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EP4654960A1 - Évaluation et traitement de mammifères ayant des polypes - Google Patents

Évaluation et traitement de mammifères ayant des polypes

Info

Publication number
EP4654960A1
EP4654960A1 EP24747847.2A EP24747847A EP4654960A1 EP 4654960 A1 EP4654960 A1 EP 4654960A1 EP 24747847 A EP24747847 A EP 24747847A EP 4654960 A1 EP4654960 A1 EP 4654960A1
Authority
EP
European Patent Office
Prior art keywords
polypeptide
mrna encoding
increased level
mammal
level
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24747847.2A
Other languages
German (de)
English (en)
Inventor
Lisa A. Boardman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mayo Foundation for Medical Education and Research
Mayo Clinic in Florida
Original Assignee
Mayo Foundation for Medical Education and Research
Mayo Clinic in Florida
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mayo Foundation for Medical Education and Research, Mayo Clinic in Florida filed Critical Mayo Foundation for Medical Education and Research
Publication of EP4654960A1 publication Critical patent/EP4654960A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57419—Specifically defined cancers of colon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • TECHNICAL FIELD This document relates to methods and materials for assessing and/or treating mammals (e.g., humans) having one or more polyps (e.g., one or more colon polyps). For example, methods and materials provided herein can be used to determine if a polyp (e.g., a colon polyp) within a mammal (e.g., a human) is or is likely to become a malignant polyp and/or is likely to recur. This document also provides methods and materials for treating a mammal having one or more polyps (e.g., one or more colon polyps).
  • CRC Colorectal cancer
  • determining whether a polyp may transform to cancer can be made based on the physical features of the polyp such as size, histology, and degree of dysplasia. Up to 60% of patients who undergo screening colonoscopy will have polyps that will recur and therefore require repeated surveillance and removal (Zachariah et al., Am. J. Gastroenterol., 115:138-144 (2020); and Harrington et al., AMIA Jt Summits Transl. Sci. Proc., 2020:211–220 (2020)).
  • the methods and materials provided herein can be used to determine if a polyp (e.g., a polyp within a mammal having one or more polyps) is or is likely to become a malignant polyp and/or if a polyp (e.g., a polyp within a mammal having one or more polyps) is likely to recur.
  • a molecular profile of a polyp can be used to determine if that polyp is or is likely to become a malignant polyp and/or if that polyp is likely to recur.
  • a sample obtained from a mammal having one or more polyps can be assessed to determine if a polyp (e.g., a polyp within a mammal having one or more polyps) is or is likely to become a malignant polyp and/or is likely to recur based, at least in part, on the molecular profile of the polyp.
  • a polyp e.g., a polyp within a mammal having one or more polyps
  • This document also Attorney Docket No.07039-2155WO1 / 2022-250 provides methods and materials for treating a mammal having one or more polyps (e.g., one or more colorectal polyps).
  • a mammal e.g., a human having one or more polyps (e.g., one or more colorectal polyps) can be administered one or more treatments that are selected based, at least in part, on the molecular profile of the polyp.
  • the molecular profile of a polyp can distinguish whether that polyp is a benign polyp or a malignant polyp.
  • a polyp is or is likely to become malignant can have a molecular profile that includes differential expression of ADAMTS4, THBS2, SERPINE1, FAP, CYR61, SOX11, CXCL13, SFRP2, and VIP, and/or overexpression of TERT (e.g., resulting in changes in telomere structure such as telomere length and telomere content), and, optionally, includes altered levels of natural killer cell (NKCs) in the resting phase, one or more chromosomal rearrangements (e.g., a genomic duplication (DUP), a genomic deletion (DEL), a genomic insertion/deletion (INDEL)), loss of heterozygosity (LOH), and/or increased copy number variation (CNV)) as compared to polyps that are clinically indistinguishable (e.g., by endoscopic and/or histological appearance) and remain benign.
  • TERT natural killer cell
  • chromosomal rearrangements e.g.,
  • the molecular profile of a polyp can distinguish whether that polyp is likely to recur. In some cases, the molecular profile of a polyp can distinguish whether that polyp is likely to recur in the same location from which the polyp was removed from a mammal (e.g., a human).
  • a mammal e.g., a human
  • a polyp that is likely to recur can have a molecular profile that includes differential expression of TPRG1, LY6G6C, DUSP4, ZIC5, CYP1A1, DMKN, and IGLL5, and, optionally, includes a mutated KRAS and/or one or more changes in genetic content (e.g., a genomic DEL and/or LOH) as compared to polyps that are not likely to recur.
  • a mutated KRAS and/or one or more changes in genetic content e.g., a genomic DEL and/or LOH
  • Having the ability to determine risk whether a polyp is or is likely to become a malignant polyp and/or is likely to recur provides a unique and unrealized opportunity to provide personalized treatment plans for patients having one or more polyps (e.g., one or more colon polyps).
  • one or more polyps within a patient are identified as being or as likely to become malignant and/or as likely to recur as described herein (e.g., based, at least in part, on the molecular profile of the polyp(s))
  • therapy can be initiated early, rather than waiting to treat the patient until after a cancer has developed.
  • a patient having one or more polyps can undergo less frequent monitoring (e.g., less frequent surveillance colonoscopies) rather than being subjected to unnecessary treatments.
  • one aspect of this document features methods for assessing a mammal having one or more colon polyps.
  • the methods can include, or consist essentially of, (a) determining (i) if a sample from a mammal having one or o more colon polyps contains the presence or absence of at least one of (1) an increased level of a TERT polypeptide or mRNA encoding the TERT polypeptide, (2) an increased level of a FAP polypeptide or mRNA encoding the FAP polypeptide, (3) an increased level of a SOX11 polypeptide or mRNA encoding the SOX11 polypeptide, and (4) an increased level of a CXCL13 polypeptide or mRNA encoding the CXCL13 polypeptide, and (ii) if the sample contains the presence or absence of at least one of (5) an increased level of an ADAMTS4 polypeptide or mRNA encoding the ADAMTS4 polypeptide, (6) an increased level of a THBS2 polypeptide or mRNA encoding the THBS2 polypeptide, (7) an increased level of a SERP
  • the mammal can be a human.
  • the presence or absence of the increased level of the TERT polypeptide or mRNA encoding the TERT polypeptide can be determined.
  • the presence or absence of the increased level of the FAP polypeptide or mRNA encoding the FAP polypeptide can be determined.
  • the presence or absence of the increased level of the SOX11 polypeptide or mRNA encoding the SOX11 polypeptide can be determined.
  • the presence or Attorney Docket No.07039-2155WO1 / 2022-250 absence of the increased level of the CXCL13 polypeptide or mRNA encoding the CXCL13 polypeptide can be determined.
  • the method can include determining the presence of each of (1)-(4).
  • the method can include determining the presence of each of (1)-(15).
  • the method can include classifying the colon polyps as being malignant.
  • the method can include determining the absence of each of (1)-(15).
  • the method can include classifying the colon polyps as not being malignant.
  • the sample can be a tissue sample including one or more polyp cells.
  • the methods can include, or consist essentially of, (a) determining (i) if a sample from a mammal having one or more colon polyps contains the presence or absence of at least one of (1) an increased level of a TPRG1 polypeptide or mRNA encoding the TPRG1 polypeptide, (2) an increased level of a LY6G6C polypeptide or mRNA encoding the LY6G6C polypeptide, (3) an increased level of a DUSP4 polypeptide or mRNA encoding the DUSP4 polypeptide, (4) an increased level of a CYP1A1 polypeptide or mRNA encoding the CYP1A1 polypeptide, and (5) an increased level of a DMKN polypeptide or mRNA encoding the DMKN polypeptide, and (ii) if the sample contains the presence or absence of at least one of (6) an increased level of a ZIC5 polypeptide or mRNA encoding the ZIC5 poly
  • the mammal can be a human.
  • the presence or absence of the increased level of the TPRG1 polypeptide or mRNA encoding the TPRG1 polypeptide can be determined.
  • the presence or absence of the increased level of the LY6G6C polypeptide or mRNA encoding the LY6G6C polypeptide can be determined.
  • the presence or absence of the increased level of the DUSP4 polypeptide or mRNA encoding the DUSP4 polypeptide can be determined.
  • the presence or absence of the increased level of the CYP1A1 polypeptide or mRNA encoding the CYP1A1 polypeptide can be determined.
  • the presence or absence of the increased level of the DMKN polypeptide or mRNA encoding the DMKN polypeptide can be determined.
  • the method can include determining the presence of each of (1)-(5).
  • the method Attorney Docket No.07039-2155WO1 / 2022-250 can include determining the presence of each of (1)-(9).
  • the method can include classifying the colon polyps as being likely to recur.
  • the method can include determining the absence of each of (1)-(9).
  • the method can include classifying the colon polyps as not being likely to recur.
  • the sample can be a tissue sample including one or more polyp cells.
  • the method also can include determining if the sample contains the presence or absence of a decreased level of an IGLL5 polypeptide or a decreased level of an mRNA encoding said IGLL5 polypeptide.
  • the method can include classifying the colon polyps as being likely to recur if the presence of the decreased level of the IGLL5 polypeptide or the decreased level of the mRNA encoding said IGLL5 polypeptide is determined.
  • the method can include classifying the colon polyps as not being likely to recur if the absence of the decreased level of said IGLL5 polypeptide or the decreased level of the mRNA encoding said IGLL5 polypeptide is determined.
  • this document features methods for selecting a treatment for a mammal having one or more colon polyps.
  • the methods can include, or consist essentially of, (a) determining (i) that a sample from mammal having one or more colon polyps contains the presence of at least one of (1) an increased level of a TERT polypeptide or mRNA encoding the TERT polypeptide, (2) an increased level of a FAP polypeptide or mRNA encoding the FAP polypeptide, (3) an increased level of a SOX11 polypeptide or mRNA encoding the SOX11 polypeptide, and (4) an increased level of a CXCL13 polypeptide or mRNA encoding the CXCL13 polypeptide, and (ii) that the sample contains the presence of at least one of (5) an increased level of an ADAMTS4 polypeptide or mRNA encoding the ADAMTS4 polypeptide, (6) an increased level of a THBS2 polypeptide or mRNA encoding the
  • the mammal can be a Attorney Docket No.07039-2155WO1 / 2022-250 human.
  • the surgery to remove the polyps can be a polypectomy.
  • the cancer treatment can include radiation therapy.
  • the cancer treatment can include administering an anti-cancer drug to the mammal.
  • the anti-cancer drug can be docetaxel, capecitabine, cyclophosphamide, epirubicin, fluorouracil, bevacizumab, cetuximab, panitumumab, ramucirumab, regorafenib, ziv-aflibercept, or any combination thereof.
  • this document features methods for selecting a treatment for a mammal having one or more colon polyps.
  • the methods can include, or consist essentially of, (a) determining that a sample from a mammal having one or more colon polyps contains the absence of (1) an increased level of a TERT polypeptide or mRNA encoding the TERT polypeptide, (2) an increased level of a FAP polypeptide or mRNA encoding the FAP polypeptide, (3) an increased level of a SOX11 polypeptide or mRNA encoding the SOX11 polypeptide, (4) an increased level of a CXCL13 polypeptide or mRNA encoding the CXCL13 polypeptide, (5) an increased level of an ADAMTS4 polypeptide or mRNA encoding the ADAMTS4 polypeptide, (6) an increased level of a THBS2 polypeptide or mRNA encoding the THBS2 polypeptide, (7) an increased level of a SERPINE1 polypeptide or mRNA encoding the SERPINE1 polypeptide, (8) an increased level of a CYR
  • the mammal can be a human.
  • the colon polyp treatment can be surgery to remove the polyps.
  • the cancer treatment can include radiation therapy.
  • the cancer treatment can include administering an anti-cancer drug to the mammal.
  • the anti-cancer drug can be docetaxel, capecitabine, cyclophosphamide, epirubicin, fluorouracil, bevacizumab, cetuximab, panitumumab, ramucirumab, regorafenib, ziv-aflibercept, or any combination thereof.
  • this document features methods for selecting a treatment for a mammal having one or more colon polyps.
  • the methods can include, or consist essentially of, (a) determining (i) that a sample from a mammal having one or more colon polyps Attorney Docket No.07039-2155WO1 / 2022-250 contains the presence of at least one of (1) an increased level of a TPRG1 polypeptide or mRNA encoding the TPRG1 polypeptide, (2) an increased level of a LY6G6C polypeptide or mRNA encoding the LY6G6C polypeptide, (3) an increased level of a DUSP4 polypeptide or mRNA encoding the DUSP4 polypeptide, (4) an increased level of a CYP1A1 polypeptide or mRNA encoding the CYP1A1 polypeptide, and (5) an increased level of a DMKN polypeptide or mRNA encoding the DMKN polypeptide, and (ii) that the sample contains the presence of at least one of (6) an increased level of a ZIC5 polypeptid
  • the mammal can be a human.
  • the method also can include determining that the sample contains the presence of a decreased level of an IGLL5 polypeptide or a decreased level of an mRNA encoding the IGLL5 polypeptide.
  • this document features methods for selecting a treatment for a mammal having one or more colon polyps.
  • the methods can include, or consist essentially of, (a) determining that a sample from a mammal having one or more colon polyps contains the absence of (1) an increased level of a TPRG1 polypeptide or mRNA encoding the TPRG1 polypeptide, (2) an increased level of a LY6G6C polypeptide or mRNA encoding the LY6G6C polypeptide, (3) an increased level of a DUSP4 polypeptide or mRNA encoding the DUSP4 polypeptide, (4) an increased level of a CYP1A1 polypeptide or mRNA encoding the CYP1A1 polypeptide, (5) an increased level of a DMKN polypeptide or mRNA encoding the DMKN polypeptide, (6) an increased level of a ZIC5 polypeptide or mRNA encoding the ZIC5 polypeptide, (7) one or more mutations in a KRAS polypeptide or a nucleic acid encoding
  • the mammal can be a human.
  • the method also can include determining that the sample from the mammal contains the absence of a decreased level of an IGLL5 polypeptide or a decreased level of an mRNA encoding the IGLL5 polypeptide.
  • Attorney Docket No.07039-2155WO1 / 2022-250 In another aspect, this document features methods for treating a mammal having one or more colon polyps.
  • the methods can include, or consist essentially of, (a) determining (i) that a sample from a mammal having one or more colon polyps includes one or more of (1) an increased level of a TERT polypeptide or mRNA encoding the TERT polypeptide, (2) an increased level of a FAP polypeptide or mRNA encoding the FAP polypeptide, (3) an increased level of a SOX11 polypeptide or mRNA encoding the SOX11 polypeptide, and (4) an increased level of a CXCL13 polypeptide or mRNA encoding the CXCL13 polypeptide and (ii) that the sample includes one or more of (5) an increased level of an ADAMTS4 polypeptide or mRNA encoding the ADAMTS4 polypeptide, (6) an increased level of a THBS2 polypeptide or mRNA encoding the THBS2 polypeptide, (7) an increased level of a SERPINE1 polypeptide or mRNA encoding the SERP
  • the mammal can be a human.
