BRCA1 -mutations (summarized in Figure 6). Thus, stromal reactive oxygen species (ROS) production, resulting in stromal DNA damage, may be an underestimated driver of tumor progression and metastasis. These findings may also have relevance for the guiding the use of DNA damaging agents and/or Poly(ADP-ribose) polymerase (PARP) inhibitors, as potential treatments for breast cancer patients with Cav-1 -deficient stroma.

[0052] Accordingly, one aspect of the present invention provides a method of therapeutic stratification of cancer patients, said method comprising: (a) providing a stromal material, wherein first stromal material is derived from a biological sample obtained from patients having a cancer tumor; (b) determining a genome -wide transcriptional profile of the stromal material, wherein the transcriptional profile compries at least a set of one or more gene transcripts up- regulated and/or at least a set of one or more gene transcripts down-regulated in the stromal material; (c) comparing the genome-wide transcriptional profile (e.g., the set of at least one or more gene transcripts up-regulated and/or at least one or more gene transcripts down-regulated in the stromal material) of said stromal material with at least one or more Cav-1 -deficient tumor stromal signatures, wherein the the at least one or more Cav-1 -deficient tumor stromal signatures comprise at least a set of one or more gene transcripts selected from the group consisting of gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combintinations thereof; and (d) stratifying the subject for a clinical trial based on the results of the comparison step (c). In one embodiment, the Cav-1 -deficient tumor stromal signature comprises gene transcripts up-regulated in the Cav-1 deficient tumor stroma, wherein the gene transcripts up-regulated in the Cav-1 deficient stroma comprise a set of at least one or more up- regulated gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combintinations thereof. In one embodiment, the Cav-1 -deficient tumor stromal signature comprises gene transcripts down-regulated in the Cav-1 deficient tumor stroma, wherein the gene transcripts down-regulated in the Cav-1 deficient stroma comprise a set of at least one or more down-regulated gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combintinations thereof. [0053] . In yet another embodiment, the Cav-1 -deficient tumor stromal signatures comprise gene transcripts up-regulated in the Cav-1 deficient tumor stroma and gene trascripts down- regulated in the Cav-1 deficient tumor stroma, wherein the gene transcripts up-regulated in the Cav-1 deficient stroma and the gene transcripts down-regulated in the Cav-1 deficient stroma comprise a set of at least one or more up-regulated gene transcripts and down-regulated gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combintinations thereof.

[0054] In another embodiment, the method of therapeutic stratification of cancer patients, comprises: (a) providing a biological sample obtained from patients having a cancer tumor; (b) determining a genome-wide transcriptional profile of the biological sample, wherein the transcriptional profile compries at least a set of one or more gene transcripts up-regulated and/or at least a set of one or more gene transcripts down-regulated in the biological sample; (c) comparing the genome-wide transcriptional profile (e.g., the set of at least one or more gene transcripts up-regulated and/or at least one or more gene transcripts down-regulated in the biological sample ) of said biological sample with Cav-1 -deficient tumor stromal signature, wherein the Cav-1 -deficient tumor stromal signature comprises at least a set of one or more sets of gene transcripts, wherein the at least one or more sets of gene transcripts comprise gene transcripts selected from the group consisting of gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combintinations thereof; and (d) stratifying the subject for a clinical trial based on the results of the comparison step (c).

[0055] In certain embodiments, the comparison of transcriptional profiles reveals stromal reactive oxygen species (ROS) production, as the driver of stromal DNA damage and tumor progression and metastasis. Accordingly, in further embodiments, the comprison results are used to identify cancer patients more likely to benefit from treatment with certain thearpeutic agents, including DNA damaging agents and/or Poly(ADP-ribose) polymerase (PARP) inhibitors. In another embodiments, the comprision of the transcriptional profiles can be used to identify cancer patients more likely to benefit from treatment with Monocarboxylate Transporter (MCTl) inhibitors and/or a combination of PARP inhibitors and MCTl inhibitors. [0056] Poly(ADP-ribose)polymerase-l (PARP- 1) is a nuclear enzyme that has been implicated in several mechanisms, including the mechanisms leading to postischemic neuronal death.

Accoridingly, PARP inhibitors have been proposed as potential therapeutic agents for treatment of various cancers as well as neuroprotective agents. PARP inhibitors are known in the art and may also be elucidated using various techniques. Non-limiting examples of PARP inhibitors include such as Iniparib (BSI-201), olaparib (AZD-2281), and veliparib (ABT-888), 3- aminobenzamide, 4-aminobenzamide, 3-aminophtalhydrazide, 1,5-dihydroxyisoquinoline.

Preferred PARP inhibitors include benzamide, 3-aminophtalhydrazide, 1,5- dihydroxyisoquinoline, 6(5H)-Phenanthridinone, 4-Amino-l,8-naphthalimide, 1,5- Isoquinolinediol, 3-Aminobenzamide, and N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N- dimethylacetamide hydrochloride (PJ34). Inhibition of PARP may be effected by a number of approaches. A preferred method of the present invention is to employ specific inhibitors of PARP. For example, specific inhibitors of PARP, such as benzamide, 3-aminobenzamide, 4- aminobenzamide, 3-aminophtalhydrazide and 1,5-dihydroxyisoquinoline, may be used to inhibit apoptosis induced by PARP activity. U.S. Pat. No. 5,756, 510 (Griffin et al.) discloses benzamide analogs having PARP inhibitory efficacy and those compounds may be used in the present invention methods and compositions; the entire contents of which are incorporated herein by reference. U.S. Pat. No. Re. 36,397 (Zhang et al.) discloses PARP inhibitors useful for vascular stroke and neurodegenerative disorders and those compounds may be used in the present invention methods and compositions. The PARP inhibitors for use in conjunction with the biological markers and methods of the present invention may also be determined by various assays described in the literature. The following publications teach various methods which may be employed to elucidate PARP inhibitors: (1) U.S. Pat. No. 5,756,510 (Griffin et al); (2) Banasik et al. Specific inhibitors of poly( ADP-ribose) synthetase and mono( ADP-ribose) transferase., J Biol Chem, volume 267, pages 1569-1575 (1992); and (3) Schanraufstatter et al. Oxidant injury of cells. DNA strand-breaks activate polyadenosine diphosphate-ribose polymerase and lead to depletion of nicotinamide adenine dinucleotide, J Clin Invest, volume 77, pages 1312-1320 (1986); the entire contents of the foregoing literature references are

incorporated herein by reference.

[0057] Other suitable therapeutic agents for use with the transcriptional gene signatures and methods of the present invention include metformin and Monocarboxylate Transporter (MCT1) inhibitors, including AR-C117977 and AR-C155858 and pharmaceutically acceptable salts thereof. AR-C155858 has the following structural formula.

[0059] Examples of suitable MCT1 inhibitors are disclosed in WO 2010/089580 (published 12 August 2010).

[0060] In some embodiments, the comparison of a set of two or more transcriptional profiles derived from biological samples obtained from the same or different biological sources (e.g., individuals), as described herein, includes identification of relative changes in the levels of gene transcripts in the respective samples. In some embodiments, the comparison at least a set of two or more trascriptional profiles are used to identify a subject or a group of subjects with a significant probability of a poor clincial outcome. In another embodiment, comparisons of transcriptional gene profiles are used to identify cancer patients that are more like to benefit from one or more thereaputic agents. In in a further embodiment, the comparison of the set of two or more trascriptional profiles is used to identify a subject or a group of subjects with a significant probability of benefiting from treatment with existing or new thereapeutic agents, including PARP inhibitors and/or MCTI inhibitors. In another embodiment, the probability that a patient or a group of patients are expected to benefit from treatment with PARP inhibitors alone or MCTI inhibitors alone or in combinations with PARP inhibitors is from about 25% to about 30%, from about 25% to about 35%, from about 25% to about 45%, from about 25% to about 50%, from about 25% to about 55%, from about 25% to about 60%, from about 25%, to about 65%, from about 25% to about 70%, from about 25%, to about 75%, from about 30% to about 35%, from about 30% to about 45%, from about 30% to about 50%, from about 30% to about 55%, from about 30% to about 60%, from about 30%, to about 65%, from about 30% to about 70%, from about 30%, to about 75%, from about 35% to about 45%, from about 35% to about 50%, from about 35% to about 55%, from about 35% to about 60%, from about 35%, to about 65%, from about 35% to about 70%, from about 35%, to about 75%, from about 40% to about 45%, from about 40% to about 50%, from about 40% to about 55%, from about 40% to about 60%, from about 40%, to about 65%, from about 40% to about 70%, from about 40%, to about 75%, from about 45% to about 50%, from about 45% to about 55%, from about 45% to about 60%, from about 45% to about 65%, from about 45% to about 70%, from about 45% to about 75%, from about 50% to about 55%, from about 50% to about 60%, from about 50% to about 65%, from about 50% to about 70%, from about 50% to about 75%, from about 55% to about 60%, from about 55% to about 65%, from about 55% to about 70%, from about 55% to about 75%, from about 60%, to about 65%, from about 60% to about 70%, from about 60% to about 75%, from about 65% to about 70%, from about 65% to about 75%, or from about 70% to about 75%.

[0061] In some embodiments, comparision of trascriptional profiles in accordance with the present invention identifies a cancer patents or a group of cancer patients having a probability of from about 25% to about75% of a poor clinical outcome, wherein the poor clinical outcome is selcted from the group consisting of cancer recurrence, progression of a cancer, overall survival of cancer, cancer metastasis and combinations thereof. In another embodiment, the probability of a poor clinical outcome is from about 25% to about 30%, from about 25% to about 35%, from about 25%o to about 45%, from about 25% to about 50%, from about 25% to about 55%, from about 25%o to about 60%, from about 25%, to about 65%, from about 25% to about 70%, from about 25%o, to about 75%, from about 30% to about 35%, from about 30% to about 45%, from about 30%) to about 50%, from about 30% to about 55%, from about 30% to about 60%, from about 30%), to about 65%, from about 30% to about 70%, from about 30%, to about 75%, from about 35%) to about 45%, from about 35% to about 50%, from about 35% to about 55%, from about 35% to about 60%, from about 35%, to about 65%, from about 35% to about 70%, from about 35%), to about 75%, from about 40% to about 45%, from about 40% to about 50%, from about 40%) to about 55%, from about 40% to about 60%, from about 40%, to about 65%, from about 40%) to about 70%, from about 40%, to about 75%, from about 45% to about 50%, from about 45%) to about 55%, from about 45% to about 60%, from about 45% to about 65%, from about 45%) to about 70%, from about 45% to about 75%, from about 50% to about 55%, from about 50%) to about 60%, from about 50% to about 65%, from about 50% to about 70%, from about 50%) to about 75%, from about 55% to about 60%, from about 55% to about 65%, from about 55%) to about 70%, from about 55% to about 75%, from about 60%, to about 65%, from about 60%) to about 70%, from about 60% to about 75%, from about 65% to about 70%, from about 65%) to about 75%, or from about 70% to about 75%.

[0062] It has also been discovered that the over-expression of several different markers of autophagy or oxidative stress in the tumor stroma are associated with increased lympho-vascular invasion, increased lymph-node metastasis, or poor clinical outcome, in a variety of different epithelial cancer subtypes. These markers include ATG16L1 and the cathepsins (K and D) for autophagy, as well as carbonic anhydrase IX (CAIX) and HIF1 -alpha for oxidative stress ^49-56.

[0063] Re-analysis of published transcriptional profiles ¹⁵ of laser-captured tumor stroma, isolated from human breast cancers, by the present inventors revealed strong evidence for the enrichment of autophagy genes, lysosomal markers, as well as indicators of oxidative stress (such as peroxisomes), which were associated with tumor recurrence and metastasis ¹⁶' ³⁰. These tumor stroma transcriptional profiles also showed significant overlap with transcriptional profiles of Cav-1 (-/-) null stromal cells ¹⁶' ³⁰' ³¹ , and Alzheimer's disease brain (known to be associated with oxidative stress) ¹⁶' ³¹. In fact the transcriptional profile of Alzheimer's disease brain was most closely related to the tumor stroma of human breast cancer patients that had undergone metastasis ¹⁶, implicating stromal oxidative stress in promoting cancer cell metastasis.

[0064] In summary, the present inventors have shown that simple immuno-staining with antibodies directed against Cav-1 can be used effectively to detect two different populations of breast cancer patients (high-risk vs. low-risk), based on their stromal Cav-1 status. Genome-wide transcriptional profiling of these two different stromal populations shows that they are dramatically different, each with a unique transcriptional profile. The present inventors focused on the stromal Cav-1 -deficient population, because they are associated with early tumor recurrence, and metastasis. Gene set enrichment analysis (GSEA) of this population provides in vivo human data to directly support the "Autophagic Tumor Stroma Model of Cancer", which is largely focused on oxidative stress, hypoxia, autophagy, and DNA damage in the tumor microenvironment, as well as the pro-inflammatory response (summarized in Figure 12).

[0065] 1. TRANSCRIPTIONAL GENE SIGNATURES/BIOLOGICAL MARKERS

[0066] In one embodiment the transcriptional gene signatures of the present invention comprise a set of at least one or more gene transcripts up-regulated in cancer tumor stroma. In another embodiment the transcriptional gene signatures of the present invention comprise a set of at least one or more gene transcripts down-regulated in cancer tumor stroma. In another embodiment, the cancer tumor stroma is derived from derived from a Cav-1 -deficient cancer tumor stromal material. In another embodiment, the cancer tumor stroma is derived from derived from a Cav-1 -positive cancer tumor stromal material. As any type of cell in the body may be a source of cancer, any suitable types of cancer cells or cellular materials may be used in the present invention. A suitable cancer type includes carcinoma (cancer of the epithelial cells), sarcoma (cancer of the bone, muscle or other connective tissues), lymphoma (cancer of the lymphatic system), leukemia (cancer of blood cells or blood precursor cells) and melanoma (cancer of the pigment-providing cells). Examples of suitable types of cancer that may be useful in conjuction with the various exemplary embodiments of the present invention include, but are not limited to, leukemias, such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias, such as, myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia leukemias and myelodysplasia syndrome; chronic leukemias, such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin's disease, non- Hodgkin's disease; multiple myelomas such as but not limited to smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; Waldenstrom's macro globulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone and connective tissue sarcomas such as but not limited to bone sarcoma, osteosarcoma,

chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, neurilemmoma, rhabdomyosarcoma, synovial sarcoma; brain tumors such as but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, primary brain lymphoma; breast cancer including but not limited to ductal carcinoma, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget's disease, and inflammatory breast cancer; adrenal cancer such as but not limited to pheochromocytom and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer such as but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; pituitary cancers such as but limited to Cushing's disease, prolactin- secreting tumor, acromegaly, and diabetes insipius; eye cancers such as but not limited to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; vaginal cancers such as squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget's disease; cervical cancers such as but not limited to, squamous cell carcinoma, and adenocarcinoma; uterine cancers such as but not limited to endometrial carcinoma and uterine sarcoma; ovarian cancers such as but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; esophageal cancers such as but not limited to, squamous cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; stomach cancers such as but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers; rectal cancers; liver cancers such as but not limited to hepatocellular carcinoma and hepatoblastoma; gallbladder cancers such as adenocarcinoma; cholangiocarcinomas such as but not limited to pappillary, nodular, and diffuse; lung cancers such as non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma and small-cell lung cancer; testicular cancers such as but not limited to germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma,

choriocarcinoma (yolk-sac tumor), prostate cancers such as but not limited to, prostatic intraepithelial neoplasia, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers such as but not limited to squamous cell carcinoma; basal cancers; salivary gland cancers such as but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; pharynx cancers such as but not limited to squamous cell cancer, and verrucous; skin cancers such as but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acral lentiginous melanoma; kidney cancers such as but not limited to renal cell carcinoma, adenocarcinoma, hypernephroma, fibrosarcoma, transitional cell cancer (renal pelvis and/or uterer); Wilms' tumor; bladder cancers such as but not limited to transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. In addition, cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary adenocarcinomas (for a review of such disorders, see Fishman et al., 1985, Medicine, 2d Ed., J. B. Lippincott Co., Philadelphia and Murphy et al, 1997, Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books U.S.A., Inc., United States of America). [0067] In one embodiment, the transcriptional gene signatures in accordance with the present invention are drived from a genome-wide transcriptional profiling of a tumor stromal material which is derived from a Cav-1 -deficient breast cancer tumor stroma, wherein the tumor stromal signatures comprise (a) a first set of up-regulated gene transcripts, wherein the first set of up- regulated gene transcripts comprises at least a set of one or more up-regulated gene transcritps having gene symbols listed Supplemental Tables 1, 3, or combintinations thereof; and (b) a second set of down-regulated gene transcripts, wherein the second set of down-regulated gene transcripts comprises at least a set of one or more gene transcripts having gene names and/or gene symbols listed Supplemental Tables 1, 3, or combintinations thereof. In one embodiment, up-regulated gene transcritps having gene symbols listed Supplemental Tables 1, 3, or combintinations thereof are selected from the group consisting of LOCI 00293390, RNF217,

PGBD2, LACTB, TRIT1, RNF217, LOC654433, DFFA, DNAJC5, ZNF365, ZNF365, MDN1, ERG, CTSB, SGSM3, MYL5, HLA-Z, IKZF1, C15orf23, CD84, C21orf7, VPS26B, SUFU, MSH6, S1PR3, FCGR2B, BCL2L11, RFC5, RAB3D, LOCI 00128943, PSMB9, GALNT11, APOC2, ISM2, PMS2CL, RDBP, GSPT2, NOD2, USP6NL, TAF13, H2AFX, CD53, CYP3A5, HLA-Z, DCAF8, CTTNBP2NL, ISM2, KCTD20, HMMR, RYR1, METTL3, BCAT1, GSPT1, MGC27345, PGPEP1, TFEB, POLG2, RBM33, LOC80054, FABP3, GCA, FANCC, RPUSD4, C21orf7, ZNF609, SAMHD1, NFATC2, SERPINB8, CYP4F11, LOC728613, SNRK,

LOC80054, SLC8A1, VMOl, IL28RA, LOC100288109, APITD1, TRIP6, TMEM165,

TBXAS1, KLHL12, LY86, KLF3, WHSC1, ZBTB46, SNRK, MLL2, KCNJ13, THG1L, CYP4V2, SLC23A2, OGFRL1, SLC02B1, PTPN1, ALOX5AP, MORC2, ABCD1P4, UCK2, TMED5, FCGR2C, FAM185A, PHF20L1, EPB41L3, LARP4B, DHRSX, PDPK1, APEX2, CTSB, MRPL9, LOCI 00293165, Clorfl04, STX7, GFI1, AP4E1, ARHGAP5, C14orfl06, SUDS3, BAT2L1, BCAS3, LMF2, INTS4, FCGR2A, ADAM 10, CCZ1, RANBP9, MATR3, SENP5, PPIL2, THNSLl , DNHD1, RBMS2, SYMPK, DNASE1, FCGR2A, KIFC2, TTC17, PDPK1, BCL2L13, MFSD7, ETF1, REEP4, TMEM165, MRPL9, HAUS2, ADAP2, ILIRAP, PARVG, C14orfl l8, ATXNl, PDE7A, DENND4B, ZNF502, Clorf77, OP A3, TNP03, KIF1B, RNASE1, ANXA11, FAM84A, C6orf26, CLTC, AMZ2, TYROBP, IFNGR2, RIOK2,

C17orf63, GPBAR1, ZNF639, TBRG4, SKP2, PHKA2, SERP1, CENPC1, MICALCL, RHOG, PDE4DIP, KIAA1147, UBAP1, C20orf7, SRRT, BTN3A2, DCP2, MIR1302-3, UFM1, PDPR, DNMT1, SMC2, GALT, LOC730235, STX8, GNB1, LOC283267, WDR1, BACH1, AGFG1, PIAS1, SNX6, ROCK1, EIF2AK1, UBXN11, APAF1, THNSL1, and combinations thereof.

[0068] In another embodiment, down-regulated gene transcritps having gene symbols listed Supplemental Tables 1, 3, or combintinations thereof are selected from the group consisting of HNRNPA0, ST3GAL3, LOC100288446, RGNEF, NTRK3, KIFAP3, FAM3A, FAM169A,

PLAG1, RAB40A, GOT1, ZNF768, CYP20A1, ASTN2, REPS2, NOL3, SERPINA9, TRA2A, , GYPE, LOC729375, ZFAND2B, BRWD1, PTPRN, ZNF687, DYM, ARMC7, PNPLA8, LMOD1, MFSD11, SERF IB, C6orfl30, TMEM138, UFSP1, SREBF2, KRT222, PIGM, C6orf26, FHL2, GLIS3, SLC7A14, ABCA10, DBT, ABLIM3, NOTCH3, PTPRN, DSG3, BACH1, LOC100131109, PLD1, , SIK3, FAM55B, PTGR1, UBE3B, PTPRS, DLG5, ZHX3,

SOX5, LOC388152, KCNKl, ITIH5, RARG, ABHD3, IRAKIBPI, TRIM38, SLC19A3, XP07, PDZD4, ESR1, LOC285147, ZNF193, MPP7, PKD1L2, PDZD4, , KCNQIOTI, RAD1, KCMF1, LOC100293798, IGF1R, ZFP3, C21orf62, TLR6, CTBP2, , DDX46, FAM156B, RUNDC3B, TMEM138, LOC100131938, UNC13C, ZNF641, OBSCN, C18orfl5, UBN2, MPHOSPH9, CRIM1, , SLC25A11, VWC2, DEAF1, DNAJC1, ADORA2B, PARK7,

NCRNA00183, MAPK1, WDR34, RCOR3, VEZT, RPL7AP8, NLGN3, LOC100128288, RABL2A, GAB1, RSPH9, AUH, SLC18A2, VCPIP1, EAPP, BTN2A2, C17orf75, Clorfl87, LOC643749, LOC100128288, RABL2A, CADPS, ZNF540, LRP2, CCDC96, SEC14L2, FBX021, WDR78, ADCYAP1, LOC100128286, C6orf26, HRH1, ZNF764, ZNF823,

LOC80154, NLK, SNORD20, THRA, XGPY2, SIGLEC6, DHCR24, LOC100129198, PTPN14, MAP7, LOCI 00128292, LOC646976, ZNF20, TMEM9B, IL17RB, TUBD1, TRIM66,

SLC12A8, PDE4DIP, LOC92249, LOC100128651, RGS7, SIGLEC6, SH3BGR, RSPH9, MGC16121, SLC16A6, OAF, SETD4, C8orf84, ZFP90, C7orf63, GAB1, TRIM66, PCSK1N, SNORD121A, GFRA1, GAB1, MS4A2, NHEDC2, HPSE2, PGR, PGR, SLC18A2, AUTS2, AUTS2, KBTBD4, ERBB4, ADCYAP 1 , ADCYAP 1 , and combinations thereof.