  • the sample can be a tissue sample including one or more polyp cells.
  • the surgery to remove the polyps can be a polypectomy.
  • the cancer treatment can include radiation therapy.
  • the cancer treatment can include administering an anti-cancer drug to the mammal.
  • the anti-cancer drug can be docetaxel, capecitabine, cyclophosphamide, epirubicin, fluorouracil, bevacizumab, cetuximab, panitumumab, ramucirumab, regorafenib, ziv-aflibercept, or any combination thereof.
  • the sample also can include a decreased level of an IGLL5 polypeptide or a decreased level of an mRNA encoding the IGLL5 polypeptide.
  • this document features methods for treating colon polyps.
  • the methods can include, or consist essentially of, subjecting a mammal identified as having a sample (i) including one or more of (1) an increased level of a TERT polypeptide or mRNA encoding the TERT polypeptide, (2) an increased level of a FAP polypeptide or mRNA encoding the FAP polypeptide, (3) an increased level of a SOX11 polypeptide or mRNA encoding the SOX11 polypeptide, and (4) an increased level of a CXCL13 polypeptide or Attorney Docket No.07039-2155WO1 / 2022-250 mRNA encoding the CXCL13 polypeptide, and (ii) including one or more of (5) an increased level of an ADAMTS4 polypeptide or mRNA encoding the ADAMT
  • the mammal can be a human.
  • the sample can be a tissue sample including one or more polyp cells.
  • the surgery to remove the polyps can be a polypectomy.
  • the cancer treatment can include radiation therapy.
  • the cancer treatment can include administering an anti-cancer drug to the mammal.
  • the anti-cancer drug can be docetaxel, capecitabine, cyclophosphamide, epirubicin, fluorouracil, bevacizumab, cetuximab, panitumumab, ramucirumab, regorafenib, ziv-aflibercept, or any combination thereof.
  • this document features methods for treating a mammal having one or more colon polyps.
  • the methods can include, or consist essentially of, (a) determining that a sample from a mammal having one or more colon polyps lacks (1) an increased level of a TERT polypeptide or mRNA encoding the TERT polypeptide, (2) an increased level of a FAP polypeptide or mRNA encoding the FAP polypeptide, (3) an increased level of a SOX11 polypeptide or mRNA encoding the SOX11 polypeptide, (4) an increased level of a CXCL13 polypeptide or mRNA encoding the CXCL13 polypeptide, (5) an increased level of an ADAMTS4 polypeptide or mRNA encoding the ADAMTS4 polypeptide, (6) an increased level of a THBS2 polypeptide or mRNA encoding the THBS2 polypeptide, (7) an increased level of a SERPINE1 polypeptide or mRNA encoding the SERPINE1 polypeptide, (8) an increased level of a CYR61 poly
  • the mammal can be a human.
  • the sample can be a tissue sample including one or more polyp cells.
  • the colon polyp treatment can be surgery to remove the polyps.
  • the cancer treatment can include radiation therapy.
  • the cancer treatment can include administering an anti-cancer drug to the mammal.
  • the anti-cancer drug can be docetaxel, capecitabine, cyclophosphamide, epirubicin, fluorouracil, bevacizumab, cetuximab, panitumumab, ramucirumab, regorafenib, ziv-aflibercept, or any combination thereof.
  • this document features methods for treating colon polyps.
  • the methods can include, or consist essentially of, subjecting a mammal identified as having a sample lacking (1) an increased level of a TERT polypeptide or mRNA encoding the TERT polypeptide, (2) an increased level of a FAP polypeptide or mRNA encoding the FAP polypeptide, (3) an increased level of a SOX11 polypeptide or mRNA encoding the SOX11 polypeptide, (4) an increased level of a CXCL13 polypeptide or mRNA encoding the CXCL13 polypeptide, (5) an increased level of an ADAMTS4 polypeptide or mRNA encoding the ADAMTS4 polypeptide, (6) an increased level of a THBS2 polypeptide or mRNA encoding the THBS2 polypeptide, (7) an increased level of a SERPINE1 polypeptide or mRNA encoding the SERPINE1 polypeptide, (8) an increased level of a CYR61 polypeptide or mRNA encoding the
  • the mammal can be a human.
  • the sample can be a tissue sample including one or more polyp cells.
  • the colon polyp treatment can be surgery to remove the polyps.
  • the cancer treatment can include radiation therapy.
  • the cancer treatment can include administering an anti-cancer drug to the mammal.
  • the anti-cancer drug can be docetaxel, capecitabine, cyclophosphamide, epirubicin, fluorouracil, bevacizumab, cetuximab, panitumumab, ramucirumab, regorafenib, ziv-aflibercept, or any combination thereof.
  • this document features methods for treating a mammal having one or more colon polyps.
  • the methods can include, or consist essentially of, (a) determining (i) that a sample from a mammal having one or more colon polyps including at least one of (1) an increased level of a TPRG1 polypeptide or mRNA encoding the TPRG1 polypeptide, (2) an increased level of a LY6G6C polypeptide or mRNA encoding the LY6G6C polypeptide, (3) an increased level of a DUSP4 polypeptide or mRNA encoding the DUSP4 polypeptide, (4) an increased level of a CYP1A1 polypeptide or mRNA encoding the CYP1A1 polypeptide, and (5) an increased level of a DMKN polypeptide or mRNA encoding the DMKN polypeptide, and (ii) that the sample including
  • the mammal can be a human.
  • the sample can be a tissue sample including one or more polyp cells.
  • the method also can include determining that the sample includes a decreased level of an IGLL5 polypeptide or a decreased level of an mRNA encoding the IGLL5 polypeptide.
  • this document features methods for treating colon polyps.
  • the methods can include, or consist essentially of, subjecting a mammal identified as having a sample (i) including at least one of (1) an increased level of a TPRG1 polypeptide or mRNA encoding the TPRG1 polypeptide, (2) an increased level of a LY6G6C polypeptide or mRNA encoding the LY6G6C polypeptide, (3) an increased level of a DUSP4 polypeptide or mRNA encoding the DUSP4 polypeptide, (4) an increased level of a CYP1A1 polypeptide or mRNA encoding the CYP1A1 polypeptide, and (5) an increased level of a DMKN polypeptide or mRNA encoding the DMKN polypeptide, and (ii) including at least one of (6) an increased level of a ZIC5 polypeptide or mRNA encoding the ZIC5 polypeptide, (7) one or more mutations in a KRAS polypeptide or a nucleic
  • the mammal can be a human.
  • the sample can be a tissue sample including one or more polyp cells.
  • the method also can include determining the said sample contains a decreased level of an IGLL5 polypeptide or a decreased level of an mRNA encoding said IGLL5 polypeptide.
  • Attorney Docket No.07039-2155WO1 / 2022-250 In another aspect, this document features methods for treating a mammal having one or more colon polyps.
  • the methods can include, or consist essentially of, (a) determining that a sample from a mammal having one or more colon polyps contains the absence of (1) an increased level of a TPRG1 polypeptide or mRNA encoding the TPRG1 polypeptide, (2) an increased level of a LY6G6C polypeptide or mRNA encoding the LY6G6C polypeptide, (3) an increased level of a DUSP4 polypeptide or mRNA encoding the DUSP4 polypeptide, (4) an increased level of a CYP1A1 polypeptide or mRNA encoding the CYP1A1 polypeptide, (5) an increased level of a DMKN polypeptide or mRNA encoding the DMKN polypeptide, (6) an increased level of a ZIC5 polypeptide or mRNA encoding the ZIC5 polypeptide, (7) one or more mutations in a KRAS polypeptide or a nucleic acid encoding
  • the mammal can be a human.
  • the sample can be a tissue sample including one or more polyp cells.
  • the method also can include determining that said sample contains the absence of a decreased level of an IGLL5 polypeptide or a decreased level of an mRNA encoding the IGLL5 polypeptide.
  • this document features methods for treating colon polyps.
  • the methods can include, or consist essentially of, subjecting a mammal identified as having a sample lacking (1) an increased level of a TPRG1 polypeptide or mRNA encoding the TPRG1 polypeptide, (2) an increased level of a LY6G6C polypeptide or mRNA encoding the LY6G6C polypeptide, (3) an increased level of a DUSP4 polypeptide or mRNA encoding the DUSP4 polypeptide, (4) an increased level of a CYP1A1 polypeptide or mRNA encoding the CYP1A1 polypeptide, (5) an increased level of a DMKN polypeptide or mRNA encoding the DMKN polypeptide, (6) an increased level of a ZIC5 polypeptide or mRNA encoding the ZIC5 polypeptide, (7) one or more mutations in a KRAS polypeptide or a nucleic acid encoding a KRAS polypeptide, (8) an increased frequency
  • the mammal can be a human.
  • the sample can be a tissue sample including one or more polyp cells.
  • the sample also can lack a Attorney Docket No.07039-2155WO1 / 2022-250 decreased level of an IGLL5 polypeptide or a decreased level of an mRNA encoding the IGLL5 polypeptide.
  • this document features methods performed by one or more computers, where the methods can include, or consist essentially of, (a) receiving a set of features characterizing a mammal having one or more colon polyps, and where the set of features comprises one or more transcriptomic features of the mammal; (b) processing the set of features characterizing the mammal using a polyp prediction machine learning model, in accordance with values of a set of machine learning model parameters, to generate a machine learning model output, where the machine learning model output defines one or more predictions characterizing the one or more colon polyps of the mammal; and generating a notification that indicates the one or more predictions characterizing the one or more colon polyps of the mammal.
  • the machine learning model output can include a likelihood that the one or more colon polyps are malignant.
  • the machine learning model output can include a likelihood that the one or more colon polyps will recur.
  • the set of features characterizing the mammal can be derived from a sample obtained from the mammal.
  • the set of features characterizing the mammal can include transcriptomic features.
  • the transcriptomic features can include normalized values of one or more protein coding genes in the mammal.
  • the transcriptomic features can include normalized values of one or more of: ADAMTS4 genes, THBS2 genes, SERPINE1 genes, FAP genes, CYR61 genes, SOX11 genes, CXCL13 genes, SFRP2 genes, VIP genes, or TERT genes.
  • the set of features characterizing the mammal can include one or more of: genomic features, epigenomic features, proteomic features, or metabolomic features.
  • the polyp prediction machine learning model can include one or more of: a linear regression model, a random forest model, a support vector machine model, a neural network model, or an XGBoost model.
  • the polyp prediction machine learning model can have been trained by operations comprising: (a) obtaining a set of training examples, where each training example comprises: (i) a set of training features characterizing a training mammal having one or more colon polyps, and (ii) a target output characterizing the one or more colon polyps of the mammal; and (b) training the set of machine learning model parameters of the polyp prediction machine learning model on the set of training examples, comprising, for each training example: (i) training the polyp prediction machine learning model to process the set of training features from the training example to generate a machine Attorney Docket No.07039-2155WO1 / 2022-250 learning model output that matches the target output from the training example.
  • the method can include taking an action based on the one or more predictions characterizing the one or more colon polyps of the mammal.
  • the action can include increasing a rate of screening for the one or more colon polyps of the mammal.
  • the action can include removing the one or more colon polyps of the mammal.
  • the method can include generating a set of explainability data that explains the one or more predictions generated by the polyp prediction machine learning model, comprising: (a) generating, for each feature in the set of features characterizing the mammal, an impact score that characterizes an impact of the feature on the one or more predictions generated by the polyp prediction machine learning model for the one or more colon polyps of the mammal.
  • the method can include: (a) identifying one or more features having the highest impact scores from among the set of features; and (b) generating a notification that indicates the one or more features having the highest impact scores from among the set of features.
  • this document features systems comprising: (a) one or more computers; and (b) one or more storage devices communicatively coupled to the one or more computers, where the one or more storage devices store instructions that, when executed by the one or more computers, cause the one or more computers to perform operations of methods performed by one or more computers, where the methods can include, or consist essentially of, (a) receiving a set of features characterizing a mammal having one or more colon polyps, and where the set of features comprises one or more transcriptomic features of the mammal; (b) processing the set of features characterizing the mammal using a polyp prediction machine learning model, in accordance with values of a set of machine learning model parameters, to generate a machine learning model output, where the machine learning model output defines one or more predictions characterizing the one or more colon
  • this document features non-transitory computer storage media storing instructions that when executed by one or more computers cause the one or more computers to perform operations of methods performed by one or more computers, where the methods can include, or consist essentially of, (a) receiving a set of features characterizing a mammal having one or more colon polyps, and where the set of features comprises one or Attorney Docket No.07039-2155WO1 / 2022-250 more transcriptomic features of the mammal; (b) processing the set of features characterizing the mammal using a polyp prediction machine learning model, in accordance with values of a set of machine learning model parameters, to generate a machine learning model output, where the machine learning model output defines one or more predictions characterizing the one or more colon polyps of the mammal; and generating a notification that indicates the one or more predictions characterizing the one or more colon polyps of the mammal.
  • FIG.1A shows a schematic of the large intestine, with a cancer free polyp (CFP) and a cancer adjacent polyp (CAP) indicated.
  • FIG.1B shows a pair of box-and-whisker plots of somatic mutation prevalence from whole-genome sequencing (WGS) data comparing CFPs and CAPs, for discovery (left) and validation (right) datasets, and also shows a pair of box-and-whisker plots of mean copy number variant (CNV) size (in basepairs) from whole-genome sequencing (WGS) data comparing CFPs and CAPs, for discovery (left) and validation (right) datasets.
  • FIG.1C shows a volcano plot of differentially expressed genes between the CAP and CFP tissues as measured by RNA-seq.
  • the x-axis is the log of the fold change in expression
  • the y-axis is the log of the false discovery rate (FDR) between CAP and CFP tissues.
  • FDR false discovery rate
  • Dots in the positive Log2 fold change to Attorney Docket No.07039-2155WO1 / 2022-250 the right of zero on the x-axis are genes that have a fold change???1, and FDR???0.05 (left), meaning upregulated in CAP compared to CFP.
  • Dots in the negative Log2 fold change to the left of zero on the x-axis represent genes that are upregulated in CFPs.
  • FIG.1D shows a pair of box-and-whisker plots of GREM1 gene expression for CFPs and CAPs, for discovery (left) and validation (right) sets.
  • FIG.1E shows Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Analysis for genes that are up-regulated in CAPs relative to CFPs.