[0069] In another embodiment, the tumor stromal signatures comprise (a) a first set of up- regulated gene transcripts, wherein the first set of up-regulated gene transcripts comprises at least a set of one or more up-regulated gene transcritps having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combintinations thereof, wherein the up-regulated gene transcripts are selected from the group consisting of LOCI 00293390, RNF217, PGBD2, LACTB, TRITl, RNF217, LOC654433, DFFA, DNAJC5, ZNF365, ZNF365, MDN1, ERG, CTSB, SGSM3, MYL5, HLA-Z, IKZF1, C15orf23, CD84, C21orf7, VPS26B, SUFU, MSH6, S1PR3, FCGR2B, BCL2L11, RFC5, RAB3D, LOC100128943, PSMB9, GALNT11, APOC2, ISM2, PMS2CL, RDBP, GSPT2, NOD2, USP6NL, TAF13, H2AFX, CD53, CYP3A5, HLA-Z, DCAF8, CTTNBP2NL, ISM2, KCTD20, HMMR, RYR1, METTL3, BCAT1, GSPT1,

MGC27345, PGPEP1, TFEB, POLG2, RBM33, LOC80054, FABP3, GCA, FANCC, RPUSD4, C21orf7, ZNF609, SAMHD1, NFATC2, SERPINB8, CYP4F11, LOC728613, SNRK,

LOC80054, SLC8A1, VMOl, IL28RA, LOC100288109, APITD1, TRIP6, TMEM165, TBXAS1, KLHL12, LY86, KLF3, WHSC1, ZBTB46, SNRK, MLL2, KCNJ13, THG1L, CYP4V2, SLC23A2, OGFRL1, SLC02B1, PTPN1, ALOX5AP, MORC2, ABCD1P4, UCK2, TMED5, FCGR2C, FAM185A, PHF20L1, EPB41L3, LARP4B, DHRSX, PDPK1, APEX2, CTSB, MRPL9, LOCI 00293165, Clorfl04, STX7, GFI1, AP4E1, ARHGAP5, C14orfl06, SUDS3, BAT2L1, BCAS3, LMF2, INTS4, FCGR2A, ADAM 10, CCZ1, RANBP9, MATR3, SENP5, PPIL2, THNSLl , DNHD1, RBMS2, SYMPK, DNASE1, FCGR2A, KIFC2, TTC17, PDPK1, BCL2L13, MFSD7, ETF1, REEP4, TMEM165, MRPL9, HAUS2, ADAP2, IL1RAP, PARVG, C14orfl l8, ATXNl, PDE7A, DENND4B, ZNF502, Clorf77, OP A3, TNP03, KIFIB, RNASEl, ANXAl l, FAM84A, C6orf26, CLTC, AMZ2, TYROBP, IFNGR2, RIOK2,

C17orf63, GPBAR1, ZNF639, TBRG4, SKP2, PHKA2, SERP1, CENPC1, MICALCL, RHOG, PDE4DIP, KIAA1147, UBAP1, C20orf7, SRRT, BTN3A2, DCP2, MIR1302-3, UFM1, PDPR, DNMT1, SMC2, GALT, LOC730235, STX8, GNB1, LOC283267, WDR1, BACH1, AGFG1, PIAS1, SNX6, ROCKl, EIF2AK1, UBXNl 1, APAFl, THNSLl, and combinations thereof; and and (b) a second set of down-regulated gene transcripts, wherein the second set of down- regulated gene transcripts comprises at least a set of one or more gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combinations thereof, wherein the down-regulated gene transcripts are selected from the group consisting of HNRNPAO, ST3GAL3, LOC100288446, RGNEF, NTRK3, KIFAP3, FAM3A, FAM169A, PLAG1, RAB40A, GOT1, ZNF768, CYP20A1, ASTN2, REPS2, NOL3, SERPINA9, TRA2A, , GYPE, LOC729375, ZFAND2B, BRWD1, PTPRN, ZNF687, DYM, ARMC7, PNPLA8, LMOD1,

MFSDl l, SERFIB, C6orfl30, TMEM138, UFSPl, SREBF2, KRT222, PIGM, C6orf26, FHL2,

GLIS3, SLC7A14, ABCA10, DBT, ABLIM3, NOTCH3, PTPRN, DSG3, BACH1,

LOC100131109, PLD1, , SIK3, FAM55B, PTGR1, UBE3B, PTPRS, DLG5, ZHX3, SOX5,

LOC388152, KCNK1, ITIH5, RARG, ABHD3, IRAK1BP1, TRIM38, SLC19A3, XP07, PDZD4, ESR1, LOC285147, ZNF193, MPP7, PKD1L2, PDZD4, , KCNQIOTI, RAD1, KCMF1, LOC100293798, IGF1R, ZFP3, C21orf62, TLR6, CTBP2, , DDX46, FAM156B, RUNDC3B, TMEM138, LOC100131938, UNC13C, ZNF641, OBSCN, C18orfl5, UBN2, MPHOSPH9, CRIM1, , SLC25A11, VWC2, DEAF1, DNAJC1, ADORA2B, PARK7,

LOC80154, NLK, SNORD20, THRA, XGPY2, SIGLEC6, DHCR24, LOC100129198, PTPNl 4, MAP7, LOCI 00128292, LOC646976, ZNF20, TMEM9B, IL17RB, TUBD1, TRIM66,

SLC12A8, PDE4DIP, LOC92249, LOC100128651, RGS7, SIGLEC6, SH3BGR, RSPH9,

MGC16121, SLC16A6, OAF, SETD4, C8orf84, ZFP90, C7orf63, GAB1, TRIM66, PCSK1N, SNORD121A, GFRA1, GAB1, MS4A2, NHEDC2, HPSE2, PGR, PGR, SLC18A2, AUTS2, AUTS2, KBTBD4, ERBB4, ADCYAP1, ADCYAP1, and combinations thereof.

[0070] In another embodiment, the transcriptional gene signature in accordance with the present invention is drived from a genome-wide transcriptional profiling of a tumor stromal material which is derived from a Cav-1 -deficient breast cancer tumor stroma, and wherein the tumor stromal signature comprises at least a set of one or more gene transcripts up-regulated in the tumore stromal material, wherein the at least set of one or more gene transcritps comprise gene transcripts having gene names and/or gene symbols selected from the group consisting of: LOC100293390, RNF217, PGBD2, LACTB, TRIT1, RNF217, LOC654433, DFFA, DNAJC5, ZNF365, ZNF365, MDN1, ERG, CTSB, SGSM3, MYL5, HLA-Z, IKZF1, C15orf23, CD84, C21orf7, VPS26B, SUFU, MSH6, S1PR3, FCGR2B, BCL2L11, RFC5, RAB3D,

LOC100128943, PSMB9, GALNT11, APOC2, ISM2, PMS2CL, RDBP, GSPT2, NOD2, USP6NL, TAF13, H2AFX, CD53, CYP3A5, HLA-Z, DCAF8, CTTNBP2NL, ISM2, KCTD20, HMMR, RYR1, METTL3, BCAT1, GSPT1, MGC27345, PGPEP1, TFEB, POLG2, RBM33, LOC80054, FABP3, GCA, FANCC, RPUSD4, C21orf7, ZNF609, SAMHD1, NFATC2, SERPINB8, CYP4F11, LOC728613, SNRK, LOC80054, SLC8A1, VMOl, IL28RA,

LOC100288109, APITD1, TRIP6, TMEM165, TBXASl, KLHL12, LY86, KLF3, WHSC1, ZBTB46, SNRK, MLL2, KCNJ13, THGIL, CYP4V2, SLC23A2, OGFRLl, SLC02B1, PTPNl, ALOX5AP, MORC2, ABCD1P4, UCK2, TMED5, FCGR2C, FAM185A, PHF20L1, EPB41L3, LARP4B, DHRSX, PDPKl, APEX2, CTSB, MRPL9, LOCI 00293165, Clorfl04, STX7, GFIl, AP4E1, ARHGAP5, C14orfl06, SUDS3, BAT2L1, BCAS3, LMF2, INTS4, FCGR2A,

ADAM 10, CCZ1, RANBP9, MATR3, SENP5, PPIL2, THNSL1, DNHD1 , RBMS2, SYMPK, DNASE1, FCGR2A, KIFC2, TTC17, PDPKl, BCL2L13, MFSD7, ETF1, REEP4, TMEM165, MRPL9, HAUS2, ADAP2, ILIRAP, PARVG, C14orfl l8, ATXNl, PDE7A, DENND4B, ZNF502, Clorf77, OPA3, TNP03, KIF1B, RNASE1, ANXA11, FAM84A, C6orf26, CLTC, AMZ2, TYROBP, IFNGR2, RIOK2, C17orf63, GPBAR1, ZNF639, TBRG4, SKP2, PHKA2, SERP1, CENPC1, MICALCL, RHOG, PDE4DIP, KIAA1147, UBAP1, C20orf7, SRRT, BTN3A2, DCP2, MIR1302-3, UFM1, PDPR, DNMT1, SMC2, GALT, LOC730235, STX8, GNB1, LOC283267, WDR1, BACH1, AGFG1, PIAS1, SNX6, ROCK1, EIF2AK1, UBXN11, APAF1, TFiNSLl, and combinations thereof.

[0071] In another embodiment, the transcriptional gene signature in accordance with the present invention is drived from a genome-wide transcriptional profiling of a tumor stromal material which is derived from a Cav-1 -deficient breast cancer tumor stroma, and wherein the tumor stromal signature comprises at least a set of one or more gene transcripts down-regulated in the tumore stromal material, wherein the at least set of one or more gene transcritps comprise gene transcripts having gene names and/or gene symbols selected from the group consisting of: at least a set of one or more genes having gene symbols selected from the group consisting of: HNRNPA0, ST3GAL3, LOC100288446, RGNEF, NTRK3, KIFAP3, FAM3A, FAM169A,

SLC12A8, PDE4DIP, LOC92249, LOC100128651, RGS7, SIGLEC6, SH3BGR, RSPH9, MGC16121, SLC16A6, OAF, SETD4, C8orf84, ZFP90, C7orf63, GAB1, TRIM66, PCSK1N, SNORD121A, GFRA1, GAB1, MS4A2, NHEDC2, HPSE2, PGR, PGR, SLC18A2, AUTS2, AUTS2, KBTBD4, ERBB4, ADCYAP1, ADCYAP1, and combinations thereof.

[0072] A. Transcriptional Profiling of a Cav-1 Deficient Tumor Microenvironment

[0073] Loss of stromal Cav-1 in human breast cancer(s) is associated with tumor recurrence, metastasis, and drug-resistance, conferring poor clinical outcome ^{1 5}. However, until now nothing was known about the identity and the characteristics of the signaling pathways activated in Cav-1 negative tumor stroma. To mechanistically understand the "lethality" of a Cav-1 negative tumor micro-environment, the present inventors performed laser capture

microdissectioin on the tumor stroma of patients that were pre-classified as stromal Cav-1 - positive(+) (N = 4) and stromal Cav-1 -negative(-) (N = 7), based on immuno-histochemical (IHC) staining. Then, the RNA extracted from these samples was subjected to genome-wide transcriptional profiling.

[0074] Based on this approach, the present inventors identified 238 gene transcripts that were specifically up-regulated and 232 gene transcripts that were down-regulated in the stroma of tumors showing a loss of Cav-1 expression (p < 0.01 and fold-change (f.c.) > 1.5) (summarized in Supplemental Table 1). Using these stringent criteria, the present inventors were able to transcriptionally separate these two patient populations, in accordance with their IHC stromal Cav-1 status (negative versus positive). A HeatMap of the total patient cohort is shown in

Figure 1, demonstrating that these two patient populations appear transcriptionally and

"genetically" distinct.

[0075] B. Gene Set Enrichment Analysis (GSEA) of a Cav-1 Deficient Tumor

Microenvironment

[0076] To understand what cellular processes are characteristic of a Cav-1 -deficient tumor microenvironment, the present inventors next performed gene set enrichment analysis (GSEA), by comparison with other gene signatures available in various public databases. For this purpose, the present inventors focused on a wider list of gene transcripts that were up-regulated in Cav-1 - deficient stroma (5,424 transcripts encoding 3,459 unique genes; p < 0.1 and fold-change (f.c.) > 1.15) (summarized in Supplemental Table 2).

[0077] Results of the GSEA are summarized in Table 1. The GSEA results show up- regulation of cellular processes normally associated with "sternness", inflammation, DNA damage, oxidative stress, hypoxia, apoptotic signaling, autophagy, and mitochondrial dysfunction in the tumor stroma of patients lacking stromal Cav-1.

[0078] Individual HeatMaps (based on 1,819 transcripts encoding 1,297 unique genes; p < 0.05 and fold-change (fc.) > 1.15) (summarized in Supplemental Table 3) for key cellular processes are shown in Figures 2-8. These HeatMaps illustrate the upregulation of gene transcripts associated with myofibroblast differentiation, autophagy, lysosomal degradation, glycolysis, hypoxia, mitochondria, inflammation and redox signaling, DNA damage and repair, aging, BRCA1 -mutation positive and ER-negative breast cancer patients, apoptosis, and neural stem cells (summarized in Supplemental Tables 4-14). [0079] The observed association between a Cav-1 -deficient tumor stroma and neural stem cells may reflect increased stromal "neurogenesis", which has previously been implicated in an

7 8

aggressive reactive stromal phenotype in a subset of prostate cancers ' . Similarly,

7 8

"neurogenesis" was associated with increased DNA damage in the tumor stroma ' .

[0080] In addition, the up-regulation of gene transcripts or gene sets associated with GOLPH3, NRFl (nuclear respiratory factor 1), PRKDC (protein kinase, DNA-activated, catalytic polypeptide), or arsenic treatment is highly suggestive of mitochondrial dysfunction (Table 1). NRFl is normally up-regulated during hypoxic-ischemic injury or oxidative stress, as an attempt to increase mitochondrial biogenesis ⁹' ¹⁰. GOLPH3 (also known as MIDAS/GPP34) is a nuclear gene whose transcription is enhanced by the absence of mitochondrial DNA (mtDNA) ^u.

MIDAS stands for mitochondrial DNA absence sensitive factor ^u. PRKDC is a component of the machinery required for the proper repair and maintenance of the fidelity of mitochondrial

12

DNA (mtDNA) , so its up-regulation is suggestive of increase mtDNA damage. Arsenic treatment is associated with increased ROS production, mtDNA damage, and mitochondrial dysfunction, with reduced ATP production, driving the onset of aerobic glycolysis ¹³' ¹⁴. [0081] C. Comparison with Other Breast Cancer Stromal Data Sets Obtained by Laser

Capture Microdissection

[0082] The results of transcriptional profiling of a Cav-1 deficient tumor Micro environment and GSEA were compared with an independent previously published transcriptional data set generated by Morag Park and colleagues ¹⁵, via laser capture of the tumor stroma of human breast cancers. However, these previously published data were not stratified based on stromal

Cav-1 status ¹⁵. More specifically, the gene transcripts up-regulated in Cav-1 -deficient tumor stroma (1,819 transcripts encoding 1,297 unique genes; p < 0.05 and fold-change (f.c.) > 1.15) (Supplemental Table 3) were compared with (1) tumor stroma and (2) recurrence stroma gene lists, as defined below:

(1) Tumor Stroma vs. Normal Stroma List: compares the transcriptional profiles of tumor stroma obtained from 53 patients to normal stroma obtained from 38 patients. Genes transcripts that were consistently upregulated in the tumor stroma were selected and assigned a p-value, with a cut-off of p <0.05 (this set contains 6,777 unique genes) ¹⁶.

(2) Recurrence Stroma List: compares the transcriptional profiles of tumor stroma obtained from 11 patients with tumor recurrence to the tumor stroma of 42 patients without tumor recurrence. Genes transcripts that were consistently upregulated in the tumor stroma of patients with recurrence were selected and assigned a p-value, with a cut-off of p <0.05 (this set contains 3,354 unique genes) ¹⁶.

[0083] Figure 9 shows that the gene transcripts up-regulated in Cav-1 -deficient tumor stroma show significant overlap with tumor stroma (a 440 transcript overlap; p = 4.76 x 10^"9) and recurrence stroma (a 214 transcript overlap; p < 0.001). Thus, the gene transcripts up-regulated in Cav-1 -deficient tumor stroma show a significant association with tumor recurrence, and are in accordance with the results of Morag Park and colleagues¹⁵.

[0084] D. Comparison with the Transcriptional Profiles of Breast Cancers that were Not

Subjected to Laser Capture Microdissection

[0085] Most of the published and publicly available transcriptional profiles for breast cancer patients are derived from the analysis of whole tumors, which are not separated into stromal and epithelial compartments prior to analysis. Thus, a comparison of the gene transcripts upregulated in Cav-1 -deficient tumor stroma (summarized in Supplemental Table 1), with the

17 18 transcriptional profiles of normal breast tissue and whole breast tumors was performed ' .

[0086] Figure 10A and B show that the Cav-1 -deficient tumor stromal signature is up- regulated in breast cancer(s), both ER(+) and ER(-) sub-types. However, a more significant association was observed with ER(-) breast cancers. In addition, the Cav-1 -deficient stromal signature was also associated with increased recurrence in breast cancer patients (Figure IOC).

[0087] Similarly, the prognostic value of the Cav-1 -deficient stromal signature was investigated in ER(+) and luminal A breast cancer patients, which account for nearly 60% of all

17 18

breast cancer patients ' . Figure 11 shows that the Cav-1 -deficient stromal signature is clearly associated with increased recurrence and decreased overall survival, despite the fact that these breast cancer-derived tumors were not subjected to laser capture microdissection.

[0088] While not wishing to be bound by a particular theory, it is believed that cancer cells induce oxidative stress (pseudo-hypoxia) in adjacent fibroblasts, which activate certain key transcription factors (namely HIF1 -alpha and NFkB), that then drive the onset of autophagy,

20 21

leading to the cancer-associated fibroblast phenotype. ' . HIF1 -alpha and NFkB are the master regulator(s) of aerobic glycolysis (the response to hypoxia and oxidative stress) and

inflammation, respectively ^25-27. In turn, these autophagic fibroblasts undego mitophagy, forcing

20 21

them to use glycolysis as their main energy source. ' . These autophagic stromal fibroblasts produced high-energy nutrients (lactate, ketones, and glutamine) that could then be used as "fuel" for oxidative mitochondrial metabolism in epithelial breast cancer cells 28-^"30. Also, the reactive oxygen species (ROS) that is generated in cancer-associated fibroblasts is associated with DNA- damage (double-strand breaks) in both cancer cells and fibroblasts ^19-21.

[0089] In certain embodiments, proteomics can be used to discover suitable biomarkers for use in accordance with the present invention. Proteomics is the study of proteome, the protein complement of the genome. The term proteome also used to refer to the totality of the proteins present in a sample (e.g. tissue, organism, or cell culture) at a certain point of time. Proteomics includes, among other things, study of the global changes of protein expression in a sample (also referred to as "expression proteomics"). Proteomics typically includes the following steps: (1) separation of individual proteins in a sample by 2-D gel electrophoresis (2-D PAGE); (2) identification of the individual proteins recovered from the gel, e.g. by mass spectrometry and/or N-terminal sequencing, and (3) analysis of the data using bioinformatics. Proteomics methods are valuable supplements to other methods of gene expression profiling, and can be used, alone or in combination with other methods of the present invention, to detect the biomarkers of the present invention.

II. Method of Use of the Biomarkers

[0090] Thus, one aspect of the present invention is to provide a prognostic method for and/or treatment of cancer. In certain embodiments particular cancers having a stromal component/cells can be diagnosed and/or treated. [0091] Stromal cells are connective tissue cells of an organ found in the loose connective tissue, including uterine mucosa (endometrium), prostate, bone marrow, bone marrow precursor cells, and the ovary and the hematopoietic system. The most common types of stromal cells include fibroblasts, immune cells, pericytes, endothelial cells, and inflammatory cells. Thus, cancers having a stromal component can occur in any organ or tissue with stromal component, including uterine mucosa (endometrium), prostate, bone marrow, bone marrow, the ovary and the hematopoietic system. [0092] In one embodiment, the present invention provides a method of stratifying a subject or a group of subjects having a cancer tumor for a clinical trial. In an embodiment, the method comprises: (a) roviding a stromal material, wherein first stromal material is derived from a biological sample obtained from a subject having a cancer tumor; (b) determining a genome-wide transcriptional profile of the stromal material; (c) comparing the genome-wide transcriptional profile (or a subgenome transcriptional profile derived therefrom) of said stromal material a Cav- 1 -deficient tumor stromal signature, wherein the Cav-1 -deficient tumor stromal signature comprises a set of at least one or more genes selected from the genes in Supplemental Table 1 ; and (d) stratifying the subject for a clinical trial based on the results of the comparison step (c).

III. EXAMPLES Experimental Procedures

[0093] Example 1: Laser Capture Microdissection and Genome- Wide Expression

Profiling

[0094] Tumor stroma was laser capture microdissected using a Leica LCM system from 4 cases showing high stromal Cav-1 expression and 7 cases with loss of stromal Cav-1. Total RNA was amplified using the NuGEN™ WT-Ovation™ FFPE RNA Amplification System V2 and cDNA was hybridized to Affymetrix GeneChip® arrays. One-way ANOVA was setup to extract differentially expressed genes between Cav-1 positive and negative stromal samples. Stromal tissue was laser capture microdissected (LCM) from fresh frozen (FF) tumor tissue samples collected from the patients pre-treatment, and samples included were closely matched for age, race, stage and grade.

[0095] All eukaryotic target preparations (ALMAC Diagnostics, Inc.) using the project- appropriate NuGEN™ RNA Amplification System in combination with the Encore™ Biotin Module were performed in accordance with the guidelines detailed in the corresponding

NuGEN™ technical manual. Total RNA was amplified using the NuGEN™ Ovation™ Pico WTA System. First-strand synthesis of cDNA was performed using a unique first-strand DNA/RNA chimeric primer mix, resulting in cDNA/mRNA hybrid molecules. Following fragmentation of the mRNA component of the cDNA/mR A molecules, second-strand synthesis was performed and double-stranded cDNA was formed with a unique DNA/RNA heteroduplex at one end. In the final amplification step, RNA within the heteroduplex was degraded using RNaseH, and replication of the resultant single-stranded cDNA was achieved through DNA/RNA chimeric primer binding and DNA polymerase enzymatic activity. The amplified single-stranded cDNA was purified for accurate quantitation of the cDNA and to ensure optimal performance during the fragmentation and labeling process. The single stranded cDNA was assessed using spectrophotometric methods in combination with the Agilent Bioanalyzer. The appropriate amount of amplified single-stranded cDNA was fragmented and labeled using the Encore™ Biotin Module. The enzymatically and chemically fragmented product (50-100 nt) was labeled via the attachment of biotinylated nucleotides onto the 3 '-end of the fragmented cDNA. The resultant fragmented and labeled cDNA was added to the hybridization cocktail in accordance with the NuGEN™ guidelines for hybridization onto Affymetrix GeneChip® arrays. Following the hybridization for 18 hours at 45°C in an Affymetrix GeneChip® Hybridization Oven 640, the array was washed and stained on the GeneChip® Fluidics Station 450 using the appropriate fluidics script, before being inserted into the Affymetrix autoloader carousel and scanned using the GeneChip® Scanner 3000.

[0096] Example 2: Gene set enrichment analysis (GSEA)

[0097] For the list of genes that are up-regulated in Cav-1 -negative patients compared to Cav-1 positive patients (fold change > 1.15 and p-value < 0.1 ) (Supplemental Table 2), we computed enrichments in gene sets contained in the latest release of Molecular Signatures Database

(MSigDB v2.5, April 2008, ⁶⁸). MSigDB is a database of gene sets:

• collected from various sources, such as online pathway databases, publications, and knowledge of domain experts,

· comprising genes that share a conserved cis-regulatory motif across the human, mouse, rat, and dog genomes,

• identified as co-regulated gene clusters by mining large collections of cancer-oriented microarray data, and

• annotated by a common Gene Ontology (GO) term.

[0098] The enrichment analysis consisted of computing p-values for the intersections between a gene list of interest X and each gene set Y in MSigDB. First, we computed the overlap between X and Y. Then, we computed the probability (p-value) that the observed overlap between sets X and Y is less than or equal to the overlap between set X and a randomly-chosen set of size equal to the size of set Y. This probability was calculated by applying the cumulative density function of the hypergeometric distribution on the size of set X, the size of set Y, the observed overlap between X and Y, and the total number of available genes. In order to account for multiple hypothesis testing, we used randomly selected gene lists of the same size as the list under consideration to estimate the false discovery rate at a given p-value threshold. The final list of significant MSigDB gene sets was determined by setting a p-value threshold which ensures that the false discovery rate does not exceed 5%.

[0099] Example 3: Analysis of Clinical Outcome in Human Breast Cancer Patients [00100] A microarray dataset that was previously compiled from the public repositories Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) ⁶⁹ and ArrayExpress

70

(http://www.ebi.ac.uk/arrayexpress/) was used to evaluate the stromal Cav-1 deficient gene

17 18

signature in the context of clinical samples ' . Samples were first analyzed in subsets based on their ER status. Additional subsets were defined by classifying samples among five canonical breast cancer subtypes, including luminal A, luminal B, normal-like, basal, and Her-2- overexpressing disease. Samples were classified by computing their correlation against five expression profile centroids representing these breast cancer subtypes and assigning them to the subtype with the highest corresponding correlation coefficient 71. Samples with a maximum correlation coefficient below 0.3 were considered unclassified. Differential expression of the averaged gene signature magnitude among these sample subsets was evaluated using a two-tailed t-test. Kaplan-meier analysis was used to evaluate survival trends within sample subsets. The Log-rank test was used to evaluate differences in survival curves for high vs. low signature- expressing populations. In the BoxPlots (Figure 10, panel A), samples with ER immuno- histochemistry (IHC) data were selected for analysis, including 959 ER-positive and 323 ER- negative, for a total of 1,282 samples; in addition, 102 normal healthy breast tissue controls were used for comparison purposes. In the BoxPlots (Figure 10, panel B), samples with information on ESR1 mRNA transcript levels were selected for analysis, including 1,674 ESR1 -positive and 478 ESR1 -negative, for a total of 2,152 samples; in addition, 102 normal healthy breast tissue controls were used for comparison purposes. The ESR1 high/low expression cutoff was defined at the RMA-normalized expression value of 7.5. This was determined from the bimodal

17 18 expression transcript profile of ESR1 , previously described in the Ertel et al. 2010 ' .

Additional Information [00102] In Supplemental Tables 1-14, the fold-change data are represented as stromal Cav-1 (negative/positive), resulting in a positive fold-change for the transcripts that are up-regulated in Cav-1 negative stromal patients.

[00103] Supplemental Table 1 contains 238 gene transcripts that were specifically up- regulated and 232 gene transcripts that were down-regulated in the stroma of tumors showing a loss of stromal Cav-1 expression (p < 0.01 and fold-change (f.c.) > 1.5). Comparison of the transcriptional profiles of Cav-1 -positive (+) tumor stroma (N = 4) versus Cav-1 -negative tumor stroma (N = 7) revealed 238 gene transcripts that were up-regulated and 232 gene transcripts that were down-regulated in the stroma of tumors showing a loss of Cav-1 expression. The two patient populations are transcriptionally different. One-way ANOVA was setup to extract differentially expressed genes between Cav-1 positive and Cav-1 negative samples. The resultant p-values were further adjusted by multi-test correction (MTC) method of FDR step-up. The standardized intensity data from the stringent gene list (p-value < 0.01 and fold change >_1.5) were used in generating the hierarchical clustering HeatMap. [00104] As provided in Figure 11, the Cav-1 -deficient stromal gene signature is associated with tumor recurrence and poor survival in ER(+) and luminal A breast cancer patients. Here the Cav- 1-deficient stromal signature (238 transcripts that were specifically up-regulated; p < 0.01 and fold-change (f.c.) > 1.5; Supplemental Table 1) is clearly associated with increased recurrence (panels A and C) and decreased overall survival (panels B and D), despite the fact that these breast cancer-derived tumors were not subjected to laser capture microdissection. Panels A and B are ER(+) breast cancer patients, while panels C and D are the luminal A subset of ER(+) breast cancer patients. Qualitatively similar results were also obtained with the longer signature included in Supplemental Table 3.

[00105] Supplemental Table 2 contains 5,424 transcripts encoding 3,459 unique genes (p < 0.1 and fold-change (f.c.) > 1.15) that were up-regulated in the stroma of tumors showing a loss of stromal Cav-1 expression.

[00106] Supplemental Table 3 contains 1,819 transcripts encoding 1,297 unique genes (p < 0.05 and fold-change (f.c.) > 1.15) that were up-regulated in the stroma of tumors showing a loss of stromal Cav-1 expression.

[00107] In Supplemental Tables 4, 5, and 10 Cav-1 -deficient stroma showed the up-regulation of myofibroblast differentiation (15 transcripts), autophagy (22 transcripts), lysosomal proteases (5 transcripts), lysosomal proteins (29 transcripts), and glycolysis/pyruvate metabolism (15

[00108] Supplemental Tables 4-14 contain the data shown in HeatMaps, as Figures 2-8.

[00109] As provided in Supplemental Tables 10, and 12 Cav-1 -deficient stroma showed the up-regulation of hypoxia target genes (65 transcripts) and mitochondrial-associated proteins (41 transcripts).

[00110] As provided in Supplemental Tables 6, and 10 Cav- 1 -deficient stroma showed the up- regulation of the TNF/NFkB signaling (11 transcripts), the immune response (31 transcripts), and redox/stress signaling (19 transcripts). [00111] As provided in Supplemental Table 11 : Cav- 1 -deficient stroma showed the up- regulation of the DNA damage response (67 transcripts).

[00112] Supplemental Tables 7, 9 and 14: Cav-1 -deficient stroma showed the up-regulation of aging (73 transcripts), apoptosis (51 transcripts), and BRCA1 -mutation associated genes (20 transcripts). [00113] As provided in Supplemental Table 3, the inventors compared the gene transcripts up- regulated in Cav-1 -deficient tumor stroma (1,819 transcripts encoding 1,297 unique genes; p < 0.05 and fold-change (f.c.) > 1.15; Supplemental Table 3) with {Upper) tumor stromal and {Lower) recurrence stromal gene lists, as defined in the text of the manuscript. The gene transcripts up-regulated in Cav-1 -deficient tumor stroma showed significant overlap with tumor stroma (a 440 transcript overlap; p = 4.76 x 10^"9) and recurrence stroma (a 214 transcript overlap; p < 0.001).

[00114] As provided in Figure 10, the Cav-1 -deficient stromal gene signature is up-regulated in breast cancer and is associated with tumor recurrence. In panels A and B. box-plots show that the Cav-1 -deficient stromal signature is up-regulated in all breast cancers, both ER(+) and ER(-) sub-types, relative to normal healthy breast tissue. In panel A, ER status was determined by immuno-histochemistry, while in panel B, ER status was inferred from ESR1 transcript expression. In panel C, the Cav-1 -deficient stromal signature was associated with increased recurrence in breast cancer patients. In panels A-C, we used the Cav-1 -deficient stromal signature included in Supplemental Table 1 (238 transcripts that were specifically up-regulated; p < 0.01 and fold-change (fc.) > 1.5) Qualitatively similar results were also obtained with the longer signature included in Supplemental Table 3.

Figure 9 illustrates Venn diagrams for the intersection of the cav-1 -deficient stromal gene signature with other breast cancer tumor stromal gene sets. Figure 9 shows that the gene transcripts up-regulated in Cav-1 -deficient tumor stroma show significant overlap with tumor stroma (a 440 transcript overlap; p = 4.76 x 10^-9) and recurrence stroma (a 214 transcript overlap; p < 0.001). Thus, the gene transcripts up-regulated in Cav-1 -deficient tumor stroma show a significant association with tumor recurrence, and are in accordance with the results of Morag Park and colleagues ¹⁵. The present inventors, compared the gene transcripts up-regulated in Cav-1 -deficient tumor stroma (1,819 transcripts encoding 1,297 unique genes; p < 0.05 and fold- change (fc.) > 1.15; Supplemental Table 3) with {Upper) tumor stromal and {Lower) recurrence stromal gene lists, as defined in the text of the manuscript. Note that the gene transcripts up- regulated in Cav-1 -deficient tumor stroma show significant overlap with tumor stroma (a 440 transcript overlap; p = 4.76 x 10^-9) and recurrence stroma (a 214 transcript overlap; p < 0.001). [00115] Supplemental Table 15 contains the 3,459 unique genes that were up-regulated in the stroma of tumors showing a loss of stromal Cav-1 expression.

[00116] Supplemental Table 16 contains the 1,297 unique genes that were up-regulated in the stroma of tumors showing a loss of stromal Cav-1 expression.

[00117] Figure 12 illustrates understanding of the hierarchy of the cellular processes associated with a Cav-1 -deficient tumor microenvironment. Oxidative stress in fibroblasts is known to be sufficient to induce 1) myo-fibroblast differentiation, 2) DNA damage, and 3) a pseudo-hypoxic

16 19 21 31 32

state ' ^" ' ' . This pseudo-hypoxic state in fibroblasts then leads to the activation of NFkB and HIF1 -alpha, which are master regulators of the immune response, and mitochondrial function, as well as autophagy ^19-21. The autophagic destruction of mitochnodria then drives aerobic glycolysis 22. We have previously shown that transient knock-down of Cav-1 in fibroblasts, using a targeted siRNA-approach, is sufficient to induce myo-fibroblast

differentation, DNA damage, and ROS production, leading to a pseudo-hypoxic state ^19-21..

Similarly, knock down of Cav-1 in fibroblasts is sufficient to drive NFkB-, and HIF1 -activation, as well as mitochondrial dys-function, autophagy, and the induction of glycolytic enzymes ^19-21. Interestingly, transcriptional profiling of a Cav-1 -deficent tumor microenvironment provides direct evidence to support the involvement of all of these biological processes (See HeatMaps in Figures 2-6). The red arrow denotes that NFkB-activation is known to augment HIF1- activation, and visa versa, indicating that they act synergistically 28.

[00118] The Examples that follow are illustrative of specific embodiments of the invention, and various uses thereof. They set forth for explanatory purposes only, and are not to be taken as limiting the invention.

[00119] Example 1: Transcriptional Profiling of a Cav-1 Deficient Tumor

Microenvironment

[00120] Loss of stromal Cav-1 in human breast cancer(s) is associated with tumor recurrence, metastasis, and drug-resistance, conferring poor clinical outcome ^{1 5}. To mechanistically understand the "lethality" of a Cav-1 negative tumor micro-environment, we performed laser capture microdissectioin on the tumor stroma of patients that were pre-classified as stromal Cav- l-positive(+) (N = 4) and stromal Cav-l-negative(-) (N = 7), based on immuno-histochemical (IHC) staining. Then, the R A extracted from these samples was subjected to genome-wide transcriptional profiling. [00121] Based on this approach, we identified 238 gene transcripts that were specifically up- regulated and 232 gene transcripts that were down-regulated in the stroma of tumors showing a loss of Cav-1 expression (p < 0.01 and fold-change (f.c.) > 1.5) (Supplemental Table 1). Using these stringent criteria, we were able to transcriptionally separate these two patient populations, in accordance with their IHC stromal Cav-1 status (negative versus positive). A HeatMap of the total patient cohort is shown in Figure 1, demonstrating that these two patient populations appear transcriptionally and "genetically" distinct.

[00122] Example 2: Gene Set Enrichment Analysis (GSEA) of a Cav-1 Deficient Tumor

Microenvironment

[00123] To understand what cellular processes that are characteristic of a Cav-1 -deficient tumor microenvironment, we next performed gene set enrichment analysis (GSEA), by comparison with other gene signatures available in various public databases. For this purpose, we focused on a wider list of gene transcripts that were up-regulated in Cav-1 -deficient stroma (5,424 transcripts encoding 3,459 unique genes; p < 0.1 and fold-change (f.c.) > 1.15) (Supplemental Table 2), as is normally recommended for GSEA. [00124] Table 1: shows the results of this detailed analysis. Note that we see the up-regulation of cellular processes normally associated with "sternness", inflammation, DNA damage, oxidative stress, hypoxia, apoptotic signaling, autophagy, and mitochondrial dysfunction in the tumor stroma of patients lacking stromal Cav-1. [00125] Individual HeatMaps (based on 1,819 transcripts encoding 1,297 unique genes; p < 0.05 and fold-change (f.c.) > 1.15) (Supplemental Table 3) for key cellular processes are shown in Figures 2-8. These HeatMaps illustrate the upregulation of gene transcripts associated with myofibroblast differentiation, autophagy, lysosomal degradation, glycolysis, hypoxia, mitochondria, inflammation and redox signaling, DNA damage and repair, aging, BRCA1- mutation positive and ER-negative breast cancer patients, apoptosis, and neural stem cells (See Supplemental Tables 4-14).

[00126] The observed association between a Cav-1 -deficient tumor stroma and neural stem cells may reflect increased stromal "neurogenesis", which has previously been implicated in an

7 8

"neurogenesis" was associated with increased DNA damage in the tumor stroma ' .

[00127] In addition, the up-regulation of gene transcripts or gene sets associated with GOLPH3, NRFl (nuclear respiratory factor 1), PRKDC (protein kinase, DNA-activated, catalytic polypeptide), or arsenic treatment is highly suggestive of mitochondrial dysfunction (Table 1). NRFl is normally up-regulated during hypoxic-ischemic injury or oxidative stress, as an attempt to increase mitochondrial biogenesis ⁹' ¹⁰. GOLPH3 (also known as MIDAS/GPP34) is a nuclear gene whose transcription is enhanced by the absence of mitochondrial DNA (mtDNA) ^u.

12

DNA (mtDNA) , so its up-regulation is suggestive of increase mtDNA damage. Arsenic treatment is associated with increased ROS production, mtDNA damage, and mitochondrial dysfunction, with reduced ATP production, driving the onset of aerobic glycolysis ¹³' ¹⁴.

[00128] Example 3: Comparison with Other Breast Cancer Stromal Data Sets Obtained by Laser Capture Microdissection

[00129] Next, we compared our new results with an independent previously published transcriptional data set generated by Morag Park and colleagues ¹⁵, via laser capture of the tumor stroma of human breast cancers. However, these previously published data were not stratified based on stromal Cav-1 status ¹⁵. [00130] More specifically, we compared the gene transcripts up-regulated in Cav-1 -deficient tumor stroma (1,819 transcripts encoding 1,297 unique genes; p < 0.05 and fold-change (f.c.) > 1.15) (Supplemental Table 3) with 1) tumor stroma and 2) recurrence stroma gene lists, as defined below: [00131] (1) Tumor Stroma vs. Normal Stroma List - Compares the transcriptional profiles of tumor stroma obtained from 53 patients to normal stroma obtained from 38 patients. Genes transcripts that were consistently upregulated in the tumor stroma were selected and assigned a p- value, with a cut-off of p <0.05 (this set contains 6,777 unique genes) ¹⁶.

[00132] (2) Recurrence Stroma List - Compares the transcriptional profiles of tumor stroma obtained from 11 patients with tumor recurrence to the tumor stroma of 42 patients without tumor recurrence. Genes transcripts that were consistently upregulated in the tumor stroma of patients with recurrence were selected and assigned a p-value, with a cut-off of p <0.05 (this set contains 3,354 unique genes) ¹⁶.

[00133] Figure 9: shows that the gene transcripts up-regulated in Cav-1 -deficient tumor stroma show significant overlap with tumor stroma (a 440 transcript overlap; p = 4.76 x 10^"9) and recurrence stroma (a 214 transcript overlap; p < 0.001). Thus, the gene transcripts up-regulated in Cav-1 -deficient tumor stroma show a significant association with tumor recurrence, and are in accordance with the results of Morag Park and colleagues ¹⁵.

[00134] Example 4: Comparison with the Transcriptional Profiles of Breast Cancers that were Not Subjected to Laser Capture Microdissection

[00135] Most of the published and publicly available transcriptional profiles for breast cancer patients are derived from the analysis of whole tumors, which are not separated into stromal and epithelial compartments prior to analysis. Thus, we compared the gene transcripts up-regulated in Cav-1 -deficient tumor stroma (Supplemental Table 1), with the transcriptional profiles of

17 18

normal breast tissue and whole breast tumors ' .

[00136] Figure ΙΟΑ,Β: shows that the Cav-1 -deficient tumor stromal signature is up-regulated in breast cancer(s), both ER(+) and ER(-) sub-types. However, a more significant association was observed with ER(-) breast cancers. In addition, the Cav-1 -deficient stromal signature was also associated with increased recurrence in breast cancer patients (Figure IOC). [00137] Similarly, we also looked at the prognostic value of the Cav-1 -deficient stromal signature in ER(+) and luminal A breast cancer patients, which account for nearly 60% of all breast cancer patients 17 ' 18. Interestingly, Figure 11 shows that the Cav-1 -deficient stromal signature is clearly associated with increased recurrence and decreased overall survival, despite the fact that these breast cancer-derived tumors were not subjected to laser capture

microdissection.

[00138] STATISTICAL ANALYSIS

[00139] The conventional statistical analysis method for gene expression microarray

experiments is to examine one gene at a time, determine a p-value that the gene is differentially expressed in different phenotypes, and then to apply a correction (penalty) to the p-value for having tested multiple genes. In contrast, Gene set enrichment analysis ("GSEA") is a statistical method to determine if predefined sets of genes are differentially expressed in different phenotypes. Predefined gene sets may be genes in a known metabolic pathway, located in the same cytogenetic band, sharing the same Gene Ontology category, or any user-defined set. In microarray experiments where no single gene shows statistically significant differential expression between phenotypes, GSEA has identified significant differentially expressed sets of genes, even where the average difference in expression between two phenotypes is only 20% for genes in the gene set. The gene set identified in the first GSEA analysis (oxidative

phosphorylation genes differentially expressed in diabetic versus non-diabetic patients) was subsequently confirmed by independent laboratory studies published in the New England Journal of Medicine. Since the first paper on GSEA was published, many extensions and alternative methods have been described in the literature. GSEA has becoming more widely used because predictions of GSEA have been validated in independent laboratory experiments (see, for example, Patti M.E. et al., "Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1" Proc. Natl. Acad. Sci. USA 2003, 100, 8466-8471; and Petersen K.F. et al. " Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes" N. Engl. J. Med. 2004, 350, 664- 671).

[00140] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein. [00141] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted.

Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non- claimed element as essential to the practice of the invention. [00142] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred

embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context [00143] REFERENCES

1. Sloan EK, Ciocca D, Pouliot N, Natoli A, Restall C, Henderson M, Fanelli M, Cuello- Carrion F, Gago F, Anderson R. Stromal Cell Expression of Caveolin-1 Predicts Outcome in Breast Cancer. Am J Pathol 2009; 174:2035-43.