  • FIG.1F shows a pair of box-and-whisker plots of telomere content from WGS data for CFPs and CAP, for discovery (left) and validation (right) sets.
  • FIG.1G shows a pair of box-and- whisker plots of normalized hTERT expression from RNA-seq for CFPs and CAPs, for discovery (left) and validation (right) sets.
  • Figures 2A – 2D Senescence-associated secretory phenotype (SASP), immune cell, and age-related analyses in polyps.
  • SASP Senescence-associated secretory phenotype
  • FIG.2A shows a pair of box-and-whisker plots of senescence-associate secretory phenotype (SASP) gene expression between CAPs (left) and CFPs (right).
  • FIG.2B shows a plot of gene set enrichment analysis (GSEA) of SASP expression in CAPs and in CFPs.
  • FIG.2C shows a pair of box-and-whisker plots of population distributions between CAPs (left) and CFPs (right) for resting natural killer (NK) cells.
  • GSEA gene set enrichment analysis
  • FIG.2D shows a heatmap of gene expression data for early onset CAPs, early onset CFPs, and telomere length based on counts from RNA-seq data, showing the differentially expressed genes between CAPs and CFPs.
  • Figures 3A – 3F hTERT edited organoids compared to alterations between CAP and CFPs.
  • FIG.3B shows a plot of gene expression measured by qPCR on RNA extracted from organoids in the unedited organoids, HeLa cells, and TERT edited organoids. Fold change expression is plotted on y-axis relative to GAPDH.
  • FIG.3C shows a table of normalized RNA-seq counts between TERT + and unedited organoids for the TERT and GAPDH genes.
  • FIG.3D shows a plot of GSEA comparing the differentially expressed genes between TERT + and unedited organoids and CAP compared to CFP tissues (absolute value lfc > 0.1, pvalue ⁇ 0.05).
  • FIG.3E shows KEGG pathway analysis for the top 600 up-regulated genes in the TERT + organoids.
  • FIG.3F shows row scaled showing relative changes in SASP panel genes between TERT unedited and TERT + organoids.
  • FIG.4A shows a schematic of framework using AutoGluon for model creation and selection.
  • FIG.4B shows a SHAP plot visualizing distribution of impacts each feature has on CAP vs CFP model output.
  • Figures 5A – 5GE Molecular features to classify POP.
  • FIG.5A shows a cartoon schematic of POP categories.
  • FIG.5B shows a box-and-whisker plot of somatic mutation prevalence from WGS data for a (POP-NR) (left), POP-R (center), and CAP (right).
  • FIG.5C shows a box-and-whisker plot of mean CNV event size from WGS data for POP-NA (left), POP-R (center), and CAP (right). All comparisons, “ns” indicates not significant a single asterisk indicates p ⁇ 0.05, and a double asterisk indicates p ⁇ 0.001.
  • FIG.5D shows a volcano plot of differentially expressed genes for POP-NR compared to POP-R as measured by RNA-seq.
  • the x-axis is the log of the fold change in expression, and the y-axis is the log of the FDR between POP-NR and POP-R tissues.
  • Dots in the negative Log2 fold change to the left of zero on the x-axis are genes that have a fold change ⁇ -1, and FDR???0.05 in the POP-NR polyps meaning these genes are upregulated in the POP-NR compared to the POP-R tissues while dots in the positive Log2 fold change to the right of zero on the x-axis are genes that have a fold change???1 and FDR???0.05 in the POP-R, meaning these genes are upregulated in the POP-R compared to the POP-NR.
  • FIG.5D also shows a volcano plot of differentially expressed genes for POP-NR compared to CAP as measured by RNA-seq.
  • the x-axis is the log of the fold change in expression
  • the y-axis is the log of the FDR between POP-NR and CAP tissues.
  • Dots in the negative Log 2 fold Attorney Docket No.07039-2155WO1 / 2022-250 change to the left of zero on the x-axis are genes that have a fold change ⁇ -1, and FDR???0.05 in the POP-NR meaning these genes are upregulated in the POP-NR compared to the CAP tissues while dots in the positive Log2 fold change to the right of zero on the x-axis are genes that have a fold change???1 and FDR???0.05 in the CAP meaning these genes are upregulated in the CAP compared to the POP-NR.
  • FIG.5D also shows a volcano plot of differentially expressed genes for POP-R compared to CAP as measured by RNA-seq.
  • the x- axis is the log of the fold change in expression, and the y-axis is the log of the FDR between POP-R and CAP tissues.
  • FIG.5E shows a heatmap of data from KEGG Pathway Analysis for genes enriched between CAP and CFP, as well as by POP status.
  • FIG.5F shows a box-and-whisker plot of telomere content from WGS data for POP-NR (left), POP-R (center), and CAP (right). All comparisons, “ns” indicates not significant, a single asterisk indicates p ⁇ 0.05, a double asterisk indicates p ⁇ 0.001, a triple asterisk indicates p ⁇ 0.0001 and a quadruple asterisk indicates p ⁇ 0.00001.
  • FIG.5G shows a box-and-whisker plot of normalized hTERT expression from RNA-seq data for POP-NR (left), POP-R (center), CAP (right). All comparisons, “ns” indicates not significant, a single asterisk indicates p ⁇ 0.05, a double asterisk indicates p ⁇ 0.001, a triple asterisk indicates p ⁇ 0.0001 and a quadruple asterisk indicates p ⁇ 0.00001.
  • Figures 6A – 6D Polyp Recurrence based on KRAS mutation.
  • FIG.6A shows KRAS mutation percentages within POPs.
  • FIG.6D shows POP-NR vs POP-R linear regression model details.
  • FIG.7A shows a Piggybac vector with hTERT inserted for gene editing.
  • FIG.8B is a table showing copy number results using the Piggybac qPCR copy number kit (Catalog: PBC100A-1; System Bioscience). Last column indicates copy number for TERT+ organoids (Piggyback row), untransfected organoids, and water control.
  • RNAscope results observed for the RNAscope assay for CFP (left) and CAP (right) polyp tissue from two patients not represented in the Discovery or Validation cohorts.
  • THBS2 mRNA is represented by dots of green signal (exemplar signal marked white arrowheads, CAP tissue only), with nuclei stained with DAPI.
  • Figure 13 Differentially expressed transcripts in epithelial and stromal compartments between POP categories for SSA-TSA polyps.
  • this document provides methods and materials that can be used to determine whether or not one or more polyps (e.g., one or more colon polyps) within a mammal (e.g., a human) are or are likely to become malignant and/or are likely to recur (e.g., likely to recur in the same location from which the polyp was removed from the mammal).
  • a mammal e.g., a human
  • a Attorney Docket No.07039-2155WO1 / 2022-250 sample e.g., a sample containing one or more polyp cells
  • a mammal e.g., a human
  • polyps e.g., one or more colon polyps
  • a distinct molecular profile can be present in a polyp that is or is likely to become malignant (e.g., as compared to a molecular profile that can be present in a benign polyp).
  • This document also provides methods and materials for treating a mammal having one or more polyps (e.g., one or more colorectal polyps).
  • a treatment for a mammal having one or more polyps can be selected based, at least in part, on the molecular profile of the mammal’s polyp(s) as described herein.
  • a mammal e.g., a human
  • having one or more polyps e.g., one or more colon polyps
  • a sample e.g., a sample containing one or more polyp cells
  • a mammal having one or more polyps e.g., one or more colon polyps
  • a sample obtained from a mammal having one or more polyps (e.g., one or more colon polyps) can be assessed to determine if the polyp(s) are or are likely to become malignant and/or are likely to recur based, at least in part, on the molecular profile of the polyp(s).
  • a sample e.g., a sample containing one or more polyp cells obtained from a mammal (e.g., a human) having one or more polyps (e.g., one or more colon polyps) can be assessed for the presence or absence of altered levels (e.g., increased levels or decreased levels) of one or more (e.g., one, two, three, four, five, or more) of an ADAMTS4 polypeptide (or mRNA encoding a ADAMTS4 polypeptide), a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), a FAP polypeptide (or mRNA encoding a FAP polypeptide), a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), a SOX11 polypeptide (or mRNA
  • a sample e.g., a sample containing one or more polyp cells obtained from a mammal (e.g., a human) having one or more polyps (e.g., one or more colon polyps) can be assessed for (a) the presence or absence of altered levels (e.g., increased levels or decreased levels) of one or more of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide), an LY6G6C polypeptide (or mRNA Attorney Docket No.07039-2155WO1 / 2022-250 encoding an LY6G6C polypeptide), a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide), a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide), a CYP1A1polypeptide (or mRNA encoding a CYP1A1 polypeptide), a CYP1
  • mammal can be assessed and/or treated as described herein.
  • mammals that can be assessed and/or treated as described herein include, without limitation, humans, non-human primates (e.g., monkeys), dogs, cats, horses, cows, pigs, sheep, rabbits, mice, and rats.
  • the mammal can be a human.
  • the mammal can be a mammal having one or more polyps.
  • the mammal can have one or more polyp disorders (e.g., one or more hereditary polyp disorders).
  • hereditary polyp disorders can include, without limitation, Lynch syndrome, familial adenomatous polyposis (FAP), Gardner’s syndrome, MYH-associated polyposis (MAP), Peutz-Jeghers syndrome, serrated polyposis syndrome and juvenile polyposis syndrome (JPS).
  • FAP familial adenomatous polyposis
  • Gardner Gardner’s syndrome
  • MYH-associated polyposis MAP
  • MAP MYH-associated polyposis
  • serrated polyposis syndrome and juvenile polyposis syndrome
  • JPS juvenile polyposis syndrome
  • a mammal having one or more polyps can be assessed for whether a polyp is or is likely to become malignant and/or may be likely to recur, and can be treated with one or more interventions as described herein.
  • a mammal (e.g., a human) having one or more polyps can have any type of polyp(s).
  • a polyp can be a non-neoplastic polyp (e.g., hyperplastic polyps, inflammatory polyps, and hamartomatous polyps).
  • a polyp can be a neoplastic polyp (e.g., adenomas and serrated polyps).
  • a mammal (e.g., a human) having one or more polyps can have polyp(s) in any location within the mammal. Examples of locations within a mammal that can have one or more polyps that can be assessed and/or treated as described herein can include, without limitation, the colon and the rectum.
  • a polyp that is assessed and/or treated using the methods and materials described herein can be a colon polyp. In some cases, a polyp that is assessed and/or treated using the methods and materials described herein can be Attorney Docket No.07039-2155WO1 / 2022-250 a colon polyp. In some cases, a polyp that is assessed and/or treated using the methods and materials described herein can be a colorectal polyp.
  • a mammal e.g., a human having one or more polyps can have any size polyp(s). In some cases, a polyp can be from about 0.5 mm to about 60 mm in size (e.g., across its diameter or longest dimension).
  • a polyp can be from about 0.5 mm to about 50 mm, from about 0.5 mm to about 40 mm, from about 0.5 mm to about 30 mm, from about 0.5 mm to about 20 mm, from about 0.5 mm to about 10 mm, from about 0.5 mm to about 5 mm, from about 1 mm to about 60 mm, from about 5 mm to about 60 mm, from about 10 mm to about 60 mm, from about 20 mm to about 60 mm, from about 30 mm to about 60 mm, from about 40 mm to about 60 mm, from about 50 mm to about 60 mm, from about 1 mm to about 50 mm, from about 10 mm to about 40 mm, from about 20 mm to about 30 mm ⁇ from about 10 mm to about 30 mm, from about 20 mm to about 40 mm, from about 30 mm to about 50 mm, from about 1 mm to about 10 mm, from about 10 mm to about 20 mm, from about 20 mm to about 30 mm
  • a mammal having one or more polyps can have any number of polyps.
  • a mammal can have from about one polyp to about 1000 polyps.
  • a mammal can have from about 1 to about 750, from about 1 to about 500, from about 1 to about 250, from about 1 to about 100, from about 1 to about 50, from about 100 to about 1000, from about 250 to about 1000, from about 500 to about 1000, from about 750 to about 1000, from about 100 to about 750, from about 200 to about 500, from about 50 to about 100 ⁇ from about 100 to about 250, from about 250 to about 500, or from about 500 to about 1000 polyps.
  • a mammal can have two or more polyps (e.g., two three, four, five, six, seven, eight, nine, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more polyps).
  • a mammal e.g., a human
  • Any appropriate method can be used to identify a mammal as having one or more polyps.
  • imaging techniques such as using a flexible tube with a light and camera attached to it to visualize internal organs (e.g., colonoscopy such as video capsule colonoscopy and sigmoidoscopy) and computerized tomography (CT) scanning (e.g., CT colonography), can be used to identify a mammal as having one or more polyps.
  • laboratory tests such as stool-based tests (e.g., Attorney Docket No.07039-2155WO1 / 2022-250 checking for the presence of blood in the stool and/or assessing DNA within stool) can be used to identify a mammal as having one or more polyps.
  • a sample can be a biological sample.
  • a sample can be a polyp sample (e.g., can contain one or more polyp cells).
  • a polyp sample can contain one or more polyp cells from a single polyp.
  • a polyp sample can contain one or more polyp cells from more than one polyp (e.g., from two, three, four, five, or more polyps).
  • a sample can contain one or more biological molecules (e.g., nucleic acids such as DNA and RNA, proteins, carbohydrates, lipids, hormones, metabolites, and/or microbiota).
  • biological molecules e.g., nucleic acids such as DNA and RNA, proteins, carbohydrates, lipids, hormones, metabolites, and/or microbiota.
  • samples that can be assessed as described herein include, without limitation, tissue samples (e.g., colon tissue samples and rectum tissue samples), stool samples, cellular samples (e.g., buccal samples and skin samples), fluid samples (e.g., blood, serum, plasma, urine, saliva, and sweat), and expired (exhaled) breath samples.
  • a biological sample can be a fresh sample or a fixed sample.
  • a biological sample can be a processed sample (e.g., an embedded sample such as a paraffin or OCT embedded sample).
  • a sample can be processed to isolate or extract one or more biological molecules.
  • a colon tissue sample and/or a rectal tissue sample can be obtained from a mammal having one or more polyps and can be assessed to determine if a polyp within the mammal is or is likely to become malignant and/or is likely to recur based, at least in part, on a molecular profile of the polyp.
  • a molecular profile described herein can include any appropriate number of biomarkers.
  • a molecular profile described herein can include a panel of biomarkers.
  • a panel of biomarkers can include any number of biomarkers.
  • a panel of biomarkers can include any two or more (e.g., two, three, four, five, six, seven, or more) biomarkers.
  • a biomarker can include the presence, absence, or level of a polypeptide (or an mRNA encoding a polypeptide).
  • a biomarker can include the presence or absence or one or more mutations within a polypeptide (or a nucleic acid encoding a polypeptide).