2. Witkiewicz AK, Casimiro MC, Dasgupta A, Mercier I, Wang C, Bonuccelli G, Jasmin JF, Frank PG, Pestell RG, Kleer CG, Sotgia F, Lisanti MP. Towards a new "stromal-based" classification system for human breast cancer prognosis and therapy. Cell Cycle 2009; 8: 1654-8. 3. Witkiewicz AK, Dasgupta A, Nguyen KH, Liu C, Kovatich AJ, Schwartz GF, Pestell RG, Sotgia F, Rui H, Lisanti MP. Stromal caveolin-1 levels predict early DCIS progression to invasive breast cancer. Cancer Biol Ther 2009; 8: 1167-75.

4. Witkiewicz AK, Dasgupta A, Sammons S, Er O, Potoczek MB, Guiles F, Sotgia F, Brody JR, Mitchell EP, Lisanti MP. Loss of Stromal Caveolin-1 Expression Predicts Poor Clinical

Outcome in Triple Negative and Basal- like Breast Cancers. Cancer Biology & Therapy 2010; 10: 135-43.

5. Witkiewicz AK, Dasgupta A, Sotgia F, Mercier I, Pestell RG, Sabel M, Kleer CG, Brody JR, Lisanti MP. An Absence of Stromal Caveolin-1 Expression Predicts Early Tumor Recurrence and Poor Clinical Outcome in Human Breast Cancers. Am J Pathol 2009; 174:2023-34.

6. Di Vizio D, Morello M, Sotgia F, Pestell RG, Freeman MR, Lisanti MP. An Absence of Stromal Caveolin-1 is Associated with Advanced Prostate Cancer, Metastatic Disease and Epithelial Akt Activation. Cell Cycle 2009; 8:2420-4.

7. Dakhova O, Ozen M, Creighton CJ, Li R, Ayala G, Rowley D, Ittmann M. Global gene expression analysis of reactive stroma in prostate cancer. Clin Cancer Res 2009; 15:3979-89.

8. Ayala GE, Dai H, Powell M, Li R, Ding Y, Wheeler TM, Shine D, Kadmon D,

Thompson T, Miles BJ, Ittmann MM, Rowley D. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin Cancer Res 2008; 14:7593-603.

9. Yin W, Signore AP, Iwai M, Cao G, Gao Y, Chen J. Rapidly increased neuronal mitochondrial biogenesis after hypoxic-ischemic brain injury. Stroke 2008; 39:3057-63.

10. Lee HM, Greeley GH, Jr., Englander EW. Sustained hypoxia modulates mitochondrial DNA content in the neonatal rat brain. Free Radic Biol Med 2008; 44:807-14.

11. Nakashima-Kamimura N, Asoh S, Ishibashi Y, Mukai Y, Shidara Y, Oda H, Munakata K, Goto Y, Ohta S. MIDAS/GPP34, a nuclear gene product, regulates total mitochondrial mass in response to mitochondrial dysfunction. J Cell Sci 2005; 118:5357-67.

12. Papeta N, Zheng Z, Schon EA, Brosel S, Altintas MM, Nasr SH, Reiser J, DAgati VD, Gharavi AG. Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin- induced nephropathy in mice. J Clin Invest 2010; 120:4055-64. 13. Jomova K, Jenisova Z, Feszterova M, Baros S, Liska J, Hudecova D, Rhodes CJ, Valko M. Arsenic: toxicity, oxidative stress and human disease. J Appl Toxicol 2011; 31 :95-107.

14. Zhang W, Liu Y, An Z, Huang D, Qi Y, Zhang Y. Mediating effect of ROS on mtDNA damage and low ATP content induced by arsenic trioxide in mouse oocytes. Toxicol In Vitro 2011; In Press.

15. Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A, Hallett M, Park M. Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 2008; 14:518-27.

16. Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, Wang C, Pestell RG, Martinez-Outschoorn UE, Howell A, Sotgia F, Lisanti MP. Transcriptional evidence for the

"Reverse Warburg Effect" in human breast cancer tumor stroma and metastasis: similarities with oxidative stress, inflammation, Alzheimer's disease, and "Neuron-Glia Metabolic Coupling". Aging (Albany NY) 2010; 2:185-99.

17. Ertel A. Bimodal gene expression and biomarker discovery. Cancer Inform 2010; 9: 11-4. 18. Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE, Knudsen ES. RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response. Cell Cycle 2010; 9:4153-63.

19. Martinez-Outschoorn UE, Pavlides S, Whitaker-Menezes D, Daumer KM, Milliman JN, Chiavarina B, Migneco G, Witkiewicz AK, Martinez-Cantarin MP, Flomenberg N, Howell A, Pestell RG, Lisanti MP, Sotgia F. Tumor Cells Induce the Cancer Associated Fibroblast

Phenotype Via Caveolin-1 Degradation: Implications for Breast Cancer and DCIS Therapy with Autophagy Inhibitors. Cell Cycle 2010; 9:2423-33.

20. Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C, Whitaker-Menezes D, Daumer KM, Lin Z, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG, Knudsen ES, Sotgia F, Lisanti MP. Oxidative Stress in Cancer Associated Fibroblasts

Drives Tumor-Stroma Co-Evolution: A New Paradigm for Understanding Tumor Metabolism, the Field Effect, and Genomic Instability in Cancer Cells. Cell Cycle 2010; 9:3256-76.

21. Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, Wang C, Pavlides S, Martinez-Cantarin MP, Capozza F, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG, Caro J, Lisanti MP, Sotgia F. Autophagy in Cancer Associated Fibroblasts Promotes Tumor Cell Survival: Role of Hypoxia, HIFl Induction, and NFKB Activation in the Tumor Stromal Microenvironment. Cell Cycle 2010; 9:3515-33.

22. Martinez-Outschoorn UE, Whitaker-Menezes D, Pavlides S, Chiavarina B, Bonuccelli G, Casey T, Tsirigos A, Migneco G, Witkiewicz A, Balliet R, Mercier I, Wang C, Flomenberg N, Howell A, Lin Z, Caro J, Pestell RG, Sotgia F, Lisanti MP. The Autophagic Tumor Stroma Model of Cancer or "Battery-Operated Tumor Growth": A Simple Solution to the Autophagy Paradox. Cell Cycle 2010; 9:4297-306.

23. Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Tanowitz HB, Sotgia F, Lisanti MP. Stromal-Epithelial Metabolic Coupling in Cancer: Integrating Autophagy and Metabolism in the Tumor Microenvironment. Int J Biochem Cell Biol 2011; In Press.

24. Lisanti MP, Martinez-Outschoorn UE, Chiavarina B, Pavlides S, Whitaker-Menezes D, Tsirigos A, Witkiewicz A, Lin Z, Balliet R, Howell A, Sotgia F. Understanding the "lethal" drivers of tumor-stroma co-evolution: Emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor micro-environment. Cancer Biol Ther 2010; 10:537-42. 25. Mazure NM, Pouyssegur J. Atypical BH3 -domains of BNIP3 and BNIP3L lead to autophagy in hypoxia. Autophagy 2009; 5:868-9.

26. Mazure NM, Pouyssegur J. Hypoxia-induced autophagy: cell death or cell survival? Curr Opin Cell Biol 2010; 22: 177-80.

27. Messadi DV, Doung HS, Zhang Q, Kelly AP, Tuan TL, Reichenberger E, Le AD.

Activation of NFkappaB signal pathways in keloid fibroblasts. Arch Dermatol Res 2004;

296: 125-33.

28. Chiavarina B, Whitaker-Menezes D, Migneco G, Martinez-Outschoorn UE, Pavlides S, Howell A, Tanowitz HB, Casimiro MC, Wang C, Pestell RG, Grieshaber P, Caro J, Sotgia F, Lisanti MP. HIFl -alpha Functions as a Tumor Promoter in Cancer Associated Fibroblasts, and as a Tumor Suppressor in Breast Cancer Cells: Autophagy Drives Compartment-Specific

Oncogenesis. Cell Cycle 2010; 9:3534-51.

29. Migneco G, Whitaker-Menezes D, Chiavarina B, Castello-Cros R, Pavlides S, Pestell RG, Fatatis A, Flomenberg N, Tsirigos A, Howell A, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: Evidence for stromal-epithelial metabolic coupling. Cell Cycle 2010; 9:2412-22.

30. Pavlides S, Tsirigos A, Migneco G, Whitaker-Menezes D, Chiavarina B, Flomenberg N, Frank PG, Casimiro MC, Wang C, Pestell RG, Martinez-Outschoorn UE, Howell A, Sotgia F, Lisanti MP. The Autophagic Tumor Stroma Model of Cancer: Role of Oxidative Stress and Ketone Production in Fueling Tumor Cell Metabolism. Cell Cycle 2010; 9:3485-505.

31. Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Rigoutsos I, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Loss of Stromal Caveolin-1 Leads to Oxidative Stress, Mimics Hypoxia, and Drives Inflammation in the Tumor Microenvironment, Conferring the "Reverse Warburg Effect": A Transcriptional Informatics Analysis with Validation. Cell Cycle 2010; 9:2201-19.

32. Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, Casimiro MC, Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 2009; 8 :3984-4001.

33. Trimmer C, Sotgia F, Whitaker-Menezes D, Balliet RM, Eaton G, Martinez-Outschoorn UE, Pavlides S, Howell A, lozzo RV, Pestell RG, Scherer PE, Capozza F, Lisanti MP. Caveolin- 1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal

microenvironment: a new genetically tractable model for human cancer associated fibroblasts. Cancer Biol Ther 2011; 11 :383-94.

34. Bonuccelli G, Whitaker-Menezes D, Castello-Cros R, Pavlides S, Pestell RG, Fatatis A, Witkiewicz AK, Vander Heiden MG, Migneco G, Chiavarina B, Frank PG, Capozza F,

Flomenberg N, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. The Reverse Warburg Effect: Glycolysis Inhibitors Prevent the Tumor Promoting Effects of Caveolin-1 Deficient Cancer Associated Fibroblasts. Cell Cycle 2010; 9: 1960-71.

35. Bonuccelli G, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell RG, Chiavarina B, Frank PG, Flomenberg N, Howell A, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Ketones and Lactate "Fuel" Tumor Growth and Metastasis: Evidence that Epithelial Cancer Cells Use Oxidative Mitochondrial Metabolism. Cell Cycle 2010; 9:3506-14. 36. Van den Eynden GG, Smid M, Van Laere SJ, Colpaert CG, Van der Auwera I, Bich TX, van Dam P, den Bakker MA, Dirix LY, Van Marck EA, Vermeulen PB, Foekens JA. Gene expression profiles associated with the presence of a fibrotic focus and the growth pattern in lymph node-negative breast cancer. Clin Cancer Res 2008; 14:2944-52. 37. Van den Eynden GG, Colpaert CG, Couvelard A, Pezzella F, Dirix LY, Vermeulen PB, Van Marck EA, Hasebe T. A fibrotic focus is a prognostic factor and a surrogate marker for hypoxia and (lymph)angiogenesis in breast cancer: review of the literature and proposal on the criteria of evaluation. Histopathology 2007; 51 :440-51.

38. Vincent AS, Phan TT, Mukhopadhyay A, Lim HY, Halliwell B, Wong KP. Human skin keloid fibroblasts display bioenergetics of cancer cells. J Invest Dermatol 2008; 128:702-9.

39. Zhang Q, Oh CK, Messadi DV, Duong HS, Kelly AP, Soo C, Wang L, Le AD. Hypoxia- induced HIF-1 alpha accumulation is augmented in a co-culture of keloid fibroblasts and human mast cells: involvement of ERK1/2 and PI-3K/Akt. Exp Cell Res 2006; 312: 145-55.

40. Qian N, Ueno T. Is dysfunction of caveolin-1 a link between systemic sclerosis and breast cancer, opening a window on both etiologies? Arch Med Res 2010; 41 :297-301.

41. Razani B, Zhang XL, Bitzer M, von Gersdorff G, Bottinger EP, Lisanti MP. Caveolin-1 regulates transforming growth factor (TGF)-beta/SMAD signaling through an interaction with the TGF-beta type I receptor. J Biol Chem 2001; 276:6727-38.

42. Del Galdo F, Lisanti MP, Jimenez SA. Caveolin-1, transforming growth factor-beta receptor internalization, and the pathogenesis of systemic sclerosis. Curr Opin Rheumatol 2008; 20:713-9.

43. Del Galdo F, Sotgia F, de Almeida CJ, Jasmin JF, Musick M, Lisanti MP, Jimenez SA. Decreased expression of caveolin-1 in patients with systemic sclerosis: Crucial role in the pathogenesis of tissue fibrosis. Arthritis Rheum 2008; 58:2854-65. 44. Kiyono K, Suzuki HI, Matsuyama H, Morishita Y, Komuro A, Kano MR, Sugimoto K, Miyazono K. Autophagy is activated by TGF-beta and potentiates TGF-beta-mediated growth inhibition in human hepatocellular carcinoma cells. Cancer Res 2009; 69:8844-52.

45. Racker E, Resnick RJ, Feldman R. Glycolysis and methylaminoisobutyrate uptake in rat- 1 cells transfected with ras or myc oncogenes. Proc Natl Acad Sci U S A 1985; 82:3535-8. 46. Fukino K, Shen L, Patocs A, Mutter GL, Eng C. Genomic instability within tumor stroma and clinicopathological characteristics of sporadic primary invasive breast carcinoma. Jama 2007; 297:2103-11.

47. Eng C, Leone G, Orloff MS, Ostrowski MC. Genomic alterations in tumor stroma.

Cancer Res 2009; 69:6759-64.

48. Weber F, Shen L, Fukino K, Patocs A, Mutter GL, Caldes T, Eng C. Total-genome analysis of BRCAl/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. Am J Hum Genet 2006; 78:961-72.

49. Nomura H, Uzawa K, Yamano Y, Fushimi K, Ishigami T, Kouzu Y, Koike H, Siiba M, Bukawa H, Yokoe H, Kubosawa H, Tanzawa H. Overexpression and altered subcellular localization of autophagy-related 16-like 1 in human oral squamous-cell carcinoma: correlation with lymphovascular invasion and lymph-node metastasis. Hum Pathol 2009; 40:83-91.

50. Kleer CG, Bloushtain-Qimron N, Chen YH, Carrasco D, Hu M, Yao J, Kraeft SK, Collins LC, Sabel MS, Argani P, Gelman R, Schnitt SJ, Krop IE, Polyak K. Epithelial and stromal cathepsin K and CXCL14 expression in breast tumor progression. Clin Cancer Res 2008;

14:5357-67.

51. Nadji M, Fresno M, Nassiri M, Conner G, Herrero A, Morales AR. Cathepsin D in host stromal cells, but not in tumor cells, is associated with aggressive behavior in node -negative breast cancer. Hum Pathol 1996; 27:890-5. 52. Colpaert CG, Vermeulen PB, Fox SB, Harris AL, Dirix LY, Van Marck EA. The presence of a fibrotic focus in invasive breast carcinoma correlates with the expression of carbonic anhydrase IX and is a marker of hypoxia and poor prognosis. Breast Cancer Res Treat 2003; 81 : 137-47.

53. Kuijper A, van der Groep P, van der Wall E, van Diest PJ. Expression of hypoxia- inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast. Breast Cancer Res 2005; 7:R808-18.

54. Nakao M, Ishii G, Nagai K, Kawase A, Kenmotsu H, Kon-No H, Hishida T, Nishimura M, Yoshida J, Ochiai A. Prognostic significance of carbonic anhydrase IX expression by cancer- associated fibroblasts in lung adenocarcinoma. Cancer 2009; 115:2732-43. 55. Cleven AH, van Engeland M, Wouters BG, de Bruine AP. Stromal expression of hypoxia regulated proteins is an adverse prognostic factor in colorectal carcinomas. Cell Oncol 2007; 29:229-40.

56. von Bonsdorf C-H, Fuller S, Simons K. Apical and basolateral endocytosis in Madin- Darby canine kidney (MDCK) cells grown on nitrocellulose filters. EMBO J 1985; 11 :2781-92.

57. Hyoudou K, Nishikawa M, Umeyama Y, Kobayashi Y, Yamashita F, Hashida M.

Inhibition of metastatic tumor growth in mouse lung by repeated administration of polyethylene glycol-conjugated catalase: quantitative analysis with firefly luciferase-expressing melanoma cells. Clin Cancer Res 2004; 10:7685-91. 58. Nishikawa M, Hyoudou K, Kobayashi Y, Umeyama Y, Takakura Y, Hashida M.

Inhibition of metastatic tumor growth by targeted delivery of antioxidant enzymes. J Control Release 2005; 109: 101-7.

59. Hyoudou K, Nishikawa M, Kobayashi Y, Umeyama Y, Yamashita F, Hashida M.

PEGylated catalase prevents metastatic tumor growth aggravated by tumor removal. Free Radic Biol Med 2006; 41 : 1449-58.

60. Nishikawa M, Hashida M, Takakura Y. Catalase delivery for inhibiting ROS-mediated tissue injury and tumor metastasis. Adv Drug Deliv Rev 2009; 61 :319-26.

61. Hyoudou K, Nishikawa M, Ikemura M, Kobayashi Y, Mendelsohn A, Miyazaki N, Tabata Y, Yamashita F, Hashida M. Prevention of pulmonary metastasis from subcutaneous tumors by binary system-based sustained delivery of catalase. J Control Release 2009; 137: 110- 5.

62. Nishikawa M, Tamada A, Hyoudou K, Umeyama Y, Takahashi Y, Kobayashi Y, Kumai H, Ishida E, Staud F, Yabe Y, Takakura Y, Yamashita F, Hashida M. Inhibition of experimental hepatic metastasis by targeted delivery of catalase in mice. Clin Exp Metastasis 2004; 21 :213-21. 63. Hyoudou K, Nishikawa M, Kobayashi Y, Ikemura M, Yamashita F, Hashida M. SOD derivatives prevent metastatic tumor growth aggravated by tumor removal. Clin Exp Metastasis 2008; 25:531-6. 64. van Rossen ME, Sluiter W, Bonthuis F, Jeekel H, Marquet RL, van Eijck CH. Scavenging of reactive oxygen species leads to diminished peritoneal tumor recurrence. Cancer Res 2000; 60:5625-9.

65. Zhao Y, Xue Y, Oberley TD, Kiningham K , Lin SM, Yen HC, Majima H, Hines J, St Clair D. Overexpression of manganese superoxide dismutase suppresses tumor formation by modulation of activator protein- 1 signaling in a multistage skin carcinogenesis model. Cancer Res 2001; 61 :6082-8.

66. Vozenin-Brotons MC, Sivan V, Gault N, Renard C, Geffrotin C, Delanian S, Lefaix JL, Martin M. Antifibrotic action of Cu/Zn SOD is mediated by TGF-betal repression and phenotypic reversion of myofibroblasts. Free Radic Biol Med 2001; 30:30-42.

67. Toullec A, Gerald D, Despouy G, Bourachot B, Cardon M, Lefort S, Richardson M, Rigaill G, Parrini MC, Lucchesi C, Bellanger D, Stern MH, Dubois T, Sastre-Garau X, Delattre O, Vincent-Salomon A, Mechta-Grigoriou F. Oxidative stress promotes myofibroblast differentiation and tumour spreading. EMBO Mol Med 2010; 2:211-30. 68. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge- based approach for interpreting genome -wide expression profiles. Proc Natl Acad Sci U S A 2005; 102: 15545-50.

69. Barrett T, Troup DB, Wilhite SE, Ledoux P, Rudnev D, Evangelista C, Kim IF, Soboleva A, Tomashevsky M, Edgar R. NCBI GEO: mining tens of millions of expression profiles- database and tools update. Nucl Acids Res 2007; 35:D760-5.

70. Brazma A, Parkinson H, Sarkans U, Shojatalab M, Vilo J, Abeygunawardena N,

Holloway E, Kapushesky M, Kemmeren P, Lara GG, Oezcimen A, Rocca-Serra P, Sansone SA. ArrayExpress— a public repository for microarray gene expression data at the EBI. Nucleic Acids Res 2003; 31 :68-71.

71. Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, Livasy C, Carey LA, Reynolds E, Dressier L, Nobel A, Parker J, Ewend MG, Sawyer LR, Wu J, Liu Y, Nanda R, Tretiakova M, Ruiz Orrico A, Dreher D, Palazzo JP, Perreard L, Nelson E, Mone M, Hansen H, Mullins M, Quackenbush JF, Ellis MJ, Olopade OI, Bernard PS, Perou CM. The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics 2006; 7:96. Supplemental Table 1 (page 46 through page 81 )

Supplemental Table 3: Cayl Negative vs. Cayl Positive (page 81 through page 158)

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

24 |ADXPCEC.12489.Cl_at iiHomo sapiens T-cell gamma receptor locus complete sequence. |TRGVB 1 0.0153 |

25 lADXEC.491.C15_x_at iiHomo sapiens RPS16 gene for ribosomal protein S16 complete cds |RPS16 [ 0.02321

ijandsequence.

26 |ADXEC.22568.Cl_s_at iHomo sapiens hypothetical LOC220906 (LOC220906) non-coding RNA. |LOC220906 I 0.0184|

27 iADXEC.16346.Cl_at iiHomo sapiens mRNA for FU00095 protein. |DNAJC5 I 0.00491

28 lADXECRS.32128_x_at iHomo sapiens RFT1 homolog (S. cerevisiae) (RFT1) mRNA. |RFTI I 0.02141

29 jADXECRS.38829_at iiHomo sapiens zinc finger protein 365 (ZNF365) transcript variant |ZNF365 I 0.0085|

30 !ADXECNTDJ.1583_s_at iHomo sapiens C2 calcium-dependent domain containing 4C (C2CD4C) jc2CD4C 1 0.0204Ϊ

31 |ADXECAD.26784_s_at iiHomo sapiens killer cell lectin-like receptor subfamily D member 1 |KLRDI I 0.03241

32 lADXECADA.18213_at iiTranscribed locus 0.0013Ϊ

33 |ADXECRS.38829_x_at iiHomo sapiens zinc finger protein 365 (ZNF365) transcript variant |ZNF365 I 0.0056Ϊ

34 iADXEC.23287.Cl_s_at i|CD300e molecule |CD300E [ 0.03841

35 jADXEC.11581.Cl_at iHomo sapiens DAZ associated protein 2 (DAZAP2) transcript variant |DAZAP2 I 0.03931

36 iADXEC.31458.Cl_x_at iiHomo sapiens polymerase (DNA directed) nu (POLN) gene complete cds. |P0LN 1 0.02681

37 !ADXECAD.12789_s_at iiHomo sapiens chromosome 19 BC335474 (CIT-HSPC_482H14) complete [LOC100128439| 0.0245;

38 jADXEC.19873.Cl_at iiHomo sapiens cDNA FLJ56914 complete cds highly similar to Rattusnorvegicus |RQCDI I 0.0514|

iircdl

39 lADXEC.17269.Cl_s_at iMDNl midasin homolog (yeast) [MDNI I 0.0078 Ϊ

40 jADXEC.27761.Cl_at iiTranscribed locus 0.0127 |

4l lADXECRS.29962_s_at iHomo sapiens neutrophil cytosolic factor 1 (NCF1) mRNA. [NCFI I 0.0367 Ϊ

42 |ADXEC.22550.Cl_at iiTranscribed locus 0.045l|

43 iADXECEMUTR.3609_at iiHomo sapiens v-ets erythroblastosis virus E26 oncogene homolog [ERG [ 0.00611

45 iADXECADA.24499_s_at iiHomo sapiens phosphodiesterase 6B cGMP-specific rod beta |PDE6B [ 0.0471

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

113i|ADXECADA.13253_at [Transcribed locus 0.0278

114 lADXECAD.14621 at [Transcribed locus 0.0505

115 ADXECRS.22704_s_at iiHomo sapiens proteasome (prosome macropain) subunit beta type 9 |PSMB9 0.0026

116 lADXEC.19258.Cl at ijpolypeptide N-acetylgalactosaminyltransferase 11 (GalNAc-Tll) !GALNTll 0.0079

117 ADXEC.31403.Cl_at jCDNA FU12399 fis clone MAMMA1002780 0.0245;

118 ADXECAD.7829 s at iHomo sapiens apolipoprotein C-ll (APOC2) mRNA. |APOC2 0.0002!

119 ADXEC.18483.C2_at Homo sapiens TRAF3 interacting protein 3 (TRAF3IP3) mRNA. [TRAF3IP3 0.0124s

120 ADXECRS.31469 s at Homo sapiens consortin connexin sorting protein (CNST) transcript ICNST 0.0211!

121;;ADXEC.14896.Cl_at [Transcribed locus 0.0349 s

122 !ADXECAD.2438 s at iHomo sapiens F-box protein 10 (FBXO10) mRNA. FBXO10 0.0491!

123j;ADXECAD.12843_at [Transcribed locus 0.0005

124 lADXECAD.8877_at iHomo sapiens protocadherin 11 X-linked (PCDH11X) transcript PCDH11X 0.0133

125iiADXECNTDJ.9365 s at ipleckstrin homology domain containing family A (phosphoinositide binding PLEKHA2 0.0141

ispecifi

126 ADXECRS.14061_at Homo sapiens tumor necrosis factor (ligand) superfamily member 8 |TNFSF8 0.0276!

127 ADXEC.12576.C1 at Homo sapiens kinesin family member 5C (KIF5C) mRNA. IKIF5C 0.0345!

128 ;ADXECAD.13677_ at Homo sapiens serine palmitoyi transferase subunit II gene complete cds ISM2 0.0005 s

129 !ADXEC.15135.C1 at Homo sapiens PMS2 C-terminal like pseudogene (PMS2CL) non-coding PMS2CL 0.0013!

130j;ADXEC.7572.Cl_at iHomo sapiens RD RNA binding protein (RDBP) mRNA. RDBP 0.0014s

131 IADXECADA.18686 s at [Transcribed locus 0.0072!

132j;ADXEC.13587.Cl_s_at iHomo sapiens solute carrier family 12 (potassium/chloride |SLC12A6 0.0208

133 iADXEC.34747.Cl s at iSerine racemase iSRR 0.0247

134 iADXEC.31099.Cl_ at Homo sapiens USP6 N-terminal like (USP6NL) transcript variant 1 |USP6NL 0.0052s

135 jADXEC.12456.Cl_ at Homo sapiens NOD2 gene for LRR-containing protein exons 1-11 [NOD2 0.0064!

136 iADXEC.4499.C2-a s at Homo sapiens Gl to S phase transition 2 (GSPT2) mRNA. IGSPT2 0.0078!

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

183ijADXEC.18082.Cl_at Homo sapiens ryanodine receptor 1 (skeletal) (RYR1) transcript jRYRl 0.004

184 lADXECAD.16653 s at Homo sapiens bromodomain adjacent to zinc finger domain IB [BAZIB 0.0236

185 ADXEC.6363.Cl_at iiHomo sapiens glycosyltransferase 25 domain containing 1 (GLT25D1) |GLT25D1 0.0432

186 ADXEC.9513.C1 x at iiHomo sapiens interferon regulatory factor 5 (IRF5) transcript i|RF5 0.0473

187 ADXEC.30999.Cl_at Homo sapiens genomic DNA chromosome 21q section 57/105. 0.0275;

188 ADXEC.2585.C3 s at Homo sapiens bromodomain containing 2 (BRD2) transcript variant 2 |BRD2 0.0534!

189 ADXECAD.9207_s_at jHomo sapiens MDN1 midasin homolog (yeast) (MDN1) mRNA. lVIDNl 0.0284s

190 ADXEC.29992.C1 s at Transcribed locus 0.0398!

191jiADXEC.1467.Cl_at UTP18 small subunit (SSU) processome component homolog (yeast) IUTP18 0.0421s

192iiADXPCEC.473.Cl-a s at FLJ21028 fis clone CAE07155 0.0006!

193jiADXECAD.20904_s_at iHomo sapiens death effector domain containing (DEDD) transcript IDEDD 0.0353

194 lADXECAD.14082 at [Transcribed locus 0.0126

195 ADXEC.13261.Cl_s_at Homo sapiens Down syndrome critical region gene 3 (DSCR3) mRNA. |DSCR3 0.0214

196 ADXECAD.371 s at Homo sapiens serologically defined colon cancer antigen 8 sDCCAG8 0.0256

197 |ADXEC.28432.Cl_s_. _at iHomo sapiens Hermansky-Pudlak syndrome 1 (HPSl) transcript variant jHPSl 0.0297

198 lADXECAD.18616 s at iHomo sapiens T cell receptor gamma variable 3 mRNA (cDNA !TRGV3 0.0338

iclonelMAGE:5229127).

199 ADXPCEC.14412.C2_at iHomo sapiens protein kinase C beta (PRKCB1) gene complete cds. 0.044

200 ADXEC.29808.C1 at iTranscribed locus 0.0064

201 Adx-200070-up_s_at iHomo sapiens chromosome 2 open reading frame 24 (C2orf24) mRNA. |C2orf24 0.0165

202 ADXECEMUTR.2840 x at iHomo sapiens T cell receptor gamma variable 3 mRNA (cDNA |TRGV3 0.0217

iclonelMAGE:5229127).

203iiADXECAD.12447_s_at iiHomo sapiens transmembrane and coiled-coil domain family 1 (TMCCl) rnvicci 0.0277;

204 ADXECADA.18527_at iiTranscribed locus 0.0367!

205 iADXEC.6350.Cl s at iiHomo sapiens dishevelled dsh homolog 3 (Drosophila) (DVL3) mRNA. iDVL3 0.038!

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

321:jADXECAD.18269_s_at Homo sapiens protein phosphatase Mg2? dependent IK (PPM1K) jPPMlK 0.029

322 lADXEC.5689.Cl s at Homo sapiens adaptor-related protein complex 4 beta 1 subunit |AP4B1 0.0331

323 ADXEC.12118.Cl_s_at iiHomo sapiens BCL2-like 13 (apoptosis facilitator) (BCL2L13) |BCL2L13 0.0417

324 ADXEC.6937.C1 s at iiHomo sapiens solute carrier family 8 (sodium/calcium exchanger) iSLC8Al 0.0066

325 IADXEC.16866.C1_ .at iHomo sapiens adenosine Al receptor (ADORA1) transcript variant 2 jADORAl 0.0304;

326 IADXEC.24462.C1 at jcytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMP-N- ICMAH 0.0359!

iacetylneuramin

327 ADXECRS.8194_x_at Homo sapiens zinc finger protein 91 pseudogene (LOC441666) LOC441666 0.0379

328 ADXECEMUTR.2994 at Homo sapiens mRNA for KIAA1652 protein partial cds. KIAA1652 0.0389

329iiADXEC.21693.Cl s at jHuman DNA sequence from clone RP11-364F8 on chromosome 13 Contains part PCCA 0.0199

iofthe PC

330 ADXECAD.9613_s_at Homo sapiens tet oncogene family member 2 (TET2) transcript |TET2 0.0214

331 ADXEC.25521.C1 s at Homo sapiens cytidine monophosphate-N-acetylneuraminic acid ICMAH 0.0273

332 ADXEC.6876.Cl_at iiHomo sapiens signal recognition particle receptor B subunit jSRPRB 0.0531

333 ADXEC.11334.Cl-a s at iiHomo sapiens target of EGR1 member 1 (nuclear) (TOE1) mRNA. HO El 0.0195

334 ADXEC.30575.Cl_x_at Homo sapiens prenylcysteine oxidase 1 (PCYOXl) mRNA. jPCYOXl 0.0238;

335 ADXEC1248.C1 at Homo sapiens dehydrogenase El and transketolase domain containing 1 jDHTKDl 0.0381!

336 IADXEC.25229.C1_ .at Homo sapiens SH2 domain containing 4A (SH2D4A) transcript variant |SH2D4A 0.0405;

337 !ADXEC.23249.C1 at Homo sapiens cDNA FU52198 complete cds. !ci7orf87 0.0418!

338;;ADXEC.13172.Cl_at Homo sapiens interleukin 28 receptor alpha (interferon lambda |I L28 A 0.0018;

339 iADXEC.13165.Cl s at Homo sapiens vitelline membrane outer layer 1 homolog (chicken) jvMOl 0.0051!

340;;ADXEC.342.Cl_at iHomo sapiens deoxyribonuclease II lysosomal (DNASE2) mRNA. |DNASE2 0.0184

34lijADXEC.27761.Cl S at [Transcribed locus 0.0204

342:jADXEC.409.C92_at iiRibosomal protein S15a |RPS15A 0.0225;

343 lADXECRS.9851 at iiHomo sapiens oculomedin (OCLM) mRNA. loCLM 0.0233!

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

460i|ADXECADA.209_at iHomo sapiens ankyrin repeat and SOCS box-containing 14 (ASB14) ASB14 0.0228

46_jADXEC.16712.Cl at iTranscribed locus 0.0301

462 ADXEC.926.Cl-a_s_at iiHomo sapiens transmembrane protein 106C (TMEM106C) transcript |TMEM106C 0.0413

463 ADXECAD.17716 x at iiProtein tyrosine phosphatase non-receptor type 1 IPTPNI 0.0087

464 iADXEC.29413.d_at iTranscribed locus 0.0099 ;

465 ADXEC.8387.C1 at !FLJ21028 fis clone CAE07155 0.0117 !

466 iADXEC.2672.Cl_s _at |Homo sapiens MORC family CW-type zinc finger 2 (MORC2) mRNA. IMORC2 0.0142

467 jADXEC.15363.C3_ x_at iTranscribed locus 0.0331

468 !ADXECADA.990 X at iHomo sapiens neuroplastoma apoptosis-related RNA-binding protein ICELF2 0.0352

i(CUGBP2)gene ex

469 iADXEC.23032.Cl_at iiHomo sapiens CD68 molecule (CD68) transcript variant 2 mRNA. |CD68 0.0395

470iiAdx-200054-up_s_at iiHomo sapiens zinc finger protein 259 (ZNF259) mRNA. |ZNF259 0.0413

471 ;ADXEC.29413.C1_. _x_at transcribed locus 0.0038

472 2328487_at 0.0084

473 iADXEC.34398.Cl x at iHomo sapiens peroxisome proliferative activated receptor alpha (PPARA)gene PPARA 0.0213

icompl

474 jADXECNTDJ.5307 _at Homo sapiens tripartite motif-containing 35 (TRIM35) transcript |TRIM35 0.0237

475 iADXEC.14809.Cl at F-box and leucine-rich repeat protein 14 FBXL14 0.0328

476 ADXEC.869.Cl_x_at Homo sapiens chromosome 17 open reading frame 106 (C17orfl06) |C17orfl06 0.0354

477 ADXECAD.20607 s at Homo sapiens serglycin (SRGN) mRNA. [SRGN 0.0377

478 ADXEC.3819.C2-a_s_at Homo sapiens family with sequence similarity 131 member A |FAM131A 0.0431

479 ADXEC.22813.Cl-a s at Homo sapiens sialophorin (SPN) transcript variant 1 mRNA. [SPN 0.0519

480i;ADXECADA.23331_s_at iiHomo sapiens high-mobility group 20B (HMG20B) mRNA. |HMG20B 0.0543;

481 ADXEC.16192.C2-a_s_at iiHomo sapiens arachidonate 5-lipoxygenase-activating protein |ALOX5AP 0.0031Ϊ

482iiADXECNTDJ.10553 at iiATP-binding cassette sub-family D (ALD) member 1 pseudogene 4 UBCD1P4 0.0046Ϊ

506iiADXECAD.8834 s at Homo sapiens KIAA1632 (KIAA1632) mRNA. IKIAA1632 0.0186s

507 !ADXECAD.7698_s_at iHomo sapiens LSM14B SCD6 homolog B (S. cerevisiae) (LSM14B) mRNA. |LSM14B 1 0.0238|

508 iADXECNTDJ.2692_s_at iiHomo sapiens kinesin family member 3C (KIF3C) mRNA. |KIF3C I 0.02731 i 509 !jADXECADA.1067 l_at itumor protein p53 binding protein 2 [Macaca mulatta] 1 0.0296;

510ijADXECRS.39826_at iiHomo sapiens phosphoglycerate kinase 1 (PGK1) mRNA. jPGKl I 0.0513| i 51l lADXECAD.11923_at itumor protein p53 binding protein 2 [Macaca mulatta] 0.052l|

! 512 |ADXEC.34337.Cl_at iiHuman DNA from chromosome 14-specific cosmid containing XRCC3 DNA |XRCC3 I 0.0528| iirepairgene gen

i 513 !ADXECAD.10006_s_at iiHomo sapiens La ribonucleoprotein domain family member 4B |LARP4B I O.OOllj

515 iADXEC.5821.Cl-a_s_at iiHomo sapiens 3-phosphoinositide dependent protein kinase-1 (PDPK1) [PDPKl [ 0.00691

516 |ADXEC.27188.Cl_s_at iHomo sapiens dehydrogenase/reductase (SDR family) X-linked (DHRSX) |DH RSX 1 0.008|

517 iADXEC.10875.Cl_at iHomo sapiens nucleoporin 210kDa (NUP210) mRNA. |NUP210 I 0.01041 i 518 lADXECAD.16644_at iPeroxisomal biogenesis factor 26 [PEX26 1 0.012;

519 |ADXECADA.18518_at iiprotein-L-isoaspartate (D-aspartate) O-methyltransferase domain containing 1 jPCMTDl I 0.0195; i 520 lADXEC.3168.C2_s_at [Transcribed locus 0.0208Ϊ

! 521 |ADXECEMUTR.5659_at iiZinc finger protein 292 |ZNF292 I 0.0224; i 522 lADXEC.5484.Cl_at iiHomo sapiens tribbles homolog 1 (Drosophila) (TRIB1) mRNA. [TRI BI I 0.0302Ϊ

! 523 !ADXEC.27117.Cl-a_s_at iiHomo sapiens signal transducer and activator of transcription 6 |STAT6 I 0.0325;

524 iADXEC.20111.Cl_x_at iHomo sapiens sideroflexin 1 (SFXN1) mRNA. [SFXNI [ 0.0338;

525 |ADXEC.30999.Cl_x_at iHomo sapiens genomic DNA chromosome 21q section 57/105. 1 0.0445 ;

526 iADXECRS.25801_s_at iiHomo sapiens zinc finger protein 45 (ZN F45) mRNA. |ZN F45 1 0.048; i 527 lADXEC.9246.Cl_at iHomo sapiens neuropilin 1 (NRP1) transcript variant 2 mRNA. [N RPI I 0.0522;

528 jADXEC.19905.Cl_s_at iCDNA FU20196 fis clone COLF0944 0.0046;

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

599i|ADXEC.2358.C2_s_at iHomo sapiens synaptogyrin 2 (SYNGR2) mRNA. ISYNGR2 0.0464

600|!ADXECEM UTR.6831 at iTranscribed locus 0.0464

601 ADXEC.20828.Cl_at iiHomo sapiens genomic DNA chromosome 21q section 61/105. RPS5P3 0.0485

602 ADXEC.7150.C1 at iiHomo sapiens N-acetylglucosamine-l-phosphodiester NAG PA 0.0491

603 ADXEC.981.C3_s_at iTranscribed locus 0.0512 ;

604 iADXEC.7491.Cl at iDnaJ (Hsp40) homolog subfamily C member 9 DNAJC9 0.0525 !

605 ADXEC.1472.Cl_at Homo sapiens family with sequence similarity 82 member A2 FAM82A2 0.0534s

606 ADXEC.17001.Cl-a s at Homo sapiens H LA-B associated transcript 2-like 1 (BAT2L1) mRNA. BAT2L1 0.0025 !

607;;ADXEC.12654.Cl_at iTranscribed locus 0.0082 s

608 !ADXECADA.1912 at 13910609 0.0146!

_- 609iiADXEC.1986.Cl s at iiHomo sapiens nuclear prelamin A recognition factor (NARF) NARF 0.0276

610ijADXEC.lll.C71 at iiHuman elongation factor EF-l-alpha gene complete cds. EEF1A1 0.0491

611 ADXEC.2453.Cl_s_at Homo sapiens lipase maturation factor 2 (LMF2) mRNA. |LM F2 0.0032

612 ADXEC.8778.C2 s at Homo sapiens integrator complex subunit 4 (I NTS4) mRNA. ilNTS4 0.0058

613 jADXEC.17718.Cl_ _at Homo sapiens breast carcinoma amplified sequence 3 (BCAS3) |BCAS3 0.0066

614 iADXECADA.6303 at Homo sapiens tetraspanin 18 (TSPAN18) mRNA. ITS PAN 18 0.0321

615 ADXEC.14775.Cl-a_s_at Homo sapiens leucine rich repeat (in F LI I ) interacting protein 2 |LRRFI P2 0.0333

616 ADXECRS.20577 s at Homo sapiens chromosome 15 open reading frame 23 (C15orf23) |ci5orf23 0.0396

617 iADXEC.13671.Cl_ .at Homo sapiens branched chain amino-acid transaminase 1 cytosolic jBCATl 0.0404

618 iADXEC.13555.Cl at Homo sapiens Src-like-adaptor (SLA) transcript variant 3 mRNA. Is LA 0.0412

619 ADXECRS.42385_at iiHomo sapiens small nucleolar RNA H/ACA box 80 (SNORA80) small |SNORA80 0.0465

620 ADXEC.6107.C3-a s at iiHomo sapiens ATPase H transporting lysosomal 38kDa VO subunit |ATP6V0D1 0.0497

621iiADXECAD.11579_x_at iiHomo sapiens sphingomyelin phosphodiesterase 1 acid lysosomal isMPDl 0.0155 !

622i|ADXEC.13922.Cl_s_at ^Transcribed locus 0.03381

623iiADXEC.15864.Cl s at iiHomo sapiens myosin heavy chain 11 smooth muscle isoform 2 (MYH ll) 0.0397 !

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

645:jADXECNTDJ.7831_s_at Homo sapiens TATA box binding protein (TBP) transcript variant 2 jTBP 0.0205

646 lADXEC.11266.Cl at Pellino homolog 1 (Drosophila) [PELIl 0.0226

647 ADXEC.14653.Cl_x_at iiTetratricopeptide repeat domain 17 |TTC17 0.0347

648 lADXEC.8047.Cl S at iiHomo sapiens nucleolar protein with MIF4G domain 1 (NOMl) mRNA. INOMI 0.0377

649 ADXEC.9580.Cl-a_s_at Homo sapiens small VCP/p97-interacting protein (SVIP) mRNA. jSVIP 0.0406;

650 ADXEC.6547.Cl-a s at Homo sapiens RCSD domain containing 1 (RCSD1) mRNA. !RCSDI 0.046!

651 ADXEC.12717.Cl_at Homo sapiens SAM and SH3 domain containing 3 (SASH3) mRNA. |SASH3 0.0514s

652 ADXECAD.11485 s at Homo sapiens RAN binding protein 9 (RANBP9) mRNA. !RANBP9 0.0053!

653;;ADXEC.692.C2_at Matrin 3 |MATR3 0.009s

654 !ADXECNTDJ.1543 at Homo sapiens solute carrier family 35 member F2 (SLC35F2) mRNA. !SLC35F2 0.0115!