  • a biomarker can include a somatic mutation Attorney Docket No.07039-2155WO1 / 2022-250 prevalence.
  • a biomarker can include an amount of copy number variation (CNVs).
  • CNVs copy number variation
  • a biomarker can be a chromosomal rearrangement. Examples of types of chromosomal rearrangements include, without limitation, genomic insertions, genomic insertion/deletions (INDELs), genomic DUPs, genomic DELs (e.g., a genomic DEL resulting in LOH).
  • a biomarker can be a change in telomere structure (e.g., telomere content and telomere length).
  • a molecular profile used to determine whether or not a polyp can include an altered level (e.g., an increased level or a decreased level) of one or more polypeptides (or mRNA encoding such polypeptides).
  • a polypeptide that can have an altered level in a polyp that is or is likely to become malignant and/or is likely to recur can be involved in a cellular pathway such as a protein digestion and absorption pathway, a viral infection pathway, a focal adhesion pathway, a PI3K-Akt pathway, a transcriptional misregulation pathway (e.g., a cancer-related transcriptional misregulation pathway), and a senescence-associated secretory phenotype (SASP)-associated pathway.
  • a cellular pathway such as a protein digestion and absorption pathway, a viral infection pathway, a focal adhesion pathway, a PI3K-Akt pathway, a transcriptional misregulation pathway (e.g., a cancer-related transcriptional misregulation pathway), and a senescence-associated secretory phenotype (SASP)-associated pathway.
  • a sample e.g., a sample containing one or more polyp cells obtained from a mammal (e.g., a human) having one or more polyps (e.g., one or more colon polyps) can be assessed for the presence or absence of an altered level (e.g., an increased level or a decreased level) of one or more polypeptides (or mRNA encoding such polypeptides) to determine whether or not the polyp(s) are malignant.
  • an altered level e.g., an increased level or a decreased level
  • a polyp within a mammal having one or more polyps can be identified as being or likely to become malignant based, at least in part, on a molecular profile that includes the presence of an altered level of one or more polypeptides (or mRNA encoding such polypeptides) in a sample (e.g., a sample containing one or more polyp cells) obtained from the mammal.
  • a sample e.g., a sample containing one or more polyp cells obtained from a mammal (e.g., a human) having one or more polyps (e.g., one or more colon polyps) can be assessed for the presence or absence of an altered level (e.g., an increased level or a decreased level) of one or more polypeptides (or mRNA encoding such polypeptides) to determine whether or not the polyp(s) are likely to recur.
  • an altered level e.g., an increased level or a decreased level
  • a polyp within a mammal having one or more polyps can be identified as being likely to recur based, at least in part, on a molecular profile Attorney Docket No.07039-2155WO1 / 2022-250 that includes the presence of an altered level of one or more polypeptides (or mRNA encoding such polypeptides) in a sample (e.g., a sample containing one or more polyp cells) obtained from the mammal.
  • an altered level can be an increased level of one or more polypeptides (or mRNA encoding such polypeptides) in a sample (e.g., a sample containing one or more polyp cells) obtained from a mammal (e.g., a human) having one or more polyps (e.g., one or more colon polyps).
  • a sample e.g., a sample containing one or more polyp cells
  • a mammal e.g., a human
  • polyps e.g., one or more colon polyps.
  • the term “increased level” as used herein with respect to a level of a polypeptide (or mRNA encoding that polypeptide) in a sample refers to any level that is higher than a reference level of the polypeptide (or mRNA).
  • an altered level can be a decreased level of a polypeptide (or mRNA encoding that polypeptide) in a sample (e.g., a sample containing one or more polyp cells) obtained from a mammal having one or more polyps (e.g., one or more colon polyps).
  • a sample e.g., a sample containing one or more polyp cells
  • the term “decreased level” as used herein with respect to a level of a polypeptide (or mRNA encoding that polypeptide) in a sample refers to any level that is lower than a reference level of the polypeptide (or mRNA).
  • control samples include, without limitation, samples obtained from mammals having no polys (e.g., samples from healthy mammals and matched normal samples from mammals having one or more polyps), and samples from mammals having one or more polyps (e.g., one or more colon polyps) that did not progress to cancer, and samples obtained from mammals having one or more polyps (e.g., one or more colon polyps) that did not recur.
  • a sample e.g., a sample containing one or more polyp cells
  • a mammal e.g., a human
  • polyps e.g., one or more colon polyps
  • polypeptides that can be present at an altered level in a sample (e.g., a sample containing one or more polyp cells) obtained from a mammal having one or more polyps (e.g., one or more colon polyps) and where the polyp(s) are or are likely to become malignant and/or are likely recur include, without limitation, an ADAMTS4 polypeptide, a THBS2 polypeptide, a SERPINE1 polypeptide, a FAP Attorney Docket No.07039-2155WO1 / 2022-250 polypeptide (or mRNA encoding a FAP polypeptide), a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide), a CXCL13 polypeptide (or mRNA encoding a CXCL13 polypeptide), a SFRP2 polypeptide,
  • a sample (e.g., a sample containing one or more polyp cells) obtained from a mammal having one or more polyps (e.g., one or more colon polyps) can be assessed for the presence, absence, or level of one or more of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), a FAP polypeptide (or mRNA encoding a FAP polypeptide), a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide), a CXCL13 polypeptide (or mRNA encoding a CXCL13 polypeptide), a
  • a sample e.g., a sample containing one or more polyp cells obtained from a mammal having one or more polyps (e.g., one or more colon polyps) can be assessed for the presence, absence, or level of one or more of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide), an LY6G6C polypeptide (or mRNA encoding an LY6G6C polypeptide), a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide), a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide), a CYP1A1 polypeptide (or mRNA encoding a CYP1A1 polypeptide), a DMKN polypeptide (or mRNA encoding a Attorney Docket No.07039-2155WO1 / 2022-250 DMKN polypeptide), and
  • a molecular profile used to determine whether or not a polyp can include an altered level of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide).
  • ADAMTS4 polypeptides and nucleic acid sequences encoding an ADAMTS4 polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensembl ID Nos.
  • an altered level of an ADAMTS4 polypeptide can be any level that is higher or lower than a reference level of the ADAMTS4 polypeptide (or a reference level of an mRNA encoding an ADAMTS4 polypeptide).
  • a reference level of an ADAMTS4 polypeptide in humans can be a level of an ADAMTS4 polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 picograms (pg) of ADAMTS4 polypeptide per polyp cell.
  • a sample e.g., a sample containing one or more polyp cells
  • an increased level of an ADAMTS4 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of an ADAMTS4 polypeptide.
  • an increased level of an ADAMTS4 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of an ADAMTS4 polypeptide.
  • a decreased level of an ADAMTS4 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of an ADAMTS4 polypeptide.
  • a decreased level of an ADAMTS4 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of an ADAMTS4 polypeptide.
  • a molecular profile used to determine whether or not a polyp e.g., a colon polyp
  • a polyp e.g., a colon polyp
  • is or is likely to become malignant and/or is likely to recur as described herein can include an altered level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide).
  • THBS2 polypeptides and nucleic acid sequences encoding a THBS2 polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensembl ID Nos. Attorney Docket No.07039-2155WO1 / 2022-250 ENST00000366787 and ENST00000617924.
  • an altered level of a THBS2 polypeptide (or an mRNA encoding a THBS2 polypeptide) can be any level that is higher or lower than a reference level of the THBS2 polypeptide (or a reference level of an mRNA encoding a THBS2 polypeptide).
  • a reference level of a THBS2 polypeptide in humans can be a level of a THBS2 polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 pg of THBS2 polypeptide per polyp cell.
  • a sample e.g., a sample containing one or more polyp cells
  • an increased level of a THBS2 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of a THBS2 polypeptide.
  • an increased level of a THBS2 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of a THBS2 polypeptide.
  • a decreased level of a THBS2 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of a THBS2 polypeptide.
  • a decreased level of a THBS2 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of a THBS2 polypeptide.
  • a molecular profile used to determine whether or not a polyp e.g., a colon polyp
  • a polyp e.g., a colon polyp
  • is or is likely to become malignant and/or is likely to recur as described herein can include an altered level of a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide).
  • SERPINE1 polypeptides and nucleic acid sequences encoding a SERPINE1 polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensembl ID No. ENST00000223095.
  • an altered level of a SERPINE1 polypeptide (or an mRNA encoding a SERPINE1 polypeptide) can be any level that is higher or lower than a reference level of the SERPINE1 polypeptide (or a reference level of an mRNA encoding a SERPINE1 polypeptide).
  • a reference level of a SERPINE1 polypeptide in humans can be a level of a SERPINE1 polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 pg of SERPINE1 polypeptide per polyp cell.
  • an increased level of a SERPINE1 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of a SERPINE1 polypeptide.
  • an Attorney Docket No.07039-2155WO1 / 2022-250 increased level of a SERPINE1 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of a SERPINE1 polypeptide.
  • a decreased level of a SERPINE1 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of a SERPINE1 polypeptide.
  • a decreased level of a SERPINE1 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of a SERPINE1 polypeptide.
  • a molecular profile used to determine whether or not a polyp e.g., a colon polyp
  • is or is likely to become malignant and/or is likely to recur as described herein can include an altered level of a FAP polypeptide (or mRNA encoding a FAP polypeptide).
  • FAP polypeptides and nucleic acid sequences encoding a FAP polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensemble ID Nos. ENST00000422436, ENST00000480044, and ENST00000188790.
  • an altered level of a FAP polypeptide can be any level that is higher or lower than a reference level of the FAP polypeptide (or a reference level of an mRNA encoding a FAP polypeptide).
  • a reference level of a FAP polypeptide in humans can be a level of a FAP polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 pg of FAP polypeptide per polyp cell.
  • an increased level of a FAP polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of a FAP polypeptide.
  • an increased level of a FAP polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of a FAP polypeptide.
  • a decreased level of a FAP polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of a FAP polypeptide.
  • a decreased level of a FAP polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of a FAP polypeptide.
  • a molecular profile used to determine whether or not a polyp can include an altered level Attorney Docket No.07039-2155WO1 / 2022-250 of a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide).
  • Examples of CYR61 polypeptides and nucleic acid sequences encoding a CYR61 polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensembl ID Nos.
  • an altered level of a CYR61 polypeptide can be any level that is higher or lower than a reference level of the CYR61 polypeptide (or a reference level of an mRNA encoding a CYR61 polypeptide).
  • a reference level of a CYR61 polypeptide in humans can be a level of a CYR61 polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 pg of CYR61 polypeptide per polyp cell.
  • an increased level of a CYR61 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of a CYR61 polypeptide.
  • an increased level of a CYR61 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of a CYR61 polypeptide.
  • a decreased level of a CYR61 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of a CYR61 polypeptide.
  • a decreased level of a CYR61 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of a CYR61 polypeptide.
  • a molecular profile used to determine whether or not a polyp can include an altered level of a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide).
  • SOX11 polypeptides and nucleic acid sequences encoding a SOX11 polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensemble ID No. ENST00000322002.
  • an altered level of a SOX11 polypeptide can be any level that is higher or lower than a reference level of the SOX11 polypeptide (or a reference level of an mRNA encoding a SOX11 polypeptide).
  • a reference level of a SOX11 polypeptide in humans can be a level of a SOX11 polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 pg of SOX11 polypeptide per polyp cell.
  • an increased level of a SOX11 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of a SOX11 polypeptide.
  • an increased level of a SOX11 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of a SOX11 polypeptide.
  • a decreased level of a SOX11 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of a SOX11 polypeptide.
  • an increased level of a SOX11 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of a SOX11 polypeptide.
  • a molecular profile used to determine whether or not a polyp can include an altered level of a CXCL13 polypeptide (or an increased level of an mRNA encoding a CXCL13 polypeptide).
  • CXCL13 polypeptides and nucleic acid sequences encoding a CXCL13 polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensemble ID Nos ENSG00000156234, ENST00000286758, and ENST00000506590.
  • an altered level of a CXCL13 polypeptide (or an mRNA encoding a CXCL13 polypeptide) can be any level that is higher or lower than a reference level of the CXCL13 polypeptide (or a reference level of an mRNA encoding a CXCL13 polypeptide).
  • a reference level of a CXCL13 polypeptide in humans can be a level of a CXCL13 polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 pg of CXCL13 polypeptide per polyp cell.
  • a sample e.g., a sample containing one or more polyp cells
  • an increased level of a CXCL13 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of a CXCL13 polypeptide.
  • an increased level of a CXCL13 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of a CXCL13 polypeptide.
  • a decreased level of a CXCL13 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of a CXCL13 polypeptide.
  • a decreased level of a CXCL13 polypeptide can be a level that is Attorney Docket No.07039-2155WO1 / 2022-250 at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of a CXCL13 polypeptide.
  • a molecular profile used to determine whether or not a polyp can include an altered level of a SFRP2 polypeptide (or mRNA encoding a SFRP2 polypeptide).
  • SFRP2 polypeptides and nucleic acid sequences encoding a SFRP2 polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensembl ID No. ENST00000274063.
  • an altered level of a SFRP2 polypeptide can be any level that is higher or lower than a reference level of the SFRP2 polypeptide (or a reference level of an mRNA encoding a SFRP2 polypeptide).
  • a reference level of a SFRP2 polypeptide in humans can be a level of a SFRP2 polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 pg of SFRP2 polypeptide per polyp cell.
  • an increased level of a SFRP2 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of a SFRP2 polypeptide.
  • an increased level of a SFRP2 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of a SFRP2 polypeptide.
  • a decreased level of a SFRP2 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of a SFRP2 polypeptide.
  • a decreased level of a SFRP2 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of a SFRP2 polypeptide.
  • a molecular profile used to determine whether or not a polyp can include altered level of a VIP polypeptide (or mRNA encoding a VIP polypeptide).
  • VIP polypeptides and nucleic acid sequences encoding a VIP polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensemble ID Nos. ENST00000367243, ENST00000431366, and ENST00000431366.
  • an altered level of a VIP polypeptide can be any level that is Attorney Docket No.07039-2155WO1 / 2022-250 higher or lower than a reference level of the VIP polypeptide (or a reference level of an mRNA encoding a VIP polypeptide).
  • a reference level of a VIP polypeptide in humans can be a level of a VIP polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 pg of VIP polypeptide per polyp cell.
  • an increased level of a VIP polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of a VIP polypeptide.
  • an increased level of a VIP polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of a VIP polypeptide.
  • a decreased level of a VIP polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of a VIP polypeptide.
  • a decreased level of a VIP polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of a VIP polypeptide.