655iiADXEC.5070.Cl s at i|Homo sapiens U2 small nuclear RNA auxiliary factor 1-like 4 U2AF1L4 0.0153

656:;ADXECAD.20947 at iiHomo sapiens membrane-spanning 4-domains subfamily A member 7 MS4A7 0.0224

657 ADXECEMUTR.2170_s_at iTetratricopeptide repeat domain 17 |TTC17 0.0226

658 ADXECADA.16003 x at iHomo sapiens hypothetical CG030 (CG030) non-coding RNA. cG030 0.0275

659 jADXECADA.13904_. _at Transcribed locus 0.0382

660 IADXEC.111.C99 S at iHomo sapiens ubiquitin specific peptidase 22 (USP22) mRNA. |USP22 0.04

661 |ADXECAD.13209_ at iTetratricopeptide repeat domain 7A ITTC7A 0.0432

662 !ADXECRS.8168 S at iHomo sapiens colony stimulating factor 1 receptor (CSF1R) mRNA. jCSFl 0.0518

663 iADXEC.19326.Cl_ _.at iHomo sapiens zinc finger protein 407 (ZNF407) transcript variant |ZNF407 0.0535

664 iADXEC.24209.Cl at iTranscribed locus 0.0544

665 ADXEC.731.C2_at iiHomo sapiens SUMOl/sentrin specific peptidase 5 (SENP5) mRNA. |SENP5 0.0047

666 ADXECRS.3185 s at iiHomo sapiens UBX domain protein 2B (UBXN2B) mRNA. iUBXN2B 0.0137

667 IADXEC.28724.C1 _x_at Homo sapiens PNAS-128 mRNA partial sequence. |SETDB2 0.0157 !

668 |ADXECAD.17716_ _.at Protein tyrosine phosphatase non-receptor type 1 jPTPNl 0.01631

669 !ADXEC.237.C1 s at Homo sapiens myotubularin related protein 14 (MTMR14) transcript MTMR14 0.0184!

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

694:iADXECAD.9122 s at jHuman DNA from chromosome 14-specific cosmid containing XRCC3 DNA XRCC3 0.0398

jrepairgene gen

695jiADXECRS.19463_at iiHomo sapiens dynein heavy chain domain 1 (DNHD1) transcript jDNHDl 0.0029

696 IADXECRS.24883 s at iiHomo sapiens transmembrane protein 86A (TMEM86A) mRNA. H^"MEM86A 0.012

697i|ADXEC.28457.Cl_s_at Homo sapiens p21 protein (Cdc42/Rac)-activated kinase 2 (PAK2) IPAK2 0.018

698 lADXEC.33002.Cl at Homo sapiens chromosome 8 clone RP11-1007J8 complete sequence. !SLC20A2 0.0252

699 ADXECRS.15653_x_at Programmed cell death 6 pseudogene |LOC728613 0.0262

700 ADXECAD.4571 at Homo sapiens mRNA containing U19H snoRNA sNHG4 0.0288

701 ADXEC.256.C5_at iHomo sapiens coiled-coil domain containing 137 (CCDC137) mRNA. |CCDC137 0.0339

702 ADXEC.33559.C1 x at iHomo sapiens stromal antigen 3 opposite strand mRNA (cDNA [GATS 0.0375

iclonelMAGE:6156265) pa

703 ADXEC.28633.Cl_s_at iHypothetical protein LOC256021 LOC256021 0.0376

704 ADXEC.725.C4 s at iTranscribed locus 0.041

705 ADXECADA.20351_x_at iiHomo sapiens growth factor independent 1 transcription repressor !GFIl 0.0455

706 lADXEC.22905.Cl at iTranscribed locus 0.0474

707 ADXECNTDJ.9516_at Homo sapiens chromosome 12 open reading frame 51 (C12orf51) mRNA. |C12orf51 0.0481

708 ADXEC.12290.C1 s at PREDICTED: Homo sapiens hypothetical LOC728836 (LOC728836) mRNA. ^LOC728836 0.0484!

709 ADXEC.34156.Cl_at Homo sapiens PAC clone RP5-991G20 from 16 complete sequence. RNU7-71P 0.0495 s

710 ADXECADA.24831 s at Homo sapiens RNA binding motif single stranded interacting protein RBMS2 0.0041!

711 |3740525_at 0.0098s

712 lADXEC.23874.Cl s at Homo sapiens endoplasmic reticulum protein 44 (ERP44) mRNA. ERP44 0.0l!

713;;ADXECAD.3802_at Homo sapiens hypothetical LOC285965 (LOC285965) non-coding RNA. LOC285965 0.0114s

714iiADXECEMUTR.2405 at iiHomo sapiens progesterone immunomodulatory binding factor 1 mRNA PIBF1 0.0134!

i(cDNAclone MGC:

715i;ADXECADA.13185 at iiHECT domain containing 1 HECTD1 0.0205s

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

738i|ADXEC.20792.Cl_at iiHomo sapiens G protein-coupled receptor 65 (GPR65) mRNA. IGPR65 0.0414

739|!ADXECEM UTR.5845 at ijCalcium homeostasis modulator 2 |CALHM2 0.0424

740 ADXEC.22819.Cl-a_s_at iiHomo sapiens NLR family apoptosis inhibitory protein (NAIP) !NAI P 0.0438

741 3275388 at 0.0468

742 ADXEC.7799.Cl_s_at iHomo sapiens kinesin family member C2 (KIFC2) mRNA. |KIFC2 0.0069;

743 ADXECAD.15346 at iTetratricopeptide repeat domain 17 ITTC17 0.0077!

744 ADXEC.31742.Cl_at [Transcribed locus 0.0193 s

745 ADXECNTDJ.4097 s at iHomo sapiens REST corepressor 1 (RCOR1) mRNA. jRCORl 0.0231!

746jiADXEC.7799.C2_s_at Homo sapiens kinesin family member C2 (KIFC2) mRNA. |KIFC2 0.0238s

747 IADXEC.17365.C1 at Homo sapiens cAMP responsive element modulator (CREM) transcript jCREM 0.0244!

748jiADXECNTDJ.8881 s at iiHomo sapiens zinc finger DHHC-type containing 2 (ZDHHC2) mRNA. |ZDHHC2 0.0288

749:;ADXECNTDJ.7782 at iiHomo sapiens retinoid X receptor beta (RXRB) mRNA. RXRB 0.03

750 ADXEC.10295.C2-a_s_at Homo sapiens KIAA0892 (KIAA0892) mRNA. KIAA0892 0.0432

751 ADXEC.1230.C1 at Homo sapiens activating transcription factor 5 (ATF5) mRNA. |ATF5 0.044

752 iADXECADA.22455_. _at Homo sapiens 3-phosphoinositide dependent protein kinase-1 (PDPKl) IPDPKI 0.0004

753 iADXEC.9451.Cl s at Homo sapiens BCL2-like 13 (apoptosis facilitator) (BCL2L13) BCL2L13 0.0005

754 ADXEC.2002.C6_s_at Homo sapiens major facilitator superfamily domain containing 7 MFSD7 0.0083

755 ADXECRS.38063 s at Homo sapiens TBC1 domain family member 5 (TBC1D5) transcript fTBClD5 0.0141

756 ADXEC.11294.C2_at Homo sapiens ribosomal protein S6 kinase 90kDa polypeptide 3 fopS6KA3 0.0144

757 ADXEC.8760.Cl-a s at Homo sapiens WD repeat domain 37 (WDR37) mRNA. |WDR37 0.0152

758 ADXECADA.12739_x_at iiCAP-GLY domain containing linker protein 1 kupi 0.0242;

759 ADXEC.7957.C1 at iiHomo sapiens potassium inwardly-rectifying channel subfamily J |KCNJ16 0.0274!

760;iADXECRS.7301_s_at iiLysine (K)-specific demethylase 2A KDM2A 0.0321!

761i|3740522_at 0.03871

762iiADXEC.26485.Cl at iiHomo sapiens tetratricopeptide repeat protein 12 (TTC12) gene completecds |TTC12 0.0415!

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

832:jADXECRS.5224_s_at Homo sapiens phosphodiesterase 7A (PDE7A) transcript variant 1 |PDE7A 0.0021

833liADXEC.6409.Cl-a s at Homo sapiens DENN/MADD domain containing 4B (DENND4B) mRNA. |DENN D4B 0.006

834 ADXEC.224.C27_at iiHomo sapiens mediator of DNA-damage checkpoint 1 (MDC1) mRNA. MDC1 0.0119

835 ADXEC.169.C9 x at iiHomo sapiens (N6-adenosine)-methyltransferase gene complete cds. METTL3 0.0126

836 ADXECADA.3305_at Full length insert cDNA clone ZB94A08 0.0136;

837 ADXEC.194.C2 at Homo sapiens family with sequence similarity 107 member B IFAM107B 0.0165!

838 ADXEC.15087.C2_s_at Homo sapiens symplekin (SYMPK) mRNA. jSYMPK 0.0181s

839 ADXEC.16630.C1 s at Homo sapiens outer dense fiber of sperm tails 2 (ODF2) transcript !0DF2 0.0222!

840;;ADXEC.30911.Cl_x_at [Transcribed locus 0.0377s

841 lADXEC.16104.C2 s at iHomo sapiens nucleotide binding protein 1 (MinD homolog E. coli) jNUBPl 0.0384!

842;;ADXEC.1293.Cl_s_at iiHomo sapiens KIAA1967 (KIAA1967) transcript variant 2 non-coding |ΚΙΑΑ1967 0.0401

843 IADXEC.16910.C1 s at iiHomo sapiens RAS protein activator like 3 (RASAL3) mRNA. RASAL3 0.0427

844 ADXECNTDJ.780_s_at Homo sapiens mitochondrial ribosomal protein L49 (MRPL49) nuclear MRPL49 0.0444

845 ADXEC.19032.C1 at PREDICTED: Homo sapiens hypothetical LOC727804 (LOC727804) mRNA. |LOC727804 0.0492

846 ADXEC.4862.C4_s_at Homo sapiens chromosome 1 open reading frame 77 (Clorf77) mRNA. !ciorf77 0.0004

847 ADXECAD.16270 at Homo sapiens zinc finger protein 502 (ZNF502) transcript variant |ZNF502 0.0038

848 ADXEC.8778.Cl_s_at IHomo sapiens integrator complex subunit 4 (INTS4) mRNA. llNTS4 0.0107

849 ADXECAD.2058 s at 12337111 mRNA sequence 0.0117

850 ADXECAD.11938_s_at Homo sapiens zinc finger CCCH-type containing 18 (ZC3H18) mRNA. |ZC3H18 0.0179

851 ADXOCEC.10681.C1 at Homo sapiens tubulin tyrosine ligase-like family member 4 (TTLL4) |TTLL4 0.0187

852 ADXEC.20776.Cl_at iiHomo sapiens hypothetical protein mRNA complete cds. |HEATR3 0.0188

853 ADXEC.1473.C1 s at iiHomo sapiens coiled-coil and C2 domain containing IB (CC2D1B) icC2DlB 0.0278

854iiADXEC.6913.Cl-a_s_at iiHomo sapiens tripartite motif-containing 25 (TRIM25) mRNA. |TRIM25 0.031!

855i|ADXEC.23124.Cl_at iiHomo sapiens NLR family pyrin domain containing 1 (NLRP1) jNLRPl 0.0421

856!iADXEC.26657.Cl at iiHomo sapiens zinc finger protein 577 (ZNF577) transcript variant zNF577 0.0461!

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

857;|ADXEC.26121.C2_s_at Homo sapiens acyl-CoA synthetase medium-chain family member 3 |ACSM3 0.0467

858 lADXEC.20884.Cl s at Homo sapiens Rho guanine nucleotide exchange factor (GEF) 1 [ARHGEFI 0.0492

859 ADXECADA.13198_x_at iiTranscribed locus 0.0492

860 ADXEC.8622.C1 at iiHomo sapiens IKAROS family zinc finger 1 (Ikaros) (IKZF1) mRNA. jlKZFl 0.0512

861 ADXEC.23062.Cl_at Homo sapiens chromosome 18 open reading frame 25 (C18orf25) ci8orf25 0.0518;

862 ADXECNTDJ.5398 s at Dual specificity phosphatase 16 |DUSP16 0.0521!

863 ADXECEMUTR.5611_x_at iHomo sapiens chromosome 19 cosmid R32889 complete sequence. bp A3 0.0053s

864 ADXEC.25318.C1 at Transcribed locus 0.0088!

865jiADXECAD.19997_at jSolute carrier family 4 (anion exchanger) member 1 adaptor protein LC4A1AP 0.0167s

866 IADXECNTDJ.7039 at iHomo sapiens Rho GTPase activating protein 18 (ARHGAP18) mRNA. kRHGAP18 0.0185!

867;;ADXEC.5920.Cl_s_at i|Homo sapiens SH3 domain binding glutamic acid-rich protein like 3 |SH3BGRL3 0.0196

868 !ADXECAD.18742 x at iiHomo sapiens nuclear factor of kappa light polypeptide gene enhancer inB-cells !LOC100288009 0.0232

869i;ADXECRS.8012 at iHomo sapiens diacylglycerol O-acyltransferase homolog 1 (mouse) mRNA DGAT1 0.0424s

i(cDNAclone

870 ADXECAD.22713_s_at Homo sapiens GRB2-associated binding protein 1 (GAB1) transcript |GAB1 0.0427!

871 ADXECNTDJ.7720 at Homo sapiens dihydropyrimidine dehydrogenase (DPYD) transcript !DPYD 0.0427!

872 ADXEC.29114.Cl_x_at Homo sapiens chemokine (C-X-C motif) receptor 3 (CXCR3) transcript |CXCR3 0.0516s

873 ADXEC.4541.C1 s at Homo sapiens transportin 3 (TNP03) mRNA. ΙΤΝΡ03 0.0002!

874iiADXEC.10626.Cl_s_at Homo sapiens zinc finger protein 611 (ZNF611) transcript variant |ZNF611 0.0114s

875 iADXEC.33841.Cl at Homo sapiens chromosome 19 clone CTB-14D10 complete sequence. !NANOS2 0.0132!

876iiADXEC.31978.Cl_at i|KB1588E7 completesequence. 0.0145

877 iADXEC.3751.C2 at iiHomo sapiens TBC1 (tre-2/USP6 BUB2 cdcl6) domain family member 1 jTBClDl 0.0157

878i|ADXEC.5304.C2_at iiHomo sapiens metastasis associated in colon cancer 1 (MACC1) mRNA. |MACCI 0.0191s

879iiADXLCEC.4623.Cl at iiHomo sapiens macrophage scavenger receptor 1 (MSRl) gene complete cds. ^MSRl O.O2 !

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

880:jADXEC.20725.Cl_at Homo sapiens cell division cycle 42 (GTP binding protein 25kDa) |CDC42 0.0268

88l !ADXECEMUTR.913 S at Homo sapiens hypothetical LOC652276 (LOC652276) non-coding RNA. |LOC652276 0.0312

882 ADXECADA.13436_at iiCoiled-coil domain containing 93 |CCDC93 0.0317

883 ADXECAD.17086 x at ijPeptidylprolyl isomerase domain and WD repeat containing 1 jpPWDl 0.033

884 ADXECNTDJ.6431_s_at iHomo sapiens CD8a molecule (CD8A) transcript variant 1 mRNA. !CD8A 0.0417;

885 ADXECEMUTR.7777 s at iHomo sapiens ZNF01 and HUMORFKG1B genes partial sequence 0.047!

icompletesequence.

886 ADXEC.15623.Cl_at Homo sapiens SET domain containing IB (SETD1B) mRNA. jSETDlB 0.0513 s

887 ADXECAD.2934 at Homo sapiens metastasis associated in colon cancer 1 (MACCl) mRNA. !MACCI 0.0523!

888;;ADXECEMUTR.7014_at Homo sapiens mRNA for PAP associated domain containing 1 variant 0.004s

889 |ADXECAD.2809_x_at Homo sapiens kinesin family member IB (KIF1B) transcript variant jKIFIB 0.008!

890;|ADXECRS.10658_s_at ijHomo sapiens myocyte enhancer factor 2A (MEF2A) transcript variant |lV1EF2A 0.0174

891 IADXECRS.16999 at iHomo sapiens POU class 3 homeobox 1 (POU3F1) mRNA. POU3F1 0.0189

892 ADXEC.522.C5_at Human mRNA for HLA class II DR-beta 1 (Dwl4) HLA-DRB1 0.027

893 ADXEC.7821.Cl-a s at Homo sapiens phosphatase and actin regulator 4 (PHACTR4) |PHACTR4 0.0303

894 ADXEC.14444.Cl_s_at iHomo sapiens chloride channel CLIC-like 1 (CLCC1) transcript !CLCCI 0.0306

895 ADXECAD.16298 at iHomo sapiens isolate 495CLS7 haplotype HLA-B3801/HLA-Cwl20301 0.0345

igenomicsequence.

896 ADXEC.409.C32_at [Transcribed locus |PTP4A2 0.0357

897 ADXEC.30057.C1 x at iLactamase beta [LACTB 0.0409

898 ADXECEMUTR.4612_s_at Homo sapiens RNA binding motif protein 41 (RBM41) transcript IRBM41 0.0437;

899 ADXECAD.6907 s at Homo sapiens single stranded DNA binding protein 4 (SSBP4) |SSBP4 0.0444!

900:;ADXECRS.27967_s_at iiHomo sapiens grancalcin EF-hand calcium binding protein (GCA) iGCA 0.0488;

901iiADXECAD.4974 at ijHuman cell line Ad-312/SV40 ectopic sequence from HMGI-C fusion mRNA 0.0524!

i|3sequence.

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

1044 iADXEC.29028.Cl_x_at Homo sapiens nasal embryonic LHRH factor (NELF) transcript variant jNELF 0.0494

1045 lADXEC.718.Cl x at Homo sapiens ethanolamine kinase 1 (ETNK1) transcript variant 1 !ETNKI 0.0495

11046 ADXEC.14372.C2_s_at ijHomo sapiens WEE1 homolog (S. pombe) (WEE1) transcript variant 1 jWEEl 0.0516

1047 lADXEC.24170.Cl S at ijHomo sapiens centromere protein C 1 (CENPC1) mRNA. IcENPCl 0.0021

1048 ADXECAD.18174_s_at Homo sapiens MICAL C-terminal like (MICALCL) mRNA. jMICALCL 0.0077;

1049 ADXEC.2954.C1 at Homo sapiens stress-associated endoplasmic reticulum protein 1 iSERPl 0.0081!

1050 ADXECADA.24803_s_at Homo sapiens GTP binding protein 2 (GTPBP2) mRNA. |GTPBP2 0.0132s

1051 ADXECRS.27469 s at PREDICTED: Homo sapiens similar to synaptophysin-like 1 !LOC100132972 0.0132!

1052 ADXEC.21098.Cl_at Homo sapiens heat shock 70kDa protein 5 (glucose-regulated protein |HSPA5 0.0184s

1053 ADXEC.731.C2-a s at Homo sapiens SUMOl/sentrin specific peptidase 5 (SENP5) mRNA. !SENP5 0.0246!

i- ^' 054i;ADXEC.22969.Cl s at iiHomo sapiens tripartite motif-containing 22 (TRIM22) mRNA. fTRIM22 0.0323

^ 1055 !ADXEC.15955.Cl-a s at iiHomo sapiens coiled-coil domain containing 82 (CCDC82) mRNA. |CCDC82 0.0373

1056 jADXEC.23381.Cl _at jAcyl-CoA synthetase family member 2 |ACSF2 0.0386

1057 jADXECAD.14017 at iTranscribed locus 0.0528

1058 ADXEC.2751.Cl_at jHomo sapiens ras homolog gene family member G (rho G) (RHOG) RHOG 0.0047

1059 ADXEC.24741.C1 at jCDNA FU42263 fis clone TKIDN2014570 0.0099

1060 ADXEC.23021.C2_at PARK2 co-regulated-like jPACRGL 0.014

1061 ADXEC.22249.C1 x at Homo sapiens mediator complex subunit 6 (MED6) mRNA. |MED6 0.0179

1062ijADXEC.8815.Cl_s_at Homo sapiens LIM domain containing preferred translocation partner jLPP s 0.0228!

1063 |ADXEC.3268.Cl_at Homo sapiens ASF1 anti-silencing function 1 homolog B (S. [ASFIB [ 0.02331

1064ijADXEC.29681.Cl at jHuman DNA sequence from clone RP1-65J11 on chromosome 1 Contains the 5 ILOC100288670| 0.0245!

iendof the

1065 jADXEC.2002.C8_x _at ijHomo sapiens major facilitator superfamily domain containing 7 |MFSD7 0.0268s

1066 jADXECNTDJ.3207_ at ijHomo sapiens genomic DNA chromosome 11 clone:RPll-856B14. [PCNXL3 0.0289!

1067 UDXEC.1852.Cl-a s at ijHomo sapiens CCR4-NOT transcription complex subunit 6 (CNOT6) |CN0T6 0.0292!

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

1184 jADXEC.6317.Cl_at Homo sapiens thioredoxin-related transmembrane protein 4 (TMX4) |TMX4 0.0203

1185 lADXEC.13567.Cl s at Homo sapiens choline kinase beta (CHKB) mRNA. [CHKB 0.0246

1186 ADXECRS.1245_s_at iiHomo sapiens zinc finger protein 805 (ZNF805) transcript variant |ZNF805 0.0265

1187 ADXECAD.28179 s at iiHomo sapiens TGF-beta activated kinase 1/MAP3K7 binding protein 2 |ΤΑΒ2 0.0287

1188 ADXEC.5808.Cl_s_at iHomo sapiens p21 protein (Cdc42/Rac)-activated kinase 2 (PAK2) PAK2 0.0331

1189 ADXEC.1890.Cl_at iTranscribed locus 0.0467

11190 ADXEC.30931.C1 x at iHuman chromosome 14 DNA sequence BAC R-639F2 of library RPCI 0.0511

ifromchromosome 1

1191 ADXECRS.10622_s_at iPREDICTED: Homo sapiens hypothetical LOC100128994 (LOC100128994) |LOC100128994| 0.0511

1192 ADXECAD.14508 at jChromosome 2 open reading frame 49 |c2orf49 [ 0.0539

193 3362762 at 0.0024

ADXEC.4957.C1 s at iiHomo sapiens GM2 ganglioside activator (GM2A) transcript variant |GM2A 0.0149

11195 ADXECADA.1623_s_at iiSMGl homolog phosphatidylinositol 3-kinase-related kinase pseudogene !LOC100271836 0.0226

1196 lADXEC.33122.Cl-a s at iZinc finger CCHC domain containing 6 |ZCCHC6 0.0255

11197 ADXEC.1517.C2_s_at iHomo sapiens solute carrier family 25 (mitochondrial carrier; sLC25All 0.0308;

1198 ADXECAD.19905 at Homo sapiens chromosome 8 clone XX-36G5 map 8p23 complete sequence. 0.0335!

1199 ADXEC.2481.Cl_at Homo sapiens RNA binding motif protein 28 (RBM28) transcript |RBM28 0.0518s

1200 ADXECEMUTR.5434 s at iHomo sapiens galactose-l-phosphate uridyl transferase (GALT) gene !GALT 0.0041!

icompletecds.