  • a molecular profile used to determine whether or not a polyp e.g., a colon polyp
  • is or is likely to become malignant and/or is likely to recur as described herein can include an altered level of a TERT polypeptide (or mRNA encoding a TERT polypeptide).
  • TERT polypeptides and nucleic acid sequences encoding a TERT polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensembl ID Nos. ENSG00000164362, ENST00000310581, ENST00000508104, ENST00000484238, and ENST00000310581.
  • an altered level of a TERT polypeptide (or an mRNA encoding a TERT polypeptide) can be any level that is higher or lower than a reference level of the TERT polypeptide (or a reference level of an mRNA encoding a TERT polypeptide).
  • a reference level of a TERT polypeptide in humans can be a level of a TERT polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 pg of TERT polypeptide per polyp cell.
  • a sample e.g., a sample containing one or more polyp cells
  • an increased level of a TERT polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of a TERT polypeptide.
  • an increased level of a TERT polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of a TERT polypeptide.
  • a decreased level of a TERT polypeptide can be at least Attorney Docket No.07039-2155WO1 / 2022-250 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of a TERT polypeptide.
  • a decreased level of a TERT polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of a TERT polypeptide.
  • a molecular profile used to determine whether or not a polyp e.g., a colon polyp
  • a polyp e.g., a colon polyp
  • is or is likely to become malignant and/or is likely to recur as described herein can include an altered level of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide).
  • TPRG1 polypeptides and nucleic acid sequences encoding a TPRG1 polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensembl ID Nos. ENST00000433971, ENST00000496671, and ENST00000345063.
  • an altered level of a TPRG1 polypeptide (or an mRNA encoding a TPRG1 polypeptide) can be any level that is higher or lower than a reference level of the TPRG1 polypeptide (or a reference level of an mRNA encoding a TPRG1 polypeptide).
  • a reference level of a TPRG1 polypeptide in humans can be a level of a TPRG1 polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 pg of TPRG1 polypeptide per polyp cell.
  • a sample e.g., a sample containing one or more polyp cells
  • an increased level of a TPRG1 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of a TPRG1 polypeptide.
  • an increased level of a TPRG1 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of a TPRG1 polypeptide.
  • a decreased level of a TPRG1 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of a TPRG1 polypeptide.
  • a decreased level of a TPRG1 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of a TPRG1 polypeptide.
  • a molecular profile used to determine whether or not a polyp e.g., a colon polyp
  • a polyp e.g., a colon polyp
  • is or is likely to become malignant and/or is likely to recur as described herein can include an altered level of an LY6G6C polypeptide (or mRNA encoding an LY6G6C polypeptide).
  • LY6G6C polypeptides and nucleic acid sequences encoding an LY6G6C polypeptide include, Attorney Docket No.07039-2155WO1 / 2022-250 without limitation, those set forth in the Ensembl genome browser at, for example, Ensembl ID Nos. ENST00000495859 and ENST00000375819.
  • an altered level of an LY6G6C polypeptide can be any level that is higher or lower than a reference level of the LY6G6C polypeptide (or a reference level of an mRNA encoding an LY6G6C polypeptide).
  • a reference level of an LY6G6C polypeptide in humans can be a level of an LY6G6C polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 pg of LY6G6C polypeptide per polyp cell.
  • an increased level of an LY6G6C polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of an LY6G6C polypeptide.
  • an increased level of an LY6G6C polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of an LY6G6C polypeptide.
  • a decreased level of an LY6G6C polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of an LY6G6C polypeptide.
  • a decreased level of an LY6G6C polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of an LY6G6C polypeptide.
  • a molecular profile used to determine whether or not a polyp e.g., a colon polyp
  • a polyp e.g., a colon polyp
  • is or is likely to become malignant and/or is likely to recur as described herein can include an altered level of a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide).
  • Examples of DUSP4 polypeptides and nucleic acid sequences encoding a DUSP4 polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensemble ID Nos. ENST00000240100 and ENST00000240101.
  • an altered level of a DUSP4 polypeptide (or an mRNA encoding a DUSP4 polypeptide) can be any level that is higher or lower than a reference level of the DUSP4 polypeptide (or a reference level of an mRNA encoding a DUSP4 polypeptide).
  • a reference level of a DUSP4 polypeptide in humans can be a level of a DUSP4 polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 pg of DUSP4 polypeptide per polyp cell.
  • an increased level of a DUSP4 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a Attorney Docket No.07039-2155WO1 / 2022-250 reference level of a DUSP4 polypeptide.
  • an increased level of a DUSP4 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of a DUSP4 polypeptide.
  • a decreased level of a DUSP4 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of a DUSP4 polypeptide.
  • a decreased level of a DUSP4 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of a DUSP4 polypeptide.
  • a molecular profile used to determine whether or not a polyp e.g., a colon polyp
  • a polyp e.g., a colon polyp
  • is or is likely to become malignant and/or is likely to recur as described herein can include an altered level of a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide).
  • ZIC5 polypeptides and nucleic acid sequences encoding a ZIC5 polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensembl ID No. ENST00000267294.
  • an altered level of a ZIC5 polypeptide (or an mRNA encoding a ZIC5 polypeptide) can be any level that is higher or lower than a reference level of the ZIC5 polypeptide (or a reference level of an mRNA encoding a ZIC5 polypeptide).
  • a reference level of a ZIC5 polypeptide in humans can be a level of a ZIC5 polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 pg of ZIC5 polypeptide per polyp cell.
  • a sample e.g., a sample containing one or more polyp cells
  • an increased level of a ZIC5 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of a ZIC5 polypeptide.
  • an increased level of a ZIC5 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of a ZIC5 polypeptide.
  • a decreased level of a ZIC5 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of a ZIC5 polypeptide.
  • a decreased level of a ZIC5 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of a ZIC5 polypeptide.
  • a molecular profile used to determine whether or not a polyp can include an altered level of a CYP1A1 polypeptide (or mRNA encoding a CYP1A1 polypeptide).
  • CYP1A1 polypeptides and nucleic acid sequences encoding a CYP1A1 polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensembl ID Nos. ENST00000379727, ENST00000567032, and ENST00000395048.
  • an altered level of a CYP1A1 polypeptide (or an mRNA encoding a CYP1A1 polypeptide) can be any level that is higher or lower than a reference level of the CYP1A1 polypeptide (or a reference level of an mRNA encoding a CYP1A1 polypeptide).
  • a reference level of a CYP1A1 polypeptide in humans can be a level of a CYP1A1 polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 pg of CYP1A1 polypeptide per polyp cell.
  • a sample e.g., a sample containing one or more polyp cells
  • an increased level of a CYP1A1 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of a CYP1A1 polypeptide.
  • an increased level of a CYP1A1 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of a CYP1A1 polypeptide.
  • a decreased level of a CYP1A1 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of a CYP1A1 polypeptide.
  • a decreased level of a CYP1A1 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of a CYP1A1 polypeptide.
  • a molecular profile used to determine whether or not a polyp e.g., a colon polyp
  • a polyp e.g., a colon polyp
  • is or is likely to become malignant and/or is likely to recur as described herein can include an altered level of a DMKN polypeptide (or mRNA encoding a DMKN polypeptide).
  • Examples of DMKN polypeptides and nucleic acid sequences encoding a DMKN polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensembl ID No. ENST00000489395.
  • an altered level of a DMKN polypeptide (or an mRNA encoding a DMKN polypeptide) can be any level that is higher or lower than a reference level of the DMKN polypeptide (or a reference level of an mRNA encoding a DMKN polypeptide).
  • a reference level of a DMKN polypeptide in humans can be a Attorney Docket No.07039-2155WO1 / 2022-250 level of a DMKN polypeptide in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of 0.00061 pg of DMKN polypeptide per polyp cell.
  • a sample e.g., a sample containing one or more polyp cells
  • an increased level of a DMKN polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of a DMKN polypeptide.
  • an increased level of a DMKN polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold greater than a reference level of a DMKN polypeptide.
  • a decreased level of a DMKN polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of a DMKN polypeptide.
  • a decreased level of a DMKN polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of a DMKN polypeptide.
  • a molecular profile used to determine whether or not a polyp e.g., a colon polyp
  • is or is likely to become malignant and/or is likely to recur as described herein can include an altered level of an IGLL5 polypeptide (or mRNA encoding an IGLL5 polypeptide).
  • IGLL5 polypeptides and nucleic acid sequences encoding an IGLL5 polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensembl ID No. ENSG00000254709.
  • a decreased level of an IGLL5 polypeptide can be at least 50% (e.g., about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) lower than a reference level of an IGLL5 polypeptide.
  • a decreased level of an IGLL5 polypeptide can be a level that is at least 0.5 (e.g., at least 1, at least 2, at least 3, at least 4, or at least 5) fold less than a reference level of an IGLL5 polypeptide.
  • Any appropriate method can be used to determine the presence, absence, or level of a polypeptide or mRNA encoding that polypeptide. In some cases, the presence, absence, or level of a polypeptide can be assessed by detecting and/or quantifying the polypeptide.
  • Examples of methods that can be used to detect and/or quantify polypeptides include, without limitation, immunohistochemistry (IHC) techniques, mass spectrometry techniques (e.g., proteomics-based mass spectrometry assays or targeted quantification-based mass spectrometry assays), and western blotting techniques.
  • IHC immunohistochemistry
  • mass spectrometry techniques e.g., proteomics-based mass spectrometry assays or targeted quantification-based mass spectrometry assays
  • western blotting techniques e.g., Western blotting techniques.
  • the presence, absence, or level of an mRNA encoding a polypeptide can be assessed by detecting and/or quantifying Attorney Docket No.07039-2155WO1 / 2022-250 the mRNA encoding a polypeptide.
  • RNA sequencing techniques examples include, without limitation, RT-PCR techniques (e.g., quantitative RT-PCR techniques), and next-generation sequencing (NGS) techniques (e.g., RNA sequencing (RNA-Seq) techniques).
  • NGS next-generation sequencing
  • RNA-Seq RNA sequencing
  • a molecular profile used to determine whether or not a polyp can include one or more mutated polypeptides.
  • a sample e.g., a sample containing one or more polyp cells
  • a mammal e.g., a human
  • having one or more polyps e.g., one or more colon polyps
  • mutant refers to a modification in the amino acid sequence as compared to a wild type amino acid for a particular species.
  • a mutation can be any type of mutation including, without limitation, an insertion of one or more amino acids, a deletion of one or more amino acids, a substitution of one or more amino acids, and combinations thereof.
  • a mutation in a polypeptide can cause altered polypeptide activity.
  • a polyp that is or is likely to become malignant and/or is likely to recur can have the presence of one or more mutations in any appropriate one or more polypeptides in a sample (e.g., a sample containing one or more polyp cells) obtained from a mammal (e.g., a human) having one or more polyps (e.g., one or more colon polyps).
  • a KRAS polypeptide within a sample e.g., a sample containing one or more polyp cells obtained from a mammal having one or more polyps (e.g., one or more colon polyps) can be assessed for the presence or absence of one or more mutations.
  • Examples of wild type KRAS polypeptides and nucleic acid sequences encoding a KRAS polypeptide include, without limitation, those set forth in the Ensembl genome browser at, for example, Ensembl ID Nos. ENST00000311936, ENSG00000133703, and ENST00000556131.
  • a mutation that can be present in a KRAS polypeptide included in a molecular profile that can be used to identify a mammal (e.g., a human) as having one or more polyps (e.g., one or more colon polyps) that are or are likely to become malignant and/or are likely to recur can be as described in Example 4.
  • any appropriate method can be used to detect the presence or absence of one or more mutations in a polypeptide within a sample (e.g., a sample containing one or more polyp cells) obtained from a mammal (e.g., a human) having one or more polyps (e.g., one or more colon polyps).
  • a sample e.g., a sample containing one or more polyp cells
  • a mammal e.g., a human
  • polyps e.g., one or more colon polyps
  • mass spectrometry, Edman degradation, and NGS techniques can be used to identify the presence or absence of one or more mutations in a polypeptide (e.g., a KRAS polypeptide).
  • nucleic acid encoding a polypeptide such as DNA or RNA
  • a polypeptide such as DNA or RNA
  • a sample e.g., a sample containing one or more polyp cells
  • a mammal e.g., a human
  • polyps e.g., one or more colon polyps
  • nucleic acid sequencing techniques can be used to detect the presence or absence of one or more mutations in a polypeptide (e.g., a KRAS polypeptide).
  • a molecular profile used to determine whether or not a polyp can include an elevated somatic mutation prevalence.
  • a sample e.g., a sample containing one or more polyp cells
  • a mammal e.g., a human
  • one or more polyps e.g., one or more colon polyps
  • an elevated somatic mutation prevalence in a sample refers to any level that is higher than a reference level of somatic mutation prevalence.
  • an elevated somatic mutation prevalence can be at least 5% (e.g., about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of somatic mutation prevalence.
  • an elevated somatic mutation prevalence can be a prevalence that is at least 2 (e.g., at least 5, at least 10, at least 15, at least 20, at least 25, at least 35, or at least 50) fold greater than a reference level of somatic mutation prevalence.
  • any appropriate method can be used to determine the somatic mutation prevalence of a polyp.
  • whole genome sequence, RNAseq, and/or gene panel tests can be used to determine a somatic mutation prevalence.
  • a molecular profile used to determine whether or not a polyp e.g., a colon polyp
  • Attorney Docket No.07039-2155WO1 / 2022-250 e.g., based, at least in part, on the molecular profile of the polyp
  • an elevated copy number variation e.g., an elevated mean copy number variation
  • a sample e.g., a sample containing one or more polyp cells obtained from a mammal (e.g., a human) having one or more polyps (e.g., one or more colon polyps) can be assessed for the presence or absence of an elevated copy number variation.
  • an elevated copy number variation e.g., a mean copy number variation
  • can include a larger size repeated region e.g., an elevated copy number variation size.
  • the term “elevated” as used herein with respect to a copy number variation size in a sample refers to any level that is higher than a reference level of copy number variation size.
  • a reference level of copy number variation size in humans can be a copy number variation size in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of about 80000 base pairs.
  • an elevated copy number variation size can be at least 5% (e.g., about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of copy number variation size.
  • an elevated copy number variation size can be a variation that is at least 2 (e.g., at least 5, at least 10, at least 15, at least 20, at least 25, at least 35, or at least 50) fold greater than a reference level of copy number variation size.
  • RNAseq can be used to determine a copy number variation.
  • a molecular profile used to determine whether or not a polyp e.g., a colon polyp
  • a molecular profile used to determine whether or not a polyp can include one or more chromosomal rearrangements (e.g., genomic insertions, genomic INDELs, genomic DUPs, and genomic DELs such as genomic DELs resulting in LOH).
  • a sample e.g., a sample containing one or more polyp cells
  • a mammal e.g., a human
  • polyps e.g., one or more colon polyps
  • chromosomal rearrangement refers to a chromosome abnormality involving a change in the structure of the native chromosome for a particular species.
  • a chromosomal rearrangement can be any type of chromosomal rearrangement including, without limitation, genomic Attorney Docket No.07039-2155WO1 / 2022-250 insertions, genomic INDELs, genomic DUPs, and genomic DELs, and combinations thereof.
  • a chromosomal rearrangement can result in LOH.
  • a polyp that is or is likely to become malignant and/or is likely to recur can have the presence of one or more chromosomal rearrangements in a sample (e.g., a sample containing one or more polyp cells) obtained from a mammal (e.g., a human) having one or more polyps (e.g., one or more colon polyps).
  • any appropriate method can be used to determine the presence or absence of a chromosomal rearrangement within a sample (e.g., a sample containing one or more polyp cells) obtained from a mammal (e.g., a human) having one or more polyps (e.g., one or more colon polyps).
  • a sample e.g., a sample containing one or more polyp cells
  • a mammal e.g., a human
  • polyps e.g., one or more colon polyps
  • comparative genomic hybridization, CNV panel testing, and/or whole genome sequencing can be used to detect a chromosomal rearrangement.
  • a molecular profile used to determine whether or not a polyp can include one or more changes in telomere structure (e.g., telomere content and telomere length).
  • a sample e.g., a sample containing one or more polyp cells obtained from a mammal (e.g., a human) having one or more polyps (e.g., one or more colon polyps) can be assessed for the presence or absence of telomere structure (e.g., telomere content and telomere length).
  • telomere structure e.g., telomere content and telomere length
  • a change in telomere structure can be an increase in telomere content (e.g., an increase in the number of TTAGG repeats present in a telomere).
  • a change in telomere structure can be an increase in telomere length.
  • a polyp that is or is likely to become malignant and/or is likely to recur can have the presence of one or more chromosomal rearrangements in a sample (e.g., a sample containing one or more polyp cells) obtained from a mammal (e.g., a human) having one or more polyps (e.g., one or more colon polyps).
  • a sample e.g., a sample containing one or more polyp cells
  • a mammal e.g., a human
  • polyps e.g., one or more colon polyps
  • telomere structure e.g., telomere content and telomere length
  • a sample e.g., a sample containing one or more polyp cells
  • a mammal e.g., a human
  • polyps e.g., one or more colon polyps.
  • TelomereHunter software, mmqPCR, TeloFISH, and/or Southern blotting can be used to detect a change in telomere structure.
  • a molecular profile used to determine whether or not a polyp can include an increased number of NKCs in the resting phase.
  • a sample e.g., a sample containing one or more polyp cells
  • a mammal e.g., a human
  • polyps e.g., one or more colon polyps
  • the term “increased” as used herein with respect to a number of NKCs in the resting phase in a sample refers to any level that is higher than a reference level of NKCs in the resting phase.
  • a reference level of NKCs in the resting phase in humans can be a number of NKCs in the resting phase in a sample (e.g., a sample containing one or more polyp cells) obtained from the human of about 1000 cells/mL sample.
  • a sample e.g., a sample containing one or more polyp cells
  • an increased number of NKCs in the resting phase can be at least 5% (e.g., about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) higher than a reference level of NKCs in the resting phase.
  • an increased number of NKCs in the resting phase can be at least 2 (e.g., at least 5, at least 10, at least 15, at least 20, at least 25, at least 35, or at least 50) fold greater than a reference level of NKCs in the resting phase.
  • Any appropriate method can be used to determine the number of NKCs in the resting phase within a sample (e.g., a sample containing one or more polyp cells) obtained from a mammal (e.g., a human) having one or more polyps (e.g., one or more colon polyps).
  • CIBERSORT and/or immunoFISH can be used to determine the number of NKCs in the resting phase.
  • the molecular profile of a polyp can be used to identify the polyp as being or likely to become malignant. For example, the presence of one or more of an increased level of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), an increased level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), an increased level of a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), an increased level of a FAP polypeptide (or mRNA encoding a FAP polypeptide), an increased level of a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), an increased level of a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide), an increased level of a CXCL13 polypeptide (or mRNA encoding a CXCL13 Attorney Docket No.0
  • the molecular profile of a polyp can be used to identify the polyp as not being or not likely to become malignant. For example, the absence of an increased level of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), an increased level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), an increased level of a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), an increased level of a FAP polypeptide (or mRNA encoding a FAP polypeptide), an increased level of a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), an increased level of a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide), an increased level of a CXCL13 polypeptide (or mRNA encoding a CXCL13 polypeptide), an increased level of a a
  • a polyp when assessed to determine whether or not the polyp is malignant as described herein (e.g., based, at least in part, on the molecular profile of the polyp), the determination can be confirmed using one or more additional diagnostic Attorney Docket No.07039-2155WO1 / 2022-250 techniques.
  • additional diagnostic Attorney Docket No.07039-2155WO1 / 2022-250 techniques examples include, without limitation, analyses of histology and degree of dysplasia in the polyp (e.g., via hematoxylin and eosin staining of tissue from a polyp).
  • the molecular profile of a polyp can be used to identify the polyp as being likely to recur.
  • an increased level of a TPRG1 polypeptide or mRNA encoding a TPRG1 polypeptide
  • an increased level of an LY6G6C polypeptide or mRNA encoding an LY6G6C polypeptide
  • an increase level of a DUSP4 polypeptide or mRNA encoding a DUSP4 polypeptide
  • an increased level of a ZIC5 polypeptide or mRNA encoding a ZIC5 polypeptide
  • an increased level of a CYP1A1 polypeptide or mRNA encoding a CYP1A1 polypeptide
  • an increased level of a DMKN polypeptide or mRNA encoding a DMKN polypeptide
  • a decreased level of an IGLL5 polypeptide or mRNA encoding an IGLL5 polypeptide
  • one or more changes in genetic content e.g., an increased frequency of genomic DELs and an increased
  • the molecular profile of a polyp can be used to identify the polyp as not being likely to recur. For example, the absence of an increased level of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide), an increased level of an LY6G6C polypeptide (or mRNA encoding an LY6G6C polypeptide), an increased level of a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide), an increased level of a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide), an increased level of a CYP1A1 polypeptide (or mRNA encoding a CYP1A1 polypeptide), an increased level of a DMKN polypeptide (or mRNA encoding a DMKN polypeptide), a decreased level of an IGLL5 polypeptide (or mRNA encoding an IGLL5 polypeptide (or
  • a mammal e.g., a human having one or more polyps (e.g., one or more colon polyps) that are assessed as described herein (e.g., to determine whether or not the polyps are or are likely to become malignant and/or likely to recur based, at least in part, on the molecular profile of the polyps) can be selected from one or more treatments where the treatments are selected based, at least in part, on the molecular profile of the mammal’s polyp(s) as described herein.
  • polyps e.g., one or more colon polyps
  • a treatment and/or intervention for one or more polyps can include any appropriate polyp treatment and/or intervention.
  • a polyp treatment and/or intervention can include surgery (e.g., colectomy and/or lymph node removal) and/or other medical interventions.
  • Examples of treatments and/or interventions that can be used to treat a mammal having one or more polyps can include, without limitation, surgery to remove of the polyp(s) (e.g., polypectomy (e.g., polypectomy with or without injection of a liquid to lift and isolate the polyp from surrounding tissue) such as colonoscopic polypectomy, proctocolectomy (e.g., segmental, subtotal, or total proctocolectomy), regular screenings (e.g., colonoscopies), eating a healthy diet, (e.g., a diet including fruits, vegetables, nuts, seeds, whole grains, omega 3 fatty acid containing foods (e.g., cold water fishes), reduced animal protein, and reduced nitrite preserved foods intake), adopting healthy lifestyle habits (e.g., limited alcohol consumption and limited tobacco usage), physical activity, maintaining a healthy body weight, taking one or more nutritional supplements (e.g., calcium, turmeric, antioxidant, polyphenols, multivitamins, and vitamin D), aspirin, non-
  • a mammal e.g., a human having at least one polyp (e.g., at least one colon polyp) that is identified as not being or not likely to become malignant and/or not likely to recur as described herein (e.g., based, at least in part, on the molecular profile of the polyps) can be selected to receive a polyp treatment (e.g., a colon polyp treatment).
  • a polyp treatment e.g., a colon polyp treatment
  • a mammal having one or more polyps that are identified as having a molecular profile that lacks an increased level of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), an increased level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), an increased level of a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), an increased level of a FAP polypeptide (or mRNA encoding a FAP polypeptide), an increased level of a CYR61 Attorney Docket No.07039-2155WO1 / 2022-250 polypeptide (or mRNA encoding a CYR61 polypeptide), an increased level of a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide), an increased level of a CXCL13 polypeptide
  • a mammal having one or more polyps that are identified as having a molecular profile that (a) lacks an increased level of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide), an increased level of an LY6G6C polypeptide (or mRNA encoding an LY6G6C polypeptide), an increased level of a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide), an increased level of a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide), an increased level of a CYP1A1 polypeptide (or mRNA encoding a CYP1A1 polypeptide), an increased level of a DMKN polypeptide (or mRNA encoding a DMKN polypeptide), a decreased level of an IGLL5 polypeptide (or mRNA
  • a mammal e.g., a human having at least one polyp (e.g., at least one colon polyp) that is identified as being or likely to become malignant and/or as likely to recur as described herein (e.g., based, at least in part, on the molecular profile of the polyps) can be selected for more frequent (e.g., additional and/or increased) screenings.
  • a mammal identified as having a malignant polyp and/or a polyp that is likely to recur can be selected for more frequent screenings for the presence or absence of polyps.
  • a mammal having one or more polyps that are identified as having a molecular profile having the presence of one or more of an increased level of an Attorney Docket No.07039-2155WO1 / 2022-250 ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), an increased level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), an increased level of a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), an increased level of a FAP polypeptide (or mRNA encoding a FAP polypeptide), an increased level of a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), an increased level of a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide), an increased level of a CX
  • a mammal having one or more polyps that are identified as having a molecular profile having the presence of one or more of an increased level of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide), an increased level of an LY6G6C polypeptide (or mRNA encoding an LY6G6C polypeptide), an increased level of a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide), an increased level of a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide), an increased level of a CYP1A1 polypeptide (or mRNA encoding a CYP1A1 polypeptide), an increased level of a DMKN polypeptide (or mRNA encoding a DMKN polypeptide), a decreased level of an IGLL5 polypeptide (or m
  • a mammal e.g., a human having at least one polyp (e.g., at least one colon polyp) that is identified as being or likely to become malignant as described herein (e.g., based, at least in part, on the molecular profile of the polyps) can be selected to receive one or more polyp treatments and can be selected for one or more cancer treatments.
  • at least one polyp e.g., at least one colon polyp
  • the molecular profile of the polyps can be selected to receive one or more polyp treatments and can be selected for one or more cancer treatments.
  • a mammal having one or more polyps that are Attorney Docket No.07039-2155WO1 / 2022-250 identified as having a molecular profile having the presence of one or more of an increased level of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), an increased level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), an increased level of a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), an increased level of a FAP polypeptide (or mRNA encoding a FAP polypeptide), an increased level of a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), an increased level of a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide), an increased level of a CX
  • This document also provides methods for treating a mammal (e.g., a human) having one or more polyps (e.g., one or more colon polyps).
  • a mammal e.g., a human
  • having one or more polyps e.g., one or more colon polyps
  • that are assessed as described herein e.g., to determine whether or not the polyps are or are likely to become malignant and/or likely to recur based, at least in part, on the molecular profile of the polyps
  • a mammal e.g., a human having one or more polyps (e.g., one or more colon polyps) can be administered or instructed to self-administer one or more treatments and/or interventions selected based, at least in part, on whether or not the polyps are or are likely to become malignant and/or are likely to recur (e.g., based, at least in part, on the molecular profile of the polyps).
  • a mammal e.g., a human
  • at least one polyp e.g., at least one colon polyp
  • the mammal can receive a polyp treatment (e.g., a colon polyp treatment).
  • a mammal having one or more polyps that are identified as having a molecular profile that lacks an increased level of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), an increased level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), an increased level of a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), an increased level of a FAP polypeptide (or mRNA encoding a FAP polypeptide), an increased level of a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), an increased level of a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide), an increased level of a CXCL13 polypeptide (or mRNA encoding a CXCL13 polypeptide), an
  • a mammal having one or more polyps that are identified as having a molecular profile that (a) lacks an increased level of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide), an increased level of an LY6G6C polypeptide (or mRNA encoding an LY6G6C polypeptide), an increased level of a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide), an increased level of a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide), an increased level of a CYP1A1 polypeptide (or mRNA encoding a CYP1A1 polypeptide), an increased level of a DMKN polypeptide (or mRNA encoding a DMKN polypeptide), a decreased level of an IGLL5 polypeptide (or mRNA
  • the one or more colon polyp treatments can be the sole treatment used to treat the mammal.
  • a mammal having one or more polyps that are identified as having a molecular profile that lacks an increased level of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), an increased level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), an increased level of a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), an increased level of a FAP polypeptide (or mRNA encoding a FAP polypeptide), an increased level of a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), an increased level of a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide), an increased level of a CXCL13 polypeptide (or mRNA encoding a CXCL13 polypeptide), an
  • a mammal having one or more polyps that are identified as having a molecular profile that (a) lacks an increased level of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide), an increased level of an LY6G6C polypeptide (or mRNA encoding an LY6G6C polypeptide), an increased level of a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide), an increased level of a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide), an increased level of a CYP1A1 polypeptide (or mRNA encoding a CYP1A1 polypeptide), an increased level of a DMKN polypeptide (or mRNA encoding a DMKN polypeptide), and a decreased level of an IGLL5 Attorney Docket No.070
  • a mammal e.g., a human
  • one or more polyps e.g., one or more colon polyps
  • the mammal can be subjected to one or more colon polyp treatments (e.g., surgery to remove the polyps) and can be administered or instructed to self-administer one or more cancer treatments.
  • a mammal having one or more polyps that are identified having a molecular profile that includes the presence of one or more of an increased level of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), an increased level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), an increased level of a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), an increased level of a FAP polypeptide (or mRNA encoding a FAP polypeptide), an increased level of a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), an increased level of a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide), an increased level of a CXCL13 polypeptide (or mRNA encoding a CXCL13 polypeptide (or mRNA encoding a CXCL
  • a cancer treatment can include any appropriate cancer treatment.