1201 ADXECRS.6935_x_at PREDICTED: Homo sapiens hypothetical LOC730235 (LOC730235) |LOC730235 0.0063 s

1202 ADXECNTDJ.789 s at Homo sapiens sulfatase modifying factor 2 (SUMF2) transcript !SUMF2 0.0263!

1203;iADXECADA.7794_x_at iTranscribed locus 0.0289s

1204iiADXEC.14840.Cl at iHomo sapiens phospholipase C beta 2 (PLCB2) mRNA. iPLCB2 0.0347!

1205 ;ADXEC.9701.Cl_at iiTranscribed locus 0.0393s

:1206;iADXEC.19638.Cl at iiHomo sapiens osteopetrosis associated transmembrane protein 1 iOSTMl 0.0462!

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

1207 !ADXECAD.16985_s_at iHomo sapiens proliferation-associated 2G4 38kDa (PA2G4) mRNA. |PA2G4 0.048

1208 lADXECAD.6191 X at iHomo sapiens NFKB inhibitor interacting Ras-like 1 (NKIRAS1) gene !N KIRASI 0.0488

jcompletecds.

1209 iADXECEMUTR.1246_. _at iiSel-1 suppressor of lin-12-like (C. elegans) jSELlL 0.0492

1210 kDXEC.7696.Cl-a s at iiHomo sapiens syntaxin 12 (STX12) mRNA. iSTX12 0.0506

11211 ADXEC.15989.Cl_x_at Homo sapiens mRNA for KIAA1652 protein partial cds. |KIAA1652 0.0542;

1212 ADXEC.1690.C5 s at Homo sapiens guanine nucleotide binding protein (G protein) beta !GN BI 0.0021!

1213 IADXEC.23256.C1_ _.at Homo sapiens syntaxin 8 (STX8) transcript variant 1 mRNA. |STX8 0.0039s

1214 !ADXEC.25945.C1 at Homo sapiens hypothetical LOC283267 (LOC283267) non-coding RNA. !LOC283267 0.0056!

1215 ADXEC.633.Cl_x_at iHomo sapiens WD repeat domain 1 (WDRl) transcript variant 1 mRNA. jWD l 0.0084s

/ 216 ADXEC.5841.C2 x at iSimilar to Serine/threonine-protein kinase PRKX (Protein kinase PKXl) !L.OC389906 0.0157!

_.217;;ADXECAD.3273_x_at 15247201 mRNA 0.0186

1218iiADXECEMUTR.898 at iiHomo sapiens anterior pharynx defective 1 homolog B (C. elegans) jAPHIB 0.0195

1219 ADXECADA.18476_x_at Homo sapiens chromosome 3 clone RP11-949J7 complete sequence. |LOC100289156 0.0196

1220 ADXEC.8002.C1 x at Homo sapiens scavenger receptor class F member 1 (SCARF1) sCARFl 0.023

1221 ADXEC.20154.C2_x_at iTranscribed locus 0.0264

1222 ADXEC.10033.Cl-a s at iHomo sapiens ankyrin repeat domain 36 (ANKRD36) mRNA. |ANKRD36 0.0264

1223 |ADXECRS.4234_s_. _at iHomo sapiens CAP adenylate cyclase-associated protein 1 (yeast) jCAPl 0.0265

1224 iADXECAD.18258 at iHuman DNA sequence from clone RP11-61K9 on chromosome 13 Contains |LOC400099 0.0366

itheZNF237 gene

1225 ADXEC.2435.C10_s_at Homo sapiens FK506 binding protein 1A 12kDa (FKBP1A) transcript jFKBPlA 0.0377

1226 ADXECADA.22533 at Homo sapiens trafficking protein particle complex 9 (TRAPPC9) |TRAPPC9 0.0386

1227iiADXEC.13730.Cl_at i;5-nucleotidase cytosolic II |NT5C2 0.0415;

1228 ADXECAD.9888_x_at iiHomo sapiens Rho-associated coiled-coil containing protein kinase |ROCKI 0.042!

1229 iADXEC.13354.Cl-a s at iiHomo sapiens SDA1 domain containing 1 (SDAD1) mRNA. ^SDADl 0.0442!

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

:1394ijADXEC.4846.C3-a_s_at Homo sapiens TATA box binding protein (TBP)-associated factor RNA iTAFlC 0.047

1395 IADXECADA.2601 x at Homo sapiens full length insert cDNA YR39D03. 0.0492

1396 ADXEC.25691.C2_at iiRing finger protein 144B RNF144B 0.05

1397 lADXEC.3724.Cl-a s at iiHomo sapiens pallidin homolog (mouse) (PLDN) mRNA. PLDN 0.0536

1398 iADXEC.34927.Cl_ _.at [Transcribed locus 0.0539;

1399 UDXEC.12953.C1 at iHomo sapiens genomic DNA chromosome 21q section 97/105. 21orf32 0.0008!

1400 ADXEC.9209.Cl_x_at iHomo sapiens cardiotrophin 1 (CTF1) transcript variant 1 mRNA. cTFl 0.0038s

1401 ADXEC.6963.C1 x at iCut-like homeobox 1 jCUXl 0.0046!

1402 ADXEC.24924.Cl_at Homo sapiens mRNA for leucyl/cystinyl aminopeptidase variant protein. [LN PEP 0.0095s

1403 ADXEC.1253.C2 s at Homo sapiens solute carrier family 37 (glycerol-3-phosphate |SLC37A1 0.0128!

; ^'".404 ADXEC.11961.Cl_at i|Homo sapiens aquarius homolog (mouse) (AQR) mRNA. [AQR 0.018

1405 IADXEC.27232.C1 s at iiHomo sapiens RNA guanylyltransferase and 5-phosphatase (RNGTT) jRNGTT 0.0206

1406 ADXECADA.1528_s_at Homo sapiens cyclin J (CCNJ) transcript variant 3 mRNA. !CCNJ 0.0207

1407 ADXECAD.17583 at Homo sapiens zinc finger protein 154 (ZNF154) mRNA. |ZNF154 0.0225

1408 ADXECAD.4765_x_at iLIM and senescent cell antigen-like domains 1 jLIMSl 0.0267

1409 ADXEC.3915.C1 at iSadl and UNC84 domain containing 1 sUNl 0.0297

1410 ADXEC.3168.Cl_at Transcribed locus 0.0336

1411 ADXEC.20369.C1 x at iHomo sapiens zinc finger protein 296 (ZNF296) mRNA. IZNF296 0.0466

1412 ADXEC.9945.C9_x_at Transcribed locus 0.049

1413 ADXEC.6.C64 x at iHomo sapiens NODI protein (NODI) gene exons 4 through 14 and complete NODI 0.0494

icds.

1414 ;ADXEC.1770.Cl-a_ at iiHomo sapiens disabled homolog 2 mitogen-responsive phosphoprotein DAB2 0.0118

1415 iADXECADA.17719 at 15296329 0.0129

1416 |ADXECRS.25333_s_at iiHomo sapiens WW domain containing adaptor with coiled-coil (WAC) jWAC 0.016!

1417 iADXECAD.10768 s at iiHomo sapiens phosphatidylinositol binding clathrin assembly protein IPICALM 0.0184!

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

1516 !ADXECAD.16634_at Homo sapiens biorientation of chromosomes in cell division 1-like jBODlL 0.0056

1517 lADXEC.33040.Cl x at Homo sapiens KIAA1161 (KIAA1161) mRNA. |ΚΙΑΑ1161 0.0202

1518 ADXECADA.4929_s_at iiHomo sapiens male-specific lethal 1 homolog (Drosophila) (MSL1) MSL1 0.0251

1519 ADXEC.11994.C2 s at iiHomo sapiens protein phosphatase 1 regulatory (inhibitor) subunit PPP1R8 0.0294

1520 ADXECRS.530_s_at PREDICTED: Homo sapiens hypothetical protein LOC100129677 |LOC100129677 0.032;

1521 ADXECRS.37691 x at Homo sapiens ovochymase 1 (OVCH1) mRNA. !OVCHI 0.0322!

1522 ADXEC.5650.Cl-a_s_at Homo sapiens iduronate 2-sulfatase (IDS) transcript variant 1 IDS 0.0393 s

1523 ADXEC.28670.C1 s at Homo sapiens NOP2/Sun domain family member 3 (NSUN3) mRNA. |NSUN3 0.0405!

1524 ;ADXECADA.4045_ _at jHomo sapiens TNF receptor-associated factor 5 (TRAF5) transcript |TRAF5 0.0427s

1525 !ADXEC.26102.C1 at Transcribed locus 0.0449!

£ ~.526jiADXEC.14515.Cl_at iiHomo sapiens erythrocyte membrane protein band 4.1-like 1 |EPB41L1 0.0528

I527:;ADXEC.10542.C1 s at iiCoiled-coil domain containing 88A !CCDC88A 0.0056

1528 ADXEC.5270.Cl_s_at Homo sapiens trans-golgi network protein 2 (TGOLN2) mRNA. |TGOLN2 0.0132

1529 ADXEC.19265.C1 s at Homo sapiens zinc finger DHHC-type containing 2 (ZDHHC2) mRNA. [ZDHHC2 0.0162

11530 ADXECAD.14031_at jNeuroblastoma amplified sequence IN BAS 0.0166

1531 ADXECADA.11791_x_at jhypothetical protein partial [Macaca mulatta] 0.0167

1532 ADXEC.31072.C1 at iHuman hereditary haemochromatosis region histone 2A-like protein iTRIM38 0.0178

igenehereditary

1533 ADXECAD.5572_at jSyntaxin 8 |STX8 0.0182s

1534 Adx-200073-up_s_at iheterogeneous nuclear ribonucleoprotein D (AU-rich element RNA binding !HN RNPD 0.0207!

iprotein 1

1535jiADXEC.24718.Cl_s_at iiHomo sapiens HRIHFB2017 mRNA partial cds. |BMP2K 0.0277

1536iiADXOCEC.15602.Cl at iiHomo sapiens chromosome 19 clone CTC-450M9 complete sequence. !SIPA1L3 0.0346

1537 ;2775487_at 0.0358s

1538 lADXECAD.13345 s at iiTranscribed locus 0.0374!

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

1564 jADXEC.16201.Cl_at Homo sapiens ubiquitin protein ligase E3 component n-recognin 2 |UBR2 0.0341

1565 lADXEC.15255.Cl at PREDICTED: Homo sapiens hypothetical protein LOC100289224 |LOC100289224 0.0346

1566 ADXECRS.241_s_at iiHomo sapiens isoprenoid synthase domain containing (ISPD) ISPD 0.0359

1567 lADXEC.11385.Cl S at !PREDICTED: Homo sapiens similar to mCG115122 (LOC100129361) mRNA. LOC100129361 0.0459

1568 ADXEC.15096.Cl_x_at Homo sapiens H2K binding factor 2 (KBF2) mRNA complete cds. jRBPJ 0.0519;

1569 ADXEC.2294.C1 x at Homo sapiens Rho GDP dissociation inhibitor (GDI) beta (ARHGDIB) IARHGDI B 0.0087!

1570 ADXEC.23922.C2_x_at Homo sapiens zinc finger protein 431 (ZNF431) mRNA. |ZNF431 0.009 s

1571 ADXEC.2424.C1 s at Homo sapiens stress-associated endoplasmic reticulum protein 1 ISERPl 0.0141!

1572 ADXEC.4522.Cl_s_at Homo sapiens fuzzy homolog (Drosophila) (FUZ) transcript variant |FUZ 0.016s

1573 ADXEC.3894.C1 at Homo sapiens SH3-domain GRB2-like endophilin Bl (SH3GLB1) mRNA. !SH3GLB1 0.0238!

~.574;;ADXEC.1357.CBl_x_at i|Homo sapiens tyrosine 3-monooxygenase/tryptophan 5-monooxygenase A/VHAZ 0.0434

l575iiADXEC.673.C16 x at iiHomo sapiens ferritin light polypeptide (FTL) mRNA. IFTL 0.0451

1576 ADXECAD.1302_s_at Homo sapiens adenylate cyclase 7 (ADCY7) mRNA. |ADCY7 0.0464

1577 ADXECADA.20635 s at Homo sapiens myocyte enhancer factor 2A (MEF2A) transcript variant lV1EF2A 0.054

1578 ADXECNTDJ.958_s_at jHomo sapiens BRF1 homolog subunit of RNA polymerase jBRFl 0.0037

1579 ADXOCEC.11956.C1- jHomo sapiens genomic region containing hypervariable LRRC27 0.0117

a s at jminisatelliteschromosome 10

1580 |ADXEC.2060.C1. _.at PREDICTED: Homo sapiens hypothetical LOC644794 (LOC644794) mRNA. |LOC644794 0.0266

1581 !ADXEC.7849.C1 at Homo sapiens kinesin family member 5B (KIF5B) mRNA. |KIF5B 0.0283

1582i|ADXEC.12048.Cl-a_s_at Transcribed locus 0.0344

1583 !ADXEC.6911.C2_s_at jHomo sapiens protein kinase N2 (PKN2) mRNA. |PKN2 ! 0.035

1584 IADXECRS.5108 x at iHuman DNA sequence from clone RP4-758J18 on chromosome lp36.31- ILOC100288271| 0.036

;36.33Contains the

: 1585 ijADXECADA.1143_at 13883659 mRNA 0.0367s

1586 iADXECRS.32618 at iisimilar to C/EBP-induced protein [Monodelphis domestical 0.0388!

Fold-Chan m Probe ID Gene Name Gene Symbol p-value

Cavl Positi

1658 jADXEC.2197.Cl_at Homo sapiens family with sequence similarity 108 member Al |FAM108A1 0.0155

1659 !ADXECRS.15841_s_at Homo sapiens radial spoke head 10 homolog B2 (Chlamydomonas) |RSPH10B2 0.0215

1660 iAdx-200055-up_s_at iTAFlO RNA polymerase II TATA box binding protein (TBP)-associated factor H^"AF10 0.0239

okDa

1661 ADXECRS.26052_s_at iChromosome 14 open reading frame 81 jC14orf81 0.0264

1662 ADXECAD.23938 s at iHomo sapiens formyl peptide receptor 2 (FPR2) transcript variant !FPR2 0.0277

1663 ADXECNTDJ.9604_at 0.0291

1664 ADXEC.13397.C1 s at Homo sapiens myeloid leukemia factor 1 (MLFl) transcript variant IMLF1 0.0372

1665 3551874_at 0.0388

1666 ADXECADA.790 s at iHomo sapiens zygote arrest 1 (ZAR1) mRNA. jZARl 0.0403

667 ADXEC.22481.Cl_s_at Transcribed locus 0.0404

..668 ADXEC.28238.C1 at ijHomo sapiens NK2 homeobox 2 (NKX2-2) mRNA. NKX2-2 0.0428

1669 ADXEC.4918.Cl_at iiHomo sapiens N-acetyltransferase 15 (GCN5-related putative) NAT15 0.0445

1670 lADXEC.2340.Cl-a s at Homo sapiens mediator complex subunit 29 (MED29) mRNA. |MED29 0.0469

11671 ADXECRS.13131_at Homo sapiens baculoviral IAP repeat-containing 5 (BIRC5) iBIRC5 0.0486;

1672 ADXEC.8137.C1 x at LUC7-like 2 (S. cerevisiae) |LUC7L2 0.0491!

1673 ADXECRS.8473_at Homo sapiens glyceraldehyde-3-phosphate dehydrogenase GAPDHS 0.0016s

1674 ADXEC.3578.C2 at Homo sapiens haplogroup Tla mitochondrion complete genome. 0.0171!

1675 iADXEC.17731.Cl_ .at Homo sapiens transmembrane protein 90A (TMEM90A) mRNA. ITMEM90A 0.0201s

1676 iADXEC.29873.Cl at Transcribed locus 0.0212!

1677;;ADXECAD.12808_at jProtein tyrosine phosphatase non-receptor type 1 IPTPNI 0.0239

1678iiADXEC.18978.Cl at iiTranscribed locus 0.0284

1679 ;ADXEC.19816.Cl_x_at iiHomo sapiens carbohydrate (N-acetylgalactosamine 4-0) |CHST9 0.0296s

1680 iADXECAD.5585_at iiHomo sapiens kinesin light chain 3 (KLC3) mRNA. [KLC3 0.0366!

1681 !ADXOCEC.6950.C1 x at iiHomo sapiens v-rel reticuloendotheliosis viral oncogene homolog IREL 0.0396!

Claims

I/We Claim:

1. A prognostic signature (also referred to herein as a biological marker or biomarker) for assessing cancer prognosis in a subject (e.g., risk of cancer recurrence, progression of a cancer in a cancer subject, overall survival of cancer by a cancer patient), said prognostic signature comprising a tumor/cancer stromal signature, wherein the tumor/stromal stromal signature is derived from a genome-wide transcriptional profiling of a tumor/cancer stromal material derived from a biological sample obtained from a set of at least one or more subjects having cancer, said tumor stromal signature comprising a first set of gene transcripts that is up-regulated in the tumor/cancer stromal material and/or a second set of gene transcripts that is down-regulated in the tumor stromal material.

3. The prognostic signature of claim 1, wherein said tumor stromal signature comprises at least a set of one or more gene transcripts up-regulated in Cav-1 deficient tumor/cancer stroma, the up-regulated gene trascripts having gene names and/or gene symbols listed in Supplemental Tables 1 , 3 or combintinations thereof. 4. The prognostic signature of claim 1, wherein said tumor stromal signature comprises at least a set of one or more gene transcripts down-regulated in Cav-1 deficient tumor/cacner stroma, the down-regulated gene trascripts having gene names and/or gene symbols listed in Supplemental Tables 1 , 3 or combintinations thereof.

5. The prognostic signature of claim 1, wherein said tumor stromal signature comprises at least a first set of one or more gene transcripts up-regulated in Cav-1 deficient tumor/cancer stroma and a second set of one or more gene transcripts down-regulated in Cav-1 deficient tumor/cancer stroma, wherein the first set of one or more gene transcripts and the second set of one or more gene transcripts are selected from the group consisting of the gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combintinations thereof. 6. The prognostic signature of claim 1, wherein the tumor/cancer stromal material is derived from a Cav-1 -deficient cancer tumor stroma.

7. The prognostic signature of claim 1, wherein the tumor/cancer stromal material is derived from a Cav-1 positive cancer tumor stroma.

8. The prognostic signature of claim 1, wherein the tumor/cancer stromal material is derived from a breast cancer tumor stroma.

9. The prognostic signature of claim 1, wherein the tumor/cancer stromal material is derived from a Cav-1 -deficient breast cancer tumor stroma.

10. The prognostic signature of claim of claim 9, wherein said tumor/cancer stromal material signature comprising a first set of gene transcripts that is up-regulated in the tumor/cancer stromal material.

11. The prognostic signature of claim of claim 9, wherein said tumor/cancer stromal material signature comprising a first set of gene transcripts that is down-regulated in the tumor/cancer stromal material.

12. The prognostic signature of claim 1, wherein the tumor/cancer stromal material is derived from a Cav-1 -deficient breast cancer tumor stroma, and wherein the tumor/cancer stromal signature comprises the first set of up-regulated gene transcripts, wherein the first set of up- regulated gene transcripts comprises at least a set of one or more gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3 or combintinations thereof.

13. The prognostic signature of claim of claim 6, wherein said tumor/cancer stromal material signature comprises a first set of gene transcripts up-regulated in the tumor/cancer stromal material, wherein the first set of up-regulated gene transcripts comprises at least a set of one or more gene transcripts having gene names and/or gene symbols selected from the group consisting of: LOC100293390, RNF217, PGBD2, LACTB, TRIT1, RNF217, LOC654433, DFFA,

DNAJC5, ZNF365, ZNF365, MDN1, ERG, CTSB, SGSM3, MYL5, HLA-Z, IKZF1, C15orf23, CD84, C21orf7, VPS26B, SUFU, MSH6, S1PR3, FCGR2B, BCL2L11, RFC 5, RAB3D, LOC100128943, PSMB9, GALNT11, APOC2, ISM2, PMS2CL, RDBP, GSPT2, NOD2, USP6NL, TAF13, H2AFX, CD53, CYP3A5, HLA-Z, DCAF8, CTTNBP2NL, ISM2, KCTD20, HMMR, RYR1, METTL3, BCAT1, GSPT1, MGC27345, PGPEP1, TFEB, POLG2, RBM33, LOC80054, FABP3, GCA, FANCC, RPUSD4, C21orf7, ZNF609, SAMHD1, NFATC2, SERPINB8, CYP4F11, LOC728613, SNRK, LOC80054, SLC8A1, VMOl, IL28RA,

LOC100288109, APITD1, TRIP6, TMEM165, TBXAS1, KLHL12, LY86, KLF3, WHSC1, ZBTB46, SNRK, MLL2, KCNJ13, THGIL, CYP4V2, SLC23A2, OGFRLl, SLC02B1, PTPNl, ALOX5AP, MORC2, ABCD1P4, UCK2, TMED5, FCGR2C, FAM185A, PHF20L1, EPB41L3, LARP4B, DHRSX, PDPK1, APEX2, CTSB, MRPL9, LOCI 00293165, Clorfl04, STX7, GFI1, AP4E1, ARHGAP5, C14orfl06, SUDS3, BAT2L1, BCAS3, LMF2, INTS4, FCGR2A,

ADAM 10, CCZ1, RANBP9, MATR3, SENP5, PPIL2, THNSL1, DNHD1 , RBMS2, SYMPK, DNASE1, FCGR2A, KIFC2, TTC17, PDPK1, BCL2L13, MFSD7, ETF1, REEP4, TMEM165, MRPL9, HAUS2, ADAP2, ILIRAP, PARVG, C14orfl l8, ATXNl, PDE7A, DENND4B, ZNF502, Clorf77, OPA3, TNP03, KIF1B, RNASE1, ANXA11, FAM84A, C6orf26, CLTC, AMZ2, TYROBP, IFNGR2, RIOK2, C17orf63, GPBAR1, ZNF639, TBRG4, SKP2, PHKA2, SERP1, CENPC1, MICALCL, RHOG, PDE4DIP, KIAA1147, UBAP1, C20orf7, SRRT, BTN3A2, DCP2, MIR1302-3, UFM1, PDPR, DNMT1, SMC2, GALT, LOC730235, STX8, GNB1, LOC283267, WDR1, BACH1, AGFG1, PIAS1, SNX6, ROCK1, EIF2AK1, UBXN11, APAF1, TFiNSLl, and combinations thereof.