  • a cancer treatment can include surgery and/or other medical interventions. Examples of surgeries and other medical interventions that can be performed on a mammal having one or more polyps (e.g., one or more colon polyps) identified as being or likely to become malignant as Attorney Docket No.07039-2155WO1 / 2022-250 described herein (e.g., based, at least in part, on the molecular profile of the polyps) to treat the mammal include, without limitation, surgery to remove the polyp(s) (e.g., polypectomy (e.g., polypectomy with or without injection of a liquid to lift and isolate the polyp from surrounding tissue), laparoscopy, total proctocolectomy), surgery to remove the tissue around the polyp(s), surgery to remove the polyp(s) and the surrounding tissue, and radiation therapy.
  • polyp(s) e.g., polypectomy (e.g., polypectomy with or without injection of a
  • a cancer treatment can include administering one or more anti-cancer drugs (e.g., chemotherapeutic agents, targeted cancer drugs, and immunotherapy drugs) to a mammal in need thereof.
  • anti-cancer drugs e.g., chemotherapeutic agents, targeted cancer drugs, and immunotherapy drugs
  • examples of anti-cancer drugs that can be administered to a mammal having one or more polyps (e.g., one or more colon polyps) identified as being or likely to become malignant as described herein (e.g., based, at least in part, on the molecular profile of the polyps) can include, without limitation, docetaxel, capecitabine, cyclophosphamide, epirubicin, fluorouracil, bevacizumab (e.g., Avastin ® ), cetuximab (e.g., ERBITUX ® ), panitumumab (e.g., Vectibix ® ), ram
  • a mammal e.g., a human
  • one or more polyps e.g., one or more colon polyps
  • the mammal can be subjected to one or more colon polyp treatments (e.g., surgery to remove the polyps) and can undergo more frequent (e.g., additional and/or increased) screenings.
  • a mammal having one or more polyps that are identified as having a molecular profile having the presence of one or more of an increased level of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide), an increased level of an LY6G6C polypeptide (or mRNA encoding an LY6G6C polypeptide), an increased level of a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide), an increased level of a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide), an increased level of a CYP1A1 polypeptide (or mRNA encoding a CYP1A1 polypeptide), an increased level of a DMKN polypeptide (or mRNA encoding a DMKN polypeptide), a decreased level of an IGLL5 polypeptide (or m
  • the treatment when treating a mammal (e.g., a human) having one or more polyps (e.g., one or more colon polyps) as described herein, the treatment can be effective to treat the polyps (e.g., while minimizing the risk of metastasis and/or recurrence).
  • the number of polyps (e.g., colon polyps) present within a mammal can be reduced using the methods and materials described herein.
  • the methods and materials described herein can be used to reduce the number of polyps (e.g., colon polyps) present within a mammal having one or more polyps (e.g., one or more colon polyps) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent (e.g., while minimizing the risk of metastasis and/or recurrence).
  • the number of polyps (e.g., colon polyps) present within a mammal does not increase.
  • the size (e.g., volume) of one or more polyps (e.g., colon polyps) present within a mammal can be reduced using the methods and materials described herein.
  • the methods and materials described herein can be used to reduce the size of one or more polyps (e.g., colon polyps) present within a mammal having one or more polyps (e.g., one or more colon polyps) by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent (e.g., while minimizing the risk of metastasis and/or recurrence).
  • the size (e.g., volume) of one or more polyps (e.g., one or more colon polyps) present within a mammal does not increase.
  • a course of treatment the number and/or size of one or more polyps (e.g., one or more colon polyps) present within a mammal can be monitored. Any appropriate method can be used to determine whether or not the number and/or size of one or more polyps (e.g., one or more colon polyps) present within a mammal is reduced. For example, imaging techniques can be used to assess the number of polyps present within a mammal.
  • Example 1 Predicting Colorectal Polyp Outcome This Example describes the identification of molecular profiles for polyps that can be used to identify the polyp as malignant and/or to predict whether or not the polyp is likely to recur.
  • Methods Patient sample characteristics and tissue preparation. All tissues were collected as described elsewhere (Druliner et al., Clin. Transl. Gastroenterol., 7(9):e188 (2016)). Polyp tissues with adjacent tumor and normal colonic epithelium full thickness specimens at least 8 cm from the polyp/tumor margin were harvested following surgical resection, were snap frozen in liquid nitrogen, and were maintained in a -80°C freezer.
  • Cancer free polyps and normal colonic epithelium at least 8 cm from the polyp were collected at the time of colonoscopic resection.
  • Cancer adjacent polyp (CAP) and cancer free polyp (CFP) cases were utilized.
  • Cancer adjacent polyps (CAPs) were matched to the cancer free polyps (CFPs) based on polyp size (categorical size: 1 to 2 cm, 2-5 cm, and > 5 cm), histology (villous features), and degree of dysplasia. All polyps presented herein were adenomatous polyps with villous features (tubulovillous or villous), and with low grade dysplasia only.
  • CAP and CFP cases exclude subjects with a prior history of any malignancy, a family history of Lynch syndrome or FAP, and any other syndrome associated with hereditary CRC or inflammatory bowel disease. All tissue used in these examples was removed prior to neoadjuvant/adjuvant therapy. CAPs were cases in which histological review of the surgically resected CRC showed the residual polyp of origin (RPO) in direct contiguity to the cancer. Peripheral blood leukocytes from the patients were obtained, when possible, prior to removal of the tissue, and any neo-adjuvant/adjuvant treatment.
  • RPO residual polyp of origin
  • POP categories include non-aggressive non-recurrent (POP-NA), recurrent advanced adenomatous polyp tissues collected at sequential procedures (POP-A), those that develop CRC (POP-CRC).
  • POP-NA non-aggressive non-recurrent
  • POP-A recurrent advanced adenomatous polyp tissues collected at sequential procedures
  • POP-CRC those that develop CRC
  • POP-NA an advanced adenomatous polyp was initially detected and removed by colonoscopy, and after the recommended colonoscopic surveillance three years post polypectomy, no polyp recurrence was detected at the site of the initial Attorney Docket No.07039-2155WO1 / 2022-250 polypectomy.
  • the site of initial polypectomy was annotated in the medical record, and was visualized in subsequent colonoscopies by the placement of a tattoo at the initial colonoscopy and/or a scar from the initial polypectomy.
  • the recurrence of the index polyp was confirmed endoscopically by observing the presence of the polyps in the scar from the previous polypectomy or at the site of a tattoo placed at the time of the index polypectomy.
  • the POP-A category refers to an advanced polyp removed by colonoscopy, but which recurred at least once at the site of initial polypectomy and was ultimately cured by colonoscopic polypectomy or surgery.
  • POP-NA had the lowest degree of aggressiveness, followed by the POP-A category.
  • telomereHunter was run on all WGS samples and resulting telomere content variable was used as a proxy for telomere length in the prediction model.
  • Whole Genome Sequencing (WGS) and RNA-seq DNA libraries were prepared at BGI from 10 ng input genomic DNA (representing roughly 2000 nuclei) from each tissue using the NEB kit (NEBNext ® UltraTM II FS DNA Library Prep Kit for Illumina. Samples were sequenced on the BGISEQ500 by 100 bp paired end. RNA-seq was performed using a Eukaryotic Transcriptome Library Construction Protocol and an RNase H method for library prep, and libraries were sequenced on HiseqXten by 150 bp paired end.
  • RNA-Seq processing and analyses WGS data was processed using the Picard Informatics Pipeline, with all data from a particular sample aggregated into a single BAM file which included all reads, all bases from all reads, and original/vendor-assigned quality scores.
  • a pooled Variant Call Format (VCF) file using the latest version of Picard GATK software was generated and provided for each sample batch.
  • Data for RNA-seq was analyzed using the Broad Picard Pipeline, which includes de-multiplexing and data aggregation.
  • MAP-RSeq is an integrated RNA-Seq bioinformatics pipeline developed for comprehensive analysis of raw RNA sequencing paired-end reads.
  • MAP-RSeq employs STAR, a splice-aware, accurate and fast aligner for aligning reads to the reference human genome (build hg38). Gene and exon expression quantification was performed using Subread package to obtain raw and normalized (FPKM – Fragments Per Kilobase per Million mapped) reads. Comprehensive quality control modules from the RSeQC package were run on aligned reads to assess the quality of the sequenced libraries. ComBat-seq was used to normalize and remove batch effects between sets A and B. Raw counts generated by ComBat-seq were used for performing differential gene expression analysis between CAP and CFP groups using R package edgeR.
  • DE differentially expressed
  • Volcano plots and PCA visualization were generated using R package ggplot2, and heatmaps were generated using R packages pheatmap and gplots.
  • DE protein coding genes were analyzed using UMAP to determine top genes that contribute most toward differentiating CAP and CFP classes.
  • SASP expression Using RNA-seq data here, gene expression of a panel of genes related to senescence- associated secretory phenotype (SASP) was determined in each of the polyp tissues.
  • Attorney Docket No.07039-2155WO1 / 2022-250 Machine learning model development For the CAP/CFP model: A total of 141 polyps across discovery and validation sets were used for CAP vs CFP binary classification. The cohort was split 80/20 into training set (112 samples) and test (29 samples) set. Model features were tested for multicollinearity and features with Pearson correlation less than 0.90 were retained. Robust QuantileTransformer was used to scale input features.
  • AutoGluon was run on training set with bagging and multi- layer stack ensembling options switched to auto-stacking which allowed AutoGluon to determine optimum number of folds and repeats of cross-fold validation.
  • AutoGluon’s default 80/20 split was used for setting training/validation sets with positive class defined as CAP.
  • Evaluation metric was set to ‘roc_auc’ and presets were set to ‘best_quality’. The best performing model was evaluated on the test set of 29 samples after re-fitting to the entire training set.
  • the initial 53 training samples (3 were removed during model cross-validation due to lack of paired blood/epithelium normal samples) were evenly split into 5 sub-cohorts using set and status variables (stage variable was not used due to small sample size).
  • Features were selected using criteria employed for CAP/CFP feature selection step.
  • KRAS mutations were also used as candidate features.
  • Model feature selection Differential gene expression was performed on 112 training samples by further splitting the training cohort into 5 sets with each set containing 80% samples. This split was performed using set (Discovery/Validation), status (CAP/CFP), and stage (villous/tubular) variables to ensure even distribution in the 5 sub-cohorts.
  • Software packages include: ggsignif, ggplot2, CMScaller, WGCNA, sva, tidyr, DESeq2, EnhancedVolcano, pheatmap, GSVA, GSEABase, ggpubr, dplyr, ggbeeswarm, rstatix, tidyverse, data.table, stringr, colorRamps, circlize, gtools, edgeR, tibble, fgsea, rbibutils, knitr, ComplexHeatmap.
  • KEGG pathway enrichment was determined by the p- value of the hypergeometric test via ShinyGO 0.76 using differential genes identified as described herein. Patient-derived organoids Organoids were generated using procedures for the isolation of crypts from fresh normal colon tissue.
  • crypts were released from freshly collected tissue using 5 mM EDTA, rocking at 4°C for 60-75 minutes. After isolation, crypts were embedded in ice-cold Matrigel (Corning ® Matrigel ® Growth Factor Reduced Product #356231), plated in 24-well plates and overlaid with Human Colon Media. Organoids were passaged using TrypLE digestion every 7-10 days. Human Colon Media contains 50% Wnt, Noggin and R-Spondin (WRN) obtained from conditioned media from the L-WRN cell line (ATCC).
  • WRN Noggin and R-Spondin
  • growth factors were added to this media including: N2 supplement (1X; Gibco), B27 supplement (1X, Gibco), EGF (40 ng/mL, R&D Systems), SB202190 (3 ?M, Sigma), A83-01 (500 nM, Tocris), Y-27632 (10 ?M, APExBio), NAC (1 ?M, Sigma), Nicotinamide (10 mM, Sigma), Gastrin I (10 nM, Sigma), Primocin (100 ?g/mL, Invivogen), and Antibiotic/Antimycotic (1X, Fisher).
  • ADMEM base media contains 50% Wnt, Noggin and R-Spondin (WRN) obtained from conditioned media from the L-WRN cell line (ATCC).
  • WRN Wnt, Noggin and R-Spondin
  • Other growth factors are added to this media including: N2 supplement (1X; Gibco), B27 supplement (1X, Gibco), EGF (40ng/mL, R&D Systems), SB202190 (3 ?M, Sigma), A83-01 (500 nM, Tocris), Y-27632 Attorney Docket No.07039-2155WO1 / 2022-250 (10 ?M, APExBio), NAC (1 ?M, Sigma), Nicotinamide (10 mM, Sigma), Gastrin I (10 nM, Sigma), Primocin (100 ?g/mL, Invivogen), Antibiotic/Antimycotic (1X, Fisher).
  • hTERT was cloned downstream of the CMV promoter followed by a stop codon and a rabbit beta globin poly adenylation sequence. Downstream of the TERT cassette, the vector also contained an EF1? promoter expressing GFP and puromycin resistance genes separated by a 2A peptide (2 ?g/ml puromycin to the organoid medium for at least 2 days or indefinitely).
  • hTERT using gene editing in organoids
  • a transposon based method was used for gene editing in the human colon organoids, using piggyBac vectors gene electrotransfer (electroporation) as the method for cargo delivery to the organoids. PiggyBac transposon (System Biosciences Cat.
  • PB513B-1 vector containing an hTERT construct was used (Addgene plasmid #1774).
  • hTERT was driven by the CMV promoter and then had a stop codon followed immediately by an EF1A promoter expressing the GFPT2APuro portion. This enabled the simultaneous visualization of transfection and editing efficiency, followed by selection via puromycin (add 2 ?g/mL puromycin to the organoid medium for at least 2 days or indefinitely).
  • the NEPA21 Electroporator (NEPA GENE) was used for cargo delivery. Integration of the cargo was verified by copy number detection, quantitative PCR (using HeLa cell as a telomerase positive control and normalized to GAPDH), and RNA-seq.
  • RNAscope Formalin fixed paraffin embedded (FFPE) tissues were obtained and sectioned at a thickness of 5 ?m and mounted on the SuperFrost ® Plus slides (Fisherbrand Cat #12-550-15). Ready-to-use reagents from RNAscopeTM HiPlex12 Reagents Kit (488, 550, 650) v2 (Advanced Cell Diagnostics #322350) were used according to the user manual (Document Number UM 324419). FFPE tissue sections were baked and deparaffinized, followed by target retrieval and protease III treatment (15 minutes at 40°C).