14. The prognostic signature of claim of claim 9, wherein said tumor/cancer stromal material signature comprising a first set of gene transcripts that is down-regulated in the tumor stromal material, and wherein the tumor/cancer stromal signature comprises the first set of up-regulated gene transcripts, wherein the first set of up-regulated gene transcripts comprises at least a set of one or more genes having gene names and/or gene symbols selected from the group consisting of: LOC100293390, RNF217, PGBD2, LACTB, TRIT1, RNF217, LOC654433, DFFA,

DNAJC5, ZNF365, ZNF365, MDNl, ERG, CTSB, SGSM3, MYL5, HLA-Z, IKZFl, C15orf23, CD84, C21orf7, VPS26B, SUFU, MSH6, S1PR3, FCGR2B, BCL2L11, RFC 5, RAB3D, LOC100128943, PSMB9, GALNT11, APOC2, ISM2, PMS2CL, RDBP, GSPT2, NOD2, USP6NL, TAF13, H2AFX, CD53, CYP3A5, HLA-Z, DCAF8, CTTNBP2NL, ISM2, KCTD20, HMMR, RYR1, METTL3, BCAT1, GSPT1, MGC27345, PGPEP1, TFEB, POLG2, RBM33, LOC80054, FABP3, GCA, FANCC, RPUSD4, C21orf7, ZNF609, SAMHD1, NFATC2, SERPINB8, CYP4F11, LOC728613, SNRK, LOC80054, SLC8A1, VMOl, IL28RA,

ADAM 10, CCZ1, RANBP9, MATR3, SENP5, PPIL2, THNSLl, DNHD1 , RBMS2, SYMPK, DNASE1, FCGR2A, KIFC2, TTC17, PDPKl, BCL2L13, MFSD7, ETF1, REEP4, TMEM165, MRPL9, HAUS2, ADAP2, ILIRAP, PARVG, C14orfl l8, ATXNl, PDE7A, DENND4B, ZNF502, Clorf77, OPA3, TNP03, KIF1B, RNASEl, ANXAl l, FAM84A, C6orf26, CLTC, AMZ2, TYROBP, IFNGR2, RIOK2, C17orf63, GPBAR1, ZNF639, TBRG4, SKP2, PHKA2, SERP1, CENPC1, MICALCL, RHOG, PDE4DIP, KIAA1147, UBAP1, C20orf7, SRRT, BTN3A2, DCP2, MIR1302-3, UFM1, PDPR, DNMT1, SMC2, GALT, LOC730235, STX8, GNB1, LOC283267, WDR1, BACH1, AGFG1, PIAS1, SNX6, ROCK1, EIF2AK1, UBXN11, APAF1, THNSL1, and combinations thereof.

15. The prognostic signature of claim 1, wherein the tumor stromal material is derived from a Cav-1 -deficient breast cancer tumor stroma, and wherein the tumor stromal signature comprises the first set of down-regulated gene transcripts, wherein the first set of down-regulated gene transcripts comprises at least a set of one or more genes having gene names and/or gene symbols selected from the group consisting of: LOC 100293390, RNF217, PGBD2, LACTB, TRIT 1 , RNF217, LOC654433, DFFA, DNAJC5, ZNF365, ZNF365, MDN1, ERG, CTSB, SGSM3, MYL5, HLA-Z, IKZF1, C15orf23, CD84, C21orf7, VPS26B, SUFU, MSH6, S1PR3, FCGR2B, BCL2L11, RFC5, RAB3D, LOC100128943, PSMB9, GALNT11, APOC2, ISM2, PMS2CL, RDBP, GSPT2, NOD2, USP6NL, TAF13, H2AFX, CD53, CYP3A5, HLA-Z, DCAF8,

CTTNBP2NL, ISM2, KCTD20, HMMR, RYR1, METTL3, BCAT1, GSPT1, MGC27345, PGPEP1, TFEB, POLG2, RBM33, LOC80054, FABP3, GCA, FANCC, RPUSD4, C21orf7, ZNF609, SAMHD1, NFATC2, SERPINB8, CYP4F11, LOC728613, SNRK, LOC80054, SLC8A1, VMOl, IL28RA, LOC100288109, APITD1, TRIP6, TMEM165, TBXAS1, KLHL12, LY86, KLF3, WHSC1, ZBTB46, SNRK, MLL2, KCNJ13, THG1L, CYP4V2, SLC23A2, OGFRL1, SLC02B1, PTPN1, ALOX5AP, MORC2, ABCD1P4, UCK2, TMED5, FCGR2C, FAM185A, PHF20L1, EPB41L3, LARP4B, DHRSX, PDPKl, APEX2, CTSB, MRPL9, LOC100293165, Clorfl04, STX7, GFI1, AP4E1, ARHGAP5, C14orfl06, SUDS3, BAT2L1, BCAS3, LMF2, INTS4, FCGR2A, ADAM 10, CCZ1, RANBP9, MATR3, SENP5, PPIL2, THNSLl, DNHDl, RBMS2, SYMPK, DNASEl, FCGR2A, KIFC2, TTC17, PDPKl, BCL2L13, MFSD7, ETF1, REEP4, TMEM165, MRPL9, HAUS2, ADAP2, IL1RAP, PARVG, C14orfl 18, ATXN1, PDE7A, DENND4B, ZNF502, Clorf77, OP A3, TNP03, KIF1B, RNASE1, ANXAl l, FAM84A, C6orf26, CLTC, AMZ2, TYROBP, IFNGR2, RIOK2, C17orf63, GPBAR1, ZNF639, TBRG4, SKP2, PHKA2, SERPl , CENPCl, MICALCL, RHOG, PDE4DIP, KIAA1147, UBAPl, C20orf7, SRRT, BTN3A2, DCP2, MIR1302-3, UFM1, PDPR, DNMT1, SMC2, GALT,

LOC730235, STX8, GNB1, LOC283267, WDR1, BACH1, AGFG1, PIAS 1, SNX6, ROCK1, EIF2AK1, UBXN11, APAF1, THNSLl, and combinations thereof.

16. The prognostic signature of claim of claim 9, wherein said tumor/cancer stromal material signature comprising a first set of gene transcripts that is up-regulated in the tumor stromal material, and wherein the tumor stromal signature comprises the first set of down-regulated gene transcripts, wherein the first set of down-regulated gene transcripts comprises at least a set of one or more genes having gene names and/or gene symbols selected from the group consisting of: LOC100293390, RNF217, PGBD2, LACTB, TRIT1, RNF217, LOC654433, DFFA, DNAJC5, ZNF365, ZNF365, MDN1, ERG, CTSB, SGSM3, MYL5, HLA-Z, IKZF1, C15orf23, CD84, C21orf7, VPS26B, SUFU, MSH6, S1PR3, FCGR2B, BCL2L11, RFC5, RAB3D, LOC100128943, PSMB9, GALNT11, APOC2, ISM2, PMS2CL, RDBP, GSPT2, NOD2, USP6NL, TAF13, H2AFX, CD53, CYP3A5, HLA-Z, DCAF8, CTTNBP2NL, ISM2, KCTD20, HMMR, RYR1, METTL3, BCAT1, GSPT1, MGC27345, PGPEP1, TFEB, POLG2, RBM33, LOC80054, FABP3, GCA, FANCC, RPUSD4, C21orf7, ZNF609, SAMHD1, NFATC2, SERPINB8, CYP4F11, LOC728613, SNRK, LOC80054, SLC8A1, VMOl, IL28RA,

ADAM 10, CCZ1, RANBP9, MATR3, SENP5, PPIL2, THNSL1, DNHD1 , RBMS2, SYMPK, DNASE1, FCGR2A, KIFC2, TTC17, PDPK1, BCL2L13, MFSD7, ETF1, REEP4, TMEM165, MRPL9, HAUS2, ADAP2, IL1RAP, PARVG, C14orfl l8, ATXN1, PDE7A, DENND4B, ZNF502, Clorf77, OPA3, TNP03, KIF1B, RNASEl, ANXAl l, FAM84A, C6orf26, CLTC, AMZ2, TYROBP, IFNGR2, RIOK2, C17orf63, GPBAR1, ZNF639, TBRG4, SKP2, PHKA2, SERP1, CENPC1, MICALCL, RHOG, PDE4DIP, KIAA1147, UBAP1, C20orf7, SRRT, BTN3A2, DCP2, MIR1302-3, UFM1, PDPR, DNMT1, SMC2, GALT, LOC730235, STX8, GNB1, LOC283267, WDR1, BACH1, AGFG1, PIAS1, SNX6, ROCK1, EIF2AK1, UBXN11, APAF1, THNSL1, and combinations thereof. 17. The prognostic signature of claim of claim 9, wherein said tumor/cancer stromal material signature comprising a first set of gene transcripts that is down-regulated in the tumor stromal material, and wherein the tumor/cancer stromal signature comprises the first set of down- regulated gene transcripts, wherein the first set of down-regulated gene transcripts comprises at least a set of one or more genes having gene names and/or gene symbols selected from the group consisting of: LOC100293390, RNF217, PGBD2, LACTB, TRIT1, RNF217, LOC654433, DFFA, DNAJC5, ZNF365, ZNF365, MDN1, ERG, CTSB, SGSM3, MYL5, HLA-Z, IKZF1, C15orf23, CD84, C21orf7, VPS26B, SUFU, MSH6, S1PR3, FCGR2B, BCL2L11, RFC5, RAB3D, LOC100128943, PSMB9, GALNT11, APOC2, ISM2, PMS2CL, RDBP, GSPT2, NOD2, USP6NL, TAF13, H2AFX, CD53, CYP3A5, HLA-Z, DCAF8, CTTNBP2NL, ISM2, KCTD20, HMMR, RYR1, METTL3, BCAT1, GSPT1, MGC27345, PGPEP1, TFEB, POLG2, RBM33, LOC80054, FABP3, GCA, FANCC, RPUSD4, C21orf7, ZNF609, SAMHD1,

NFATC2, SERPINB8, CYP4F11, LOC728613, SNRK, LOC80054, SLC8A1, VMOl, IL28RA, LOC100288109, APITD1, TRIP6, TMEM165, TBXASl, KLHL12, LY86, KLF3, WHSC1, ZBTB46, SNRK, MLL2, KCNJ13, THGIL, CYP4V2, SLC23A2, OGFRLl, SLC02B1, PTPNl, ALOX5AP, MORC2, ABCD1P4, UCK2, TMED5, FCGR2C, FAM185A, PHF20L1, EPB41L3, LARP4B, DHRSX, PDPKl, APEX2, CTSB, MRPL9, LOCI 00293165, Clorfl04, STX7, GFIl, AP4E1, ARHGAP5, C14orfl06, SUDS3, BAT2L1, BCAS3, LMF2, INTS4, FCGR2A,

ADAM 10, CCZ1, RANBP9, MATR3, SENP5, PPIL2, THNSL1, DNHD1 , RBMS2, SYMPK, DNASE1, FCGR2A, KIFC2, TTC17, PDPKl, BCL2L13, MFSD7, ETF1, REEP4, TMEM165, MRPL9, HAUS2, ADAP2, IL1RAP, PARVG, C14orfl l8, ATXN1, PDE7A, DE ND4B, ZNF502, Clorf77, OPA3, TNP03, KIF1B, RNASE1, ANXAl l, FAM84A, C6orf26, CLTC, AMZ2, TYROBP, IFNGR2, RIOK2, C17orf63, GPBAR1, ZNF639, TBRG4, SKP2, PHKA2, SERP1, CENPC1, MICALCL, RHOG, PDE4DIP, KIAA1147, UBAP1, C20orf7, SRRT, BTN3A2, DCP2, MIR1302-3, UFM1, PDPR, DNMT1, SMC2, GALT, LOC730235, STX8, GNB1, LOC283267, WDR1, BACH1, AGFG1, PIAS1, SNX6, ROCK1, EIF2AK1, UBXN11, APAF1, THNSL1, and combinations thereof.

18. The prognostic signature of claim 1, wherein the tumor/cancer stromal material is derived from a Cav-1 positive breast cancer tumor stroma. 19. The prognostic signature of claim 1, wherein the tumor/cancer stromal material is derived from a breast cancer stroma, wherein the breast cancer stroma is in turn derived from a breast cancer of a subtype selected from the group consisting of ER positive (or ER(+) ), ER negative (or ER(-), and HER2 positive (or HER2(+)).

20. The prognostic signature of claim 1, wherein the tumor/cancer stromal material is derived from a Cav-1 -deficient cancer tumor stroma, and wherein the cancer tumor/cancer stromal signature comprises the first set of gene transcripts up-regulated in the Cav-1 -deficient tumor stroma.

21. The prognostic signature of claim 1, wherein the tumor/cancer stromal material is derived from a Cav-1 -deficient cancer tumor stroma, and wherein the cancer tumor stromal signature comprises the second set of gene transcripts down-regulated in the Cav-1 -deficient tumor stroma.

22. The prognostic signature of claim 1, wherein the tumor/cancer stromal material is derived from a Cav-1 -positive cancer tumor stroma, and wherein the cancer tumor stromal signature comprises the first set of gene transcripts up-regulated in the Cav-1 -positive tumor stroma.

23. The prognostic signature of claim 1, wherein the tumor/cancer stromal material is derived from a Cav-1 -positive cancer tumor stroma, and wherein the cancer tumor stromal signature comprises the second set of gene transcripts down-regulated in the Cav-1 -positive tumor stroma.

24. The prognostic signature of claim 1, wherein the cancer tumor stromal signature comprises at least one or more sets of gene transcripts from the gene transcripts in Supplemental Table 1.

25. The prognostic signature of claim 8, wherein the Cav-1 -deficient tumor stromal signature comprises a set of at least one or more genes selected from the genes in Supplemental Table 1.

26. A method of assessing cancer prognosis, wherein the method comprises: (a) determining a genome-wide transcriptional profile of a first stromal material, wherein the first stromal material is derived from a biological sample obtained from a subject afflicted with cancer or suspected of having cancer; (b) comparing the genome-wide transcriptional profile (or a subgenome-transcriptional profile derived therefrom) to a Cav-1 -deficient tumor stromal signature, wherein the Cav-1 -deficient tumor stromal signature comprises a set of at least one or more genes selected from the genes in Supplemental Table 1, whereby an overlap of between the genome-wide transcriptional profile (or a subgenome-transcriptional profile derived therefrom) and the Cav-1 -deficient tumor stromal signature indicates a poor prognosis (increased risk of recurrence, decreased overall survival, increased risk of cancer progression).

27. A method of monitoring progression of breast cancer in a subject, the method comprising:

(a) obtaining a first sample from a subject at a first time point and a second sample from said subject at a second time point;

(b) determining a genome-wide transcriptional profile of said first and second samples; (c) comparing the genome-wide transcriptional profile (or a subgenome transcriptional profile derived therefrom) of said first sample to the genome-wide transcriptional profile (or a subgenome transcriptional profile derived therefrom) of said second sample; and

(d) thereafter, comparing any difference in transcriptional profile between the genome- wide transcriptional profile (or a subgenome transcriptional profile derived therefrom) of said first sample and the genome-wide transcriptional profile (or a subgenome transcriptional profile derived therefrom) of said second sample to a Cav-1 -deficient tumor stromal signature, wherein the Cav-1 -deficient tumor stromal signature comprises a set of at least one or more genes having gene names and/or gene symbols selected from Supplemental Tables 1, 3, 4, or combintinations thereof, whereby an overlap of from about 25% to about 75% is indicative of a poor clincial outcome (e.g., recurrence of the cancer in said subject, or decreased overall survival of the cancer by the subject, or is an indication that the cancer has progressed in said subject, or is an indication that the cancer has metastasized in said subject).

28. A method of stratifying a subject or a group of subjects having a cancer tumor for a clinical trial, comprising: (a) providing a stromal material, wherein the stromal material is derived from a biological sample obtained from the subject or each member of the group of subjects having a cancer tumor;

(b) determining a genome-wide transcriptional profile of the stromal material;

(c) comparing the genome-wide transcriptional profile (or a set of gene trascripts derived therefrom) of said stromal material to a Cav-1 -deficient tumor stromal signature, wherein the Cav-1 -deficient tumor stromal signature comprises a set of at least one or more gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combintinations thereof; and

(d) stratifying the subject for a clinical trial based on the results of the comparison step

(c). 29. A method of identifying a set of genes, expression of which is modulated by the status of stromal Cav-1 in a cancer tumor stroma, the method comprising:

(a) subjecting a first stromal material deficient in stromal Caveolin-1 (Cav-1) to a genome-wide transcriptional profiling to generate a first stromal transcriptional profile, wherein the first stromal material is derived from a biological sample obtained from a subject having cancer or suspected of having cancer;

(b) comparing the first stromal transcriptional profile to a second stromal transcriptional profile derived from a genome-wide transcriptional profiling of a second stromal material, wherein said second stromal material is Cav-1 -positive (+) (or Cav-1 -(+)); whereby a difference in gene expression patterns between the first stromal transcriptional profile and the second stromal transcriptional profile is indicative of a set of one or more genes that is differentially expressed in the stromal Cav-1 -deficient tumor relative to the stromal Cav-1 positive (+) tumor.

30. A method of stratifying a subject or a group of subjects having a cancer tumor for a clinical trial, comprising:

(a) providing a biological sample, wherein the biological sample is obtained from the subject or each member of the group of subjects having a cancer tumor; (b) determining a genome -wide transcriptional profile of the biological sample;

(c) comparing the genome-wide transcriptional profile (or a set of gene trascripts derived therefrom) of said biological sample to a Cav-1 -deficient tumor stromal signature, wherein the Cav-1 -deficient tumor stromal signature comprises a set of at least one or more gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combintinations thereof; and

(c).

31. The prognostic signature of claim 12, wherein the at least a set of one or more gene transcripts having gene names and/or gene symbols listed in Supplemental Tables 1, 3, or combintinations thereof is sleeted from the group consisting of LOCI 00293390, RNF217,

PGBD2, LACTB, TRIT1, RNF217, LOC654433, DFFA, DNAJC5, ZNF365, ZNF365, MDN1, ERG, CTSB, SGSM3, MYL5, HLA-Z, IKZF1, C15orf23, CD84, C21orf7, VPS26B, SUFU, MSH6, S1PR3, FCGR2B, BCL2L11, RFC5, RAB3D, LOCI 00128943, PSMB9, GALNT11, APOC2, ISM2, PMS2CL, RDBP, GSPT2, NOD2, USP6NL, TAF13, H2AFX, CD53, CYP3A5, HLA-Z, DCAF8, CTTNBP2NL, ISM2, KCTD20, HMMR, RYRl, METTL3, BCATl, GSPTl, MGC27345, PGPEPl, TFEB, POLG2, RBM33, LOC80054, FABP3, GCA, FANCC, RPUSD4, C21orf7, ZNF609, SAMHD1, NFATC2, SERPINB8, CYP4F11, LOC728613, SNRK,

LOC80054, SLC8A1, VMOl, IL28RA, LOC100288109, APITD1, TRIP6, TMEM165, TBXAS1, KLHL12, LY86, KLF3, WHSC1, ZBTB46, SNRK, MLL2, KCNJ13, THG1L, CYP4V2, SLC23A2, OGFRL1, SLC02B1, PTPN1, ALOX5AP, MORC2, ABCD1P4, UCK2, TMED5, FCGR2C, FAM185A, PHF20L1, EPB41L3, LARP4B, DHRSX, PDPK1, APEX2, CTSB, MRPL9, LOCI 00293165, Clorfl04, STX7, GFI1, AP4E1, ARHGAP5, C14orfl06, SUDS3, BAT2L1, BCAS3, LMF2, INTS4, FCGR2A, ADAM 10, CCZ1, RANBP9, MATR3, SENP5, PPIL2, THNSL1 , DNHD1, RBMS2, SYMPK, DNASE1, FCGR2A, KIFC2, TTC17, PDPK1, BCL2L13, MFSD7, ETF1, REEP4, TMEM165, MRPL9, HAUS2, ADAP2, IL1RAP,

PARVG, C14orfl l8, ATXNl, PDE7A, DENND4B, ZNF502, Clorf77, OP A3, TNP03, KIFIB,

RNASEl, ANXAl l, FAM84A, C6orf26, CLTC, AMZ2, TYROBP, IFNGR2, RIOK2, C17orf63, GPBARl, ZNF639, TBRG4, SKP2, PHKA2, SERPl, CENPCl, MICALCL, RHOG, PDE4DIP, KIAA1147, UBAPl, C20orf7, SRRT, BTN3A2, DCP2, MIR1302-3, UFMl, PDPR, DNMTl, SMC2, GALT, LOC730235, STX8, GNBl, LOC283267, WDRl, BACHl, AGFGl, PIAS1, SNX6, ROCKl, EIF2AK1, UBXNl l, APAFl, THNSLl, and combinations thereof.