  • RNAscope ® HiPlex Probes targeting the human SFRP2, THBS2, SERPINE1, CYR61, and ADAMTS4 mRNA were used. Probe hybridization, signal amplification, colorimetric detection, and counterstaining were subsequently performed. Following DAPI stain, the cells were mounted and imaged using confocal microscope. Attorney Docket No.07039-2155WO1 / 2022-250 Results Molecular features distinguish CAPs and CFPs in a validated cohort To molecularly characterize polyps, cancer adjacent polyp (CAP) and cancer free polyp (CFP) cases were utilized (Figure 1A).
  • CAP cancer adjacent polyp
  • CFP cancer free polyp
  • telomere length a discovery set using telomere length, telomere maintenance mechanisms, genetic, transcriptional and methylation profiles distinguish CFPs and CAPs as described elsewhere (Druliner et al., Clin. Transl. Gastroenterol., 7(9):e188 (2016)) was used. Findings of a discovery set were validated in an independent cohort of 100 patients (the validation set), all of which represent advanced adenomatous polyps. Patient demographics for this cohort can be found in Table 1.
  • Whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) were performed on normal colon, polyp and cancer tissues from 50 CFPs and 50 CAPs ( Figure 1A).
  • Somatic mutation prevalence ( Figure 1B), copy number variant (CNV) mean event size (Figure 1C), differential gene expression (Figure 1D and Example 2), KEGG pathway enrichment (Figure 1E), telomere length (Figure 1F), and the telomere maintenance mechanism of hTERT based on expression ( Figure 1G) were differential between CFPs and CAPs, and consistent between the discovery and validation sets.
  • Gene expression analysis revealed 794 genes that were differentially expressed between CAPs and CFPs ( Figure 1D), with an exemplary gene, GREM1, showing higher expression in the CAP category in both discovery and validation sets.
  • CAPs had significantly more mutations, altered expression, longer telomeres, and greater hTERT expression than CFPs. Table 1.
  • telomere maintenance mechanism of telomerase was modified by overexpressing hTERT, the catalytic subunit of telomerase, in an organoid system.
  • An organoid line derived from normal colon tissue collected during surgery for a stage T2 N1b M0 pMMR ascending colon cancer was utilized.
  • a piggyBac transposon system was used to integrate the hTERT gene, along with GFP and a puromycin resistance gene, into the normal human colon organoid line to generate TERT overexpression (TERT+) (Figure 3A, Figure 8A).
  • TERT+ normal human colon organoid line
  • Figure 8B There was an integration of over 11 copies of the hTERT in the organoids ( Figure 8B).
  • qPCR showed TERT expression was nearly 1000-fold higher in the edited organoids compared to an unedited organoid line ( Figure 3B).
  • RNA-seq was performed on the unedited and TERT + organoid lines to determine global gene expression changes in the presence of TERT overexpression.
  • Overexpression of TERT in the TERT + organoid line compared to unedited was verified (Figure 3C).
  • the top 200 most highly confidently differentially expressed genes (DEGs) in the organoids were identified and a GSEA was performed on the polyp RNA-seq data with a mean CPM > 0.1.
  • the GSEA showed strong enrichment of the TERT + DEGs in CAP polyps compared to CFP ( Figure 3D).
  • KEGG pathways in the TERT + organoids were viral infection, lysosome, circadian rhythm, and inflammation related genes (Figure 3E), many of which also overlapped with the CAP vs CFP DEGs pathways shown in Figure 1D.
  • Multiomics Machine Learning Model identifies signature that distinguishes a cancerous from a non-cancerous polyp It was next sought to integrate multiomics features in a machine learning framework to predict whether a polyp would progress to cancer (Figure 4A). SHapley Additive exPlanations (SHAP) python package was used for exploring model output and visualizing feature importance (Figure 4B).
  • SHapley Additive exPlanations (SHAP) python package was used for exploring model output and visualizing feature importance (Figure 4B).
  • AUROC 0.9134 [0.8059, 1]
  • PPV 85.71%
  • NPV 73.33%.
  • a set of genes identified as predictive of outcome were then evaluated using RNAscope to visually detect genes that were predictive in tissues from a third cohort of CAP and CFP cases.
  • Figure 10 shows THBS2 mRNA expression in CFP (left) and CAP (right) tissues, from two patients that were not included in the Discovery or Validation cohorts, for an independent assessment of detecting differential expression of these genes at the tissue level between a CFP and CAP.
  • POP polyp outcome phenotypes
  • Somatic mutation prevalence ( Figure 5B), copy number Attorney Docket No.07039-2155WO1 / 2022-250 variation (Figure 5C), and gene expression (Figure 5D and Example 3) vary between the POP categories and CAPs The most significant difference was between the POP-NR and CAP categories.
  • KEGG pathway analysis on DEGs showed greater overlap between POP-R and categories ( Figure 5E).
  • genes enriched in protein digestion and absorption, viral and inflammation related pathways were primarily restricted to CAP cases and not seen in CFPs, regardless of POP status (top four rows in Figure 5E).
  • Genes enriched in metabolism-related pathways were related to CFPs, but most prominently the POP-NR cases.
  • KRAS mutations were only present in 20% of POP-NR cases, whereas they were present in 64.5% and 52.3% of POP-R and CAP cases, respectively ( Figure 6A, Table 6). These mutations represented several missense mutations (Example 4). KRAS mutation status amongst the POP-R cases was associated with transcriptomic differences in 328 genes associated with a log2FC>
  • SSA-TSA polyps The expression of specific markers was evaluated in specific cellular compartments (epithelial compartments or stromal compartments) in a sessile serrated adenoma (SSA) or a traditional serrated adenoma (TSA) that was cancer free when it was first removed (Figure 12).
  • IGLL5 was downregulated in POP-CRC SSA-TSA and TA-TV-VA polyps, and the presence of a decreased level of an IGLL5 polypeptide (or mRNA encoding an IGLL5 polypeptide) can be used to identify a polyp as being likely to become malignant.
  • Example 8 Assessing Colon Polyps A tissue sample containing one or more polyp cells is obtained from a human having one or more colon polyps.
  • the obtained sample is examined for the presence or absence of an increased level of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), an increased level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), an increased level of a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), an increased level of a FAP polypeptide (or mRNA encoding a FAP polypeptide), an increased level of a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), an increased level of a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide), an increased level of a CXCL13 polypeptide (or mRNA encoding a CXCL13 polypeptide), an increased level of a SFRP2 polypeptide (or mRNA encoding a SFRP2 polypeptide), an
  • the sample includes the presence of one or more of an increased level of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), an increased level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), an increased level of a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), an increased level of a FAP polypeptide (or mRNA encoding a FAP polypeptide), an increased level of a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), an increased level of a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide), an increased level of a CXCL13 polypeptide (or mRNA encoding a CXCL13 polypeptide), an increased level of a SFRP2 Attorney Docket No.07039-2155WO1 / 2022-250 polypeptide (
  • the sample lacks an increased level of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), an increased level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), an increased level of a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), an increased level of a FAP polypeptide (or mRNA encoding a FAP polypeptide), an increased level of a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), an increased level of a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide), an increased level of a CXCL13 polypeptide (or mRNA encoding a CXCL13 polypeptide), an increased level of a SFRP2 polypeptide (or mRNA encoding a SFRP2 polypeptide), an increased level of a VIP poly
  • Example 9 Treating Colon Polyps
  • a tissue sample containing one or more polyp cells is obtained from a human having one or more colon polyps. The obtained sample is examined for the presence or absence of an increased level of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), an increased level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), an increased level of a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), an increased level of a FAP polypeptide (or mRNA encoding a FAP polypeptide), an increased level of a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), an increased level of a SOX11 polypeptide (or mRNA encoding a SOX11 Attorney Docket No.07039-2155WO1 / 2022-250 polypeptide), an increased level of a C
  • the sample includes the presence of one or more of an increased level of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), an increased level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), an increased level of a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), an increased level of a FAP polypeptide (or mRNA encoding a FAP polypeptide), an increased level of a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), an increased level of a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide), an increased level of a CXCL13 polypeptide (or mRNA encoding a CXCL13 polypeptide), an increased level of a SFRP2 polypeptide (or mRNA encoding a SFRP2 polypeptide), an increased
  • Example 10 Treating Colon Polyps A tissue sample containing one or more polyp cells is obtained from a human having one or more colon polyps. The obtained sample is examined for the presence or absence of an increased level of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), an increased level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), an increased level of a SERPINE1 polypeptide (or mRNA encoding a Attorney Docket No.07039-2155WO1 / 2022-250 SERPINE1 polypeptide), an increased level of a FAP polypeptide (or mRNA encoding a FAP polypeptide), an increased level of a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), an increased level of a SOX11 polypeptide (or
  • the sample lacks an increased level of an ADAMTS4 polypeptide (or mRNA encoding an ADAMTS4 polypeptide), an increased level of a THBS2 polypeptide (or mRNA encoding a THBS2 polypeptide), an increased level of a SERPINE1 polypeptide (or mRNA encoding a SERPINE1 polypeptide), an increased level of a FAP polypeptide (or mRNA encoding a FAP polypeptide), an increased level of a CYR61 polypeptide (or mRNA encoding a CYR61 polypeptide), an increased level of a SOX11 polypeptide (or mRNA encoding a SOX11 polypeptide), an increased level of a CXCL13 polypeptide (or mRNA encoding a CXCL13 polypeptide), an increased level of a SFRP2 polypeptide (or mRNA encoding a SFRP2 polypeptide), an increased level of a VIP poly
  • Example 11 Assessing Colon Polyps A tissue sample containing one or more polyp cells is obtained from a human having one or more colon polyps.
  • the obtained sample is examined for the presence or absence of Attorney Docket No.07039-2155WO1 / 2022-250 an increased level of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide), an increased level of an LY6G6C polypeptide (or mRNA encoding an LY6G6C polypeptide), an increased level of a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide), an increased level of a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide), an increased level of a CYP1A1 polypeptide (or mRNA encoding a CYP1A1 polypeptide), an increased level of a DMKN polypeptide (or mRNA encoding a DMKN polypeptide), a decreased level of an IGLL5 polypeptide (or mRNA encoding an IGLL5 polypeptide), one or more mutation
  • the sample includes the presence of one or more of an increased level of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide), an increased level of an LY6G6C polypeptide (or mRNA encoding an LY6G6C polypeptide), an increased level of a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide), an increased level of a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide), an increased level of a CYP1A1 polypeptide (or mRNA encoding a CYP1A1 polypeptide), an increased level of a DMKN polypeptide (or mRNA encoding a DMKN polypeptide), a decreased level of an IGLL5 polypeptide (or mRNA encoding an IGLL5 polypeptide), one or more mutations in a KRAS polypeptide (or a nucleic acid en
  • sample (a) lacks an increased level of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide), an increased level of an LY6G6C polypeptide (or mRNA encoding an LY6G6C polypeptide), an increased level of a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide), an increased level of a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide), an increased level of a CYP1A1 polypeptide (or mRNA encoding a CYP1A1 polypeptide), an increased level of a DMKN polypeptide (or mRNA encoding a DMKN polypeptide), and a decreased level of an IGLL5 polypeptide (or mRNA encoding an IGLL5 polypeptide), and one or more changes in genetic content (e.g., an increased frequency of genomic DELs and an increased frequency of
  • Example 12 Treating Colon Polyps A tissue sample containing one or more polyp cells is obtained from a human having one or more colon polyps. The obtained sample is examined for the presence or absence of an increased level of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide), an increased level of an LY6G6C polypeptide (or mRNA encoding an LY6G6C polypeptide), an increased level of a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide), an increased level of a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide), an increased level of a CYP1A1 polypeptide (or mRNA encoding a CYP1A1 polypeptide), an increased level of a DMKN polypeptide (or mRNA encoding a DMKN polypeptide), and a decreased level of an IGLL5 polypeptide (or m
  • the sample includes the presence of one or more of an increased level of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide), an increased level of an LY6G6C polypeptide (or mRNA encoding an LY6G6C polypeptide), an increased level of a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide), an increased level of a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide), an increased level of a CYP1A1 polypeptide (or mRNA encoding a CYP1A1 polypeptide), an increased level of a DMKN polypeptide (or mRNA encoding a DMKN polypeptide), and a decreased level of an IGLL5 polypeptide (or mRNA encoding an IGLL5 polypeptide), one or more mutations in a KRAS polypeptide (or a nucleic acid
  • the treatment can reduce number of polyps within the human while minimizing the risk of recurrence.
  • Example 13 Treating Colon Polyps A tissue sample containing one or more polyp cells is obtained from a human having one or more colon polyps.
  • the obtained sample is examined for the presence or absence of an increased level of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide), an increased level of an LY6G6C polypeptide (or mRNA encoding an LY6G6C polypeptide), an increased level of a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide), an increased level of a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide), an increased level of a CYP1A1 polypeptide (or mRNA encoding a CYP1A1 polypeptide), an increased level of a DMKN polypeptide (or mRNA encoding a DMKN polypeptide), and a decreased level of an IGLL5 polypeptide (or mRNA encoding an IGLL5 polypeptide), one or more mutations in a KRAS polypeptide (or a nucleic acid
  • sample lacks (a) an increased level of a TPRG1 polypeptide (or mRNA encoding a TPRG1 polypeptide), an increased level of an LY6G6C polypeptide (or mRNA encoding an LY6G6C polypeptide), an increased level of a DUSP4 polypeptide (or mRNA encoding a DUSP4 polypeptide), an increased level of a ZIC5 polypeptide (or mRNA encoding a ZIC5 polypeptide), an increased level of a CYP1A1 polypeptide (or mRNA encoding a CYP1A1 polypeptide), an increased level of a DMKN polypeptide (or mRNA encoding a DMKN polypeptide), and a decreased level of an IGLL5 polypeptide (or mRNA encoding an IGLL5 polypeptide), and one or more changes in genetic content (e.g., an increased frequency of genomic DELs and an increased frequency of

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Abstract

Ce document concerne des procédés et des matériaux pour évaluer et/ou traiter des mammifères (par exemple, des êtres humains) ayant un ou plusieurs polypes (par exemple, un ou plusieurs polypes du côlon). Par exemple, l'invention concerne des procédés et des matériaux qui peuvent être utilisés pour déterminer si un polype (par exemple, un polype du côlon) à l'intérieur d'un mammifère (par exemple, un être humain) est un polype malin et/ou est susceptible de réapparaître. L'invention concerne également des procédés et des matériaux pour traiter un mammifère ayant un ou plusieurs polypes (par exemple, un ou plusieurs polypes du côlon).
EP24747847.2A 2023-01-26 2024-01-26 Évaluation et traitement de mammifères ayant des polypes Pending EP4654960A1 (fr)

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WO2002087503A2 (fr) * 2001-04-26 2002-11-07 Vanderbilt University Compositions et methodes de traitement des polypes colorectaux et du cancer colorectal
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