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WO2025014239A1 - Composition pour le diagnostic du cancer hépatique par l'utilisation du changement de méthylation du promoteur du gène sort1 et son utilisation - Google Patents

Composition pour le diagnostic du cancer hépatique par l'utilisation du changement de méthylation du promoteur du gène sort1 et son utilisation Download PDF

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WO2025014239A1
WO2025014239A1 PCT/KR2024/009723 KR2024009723W WO2025014239A1 WO 2025014239 A1 WO2025014239 A1 WO 2025014239A1 KR 2024009723 W KR2024009723 W KR 2024009723W WO 2025014239 A1 WO2025014239 A1 WO 2025014239A1
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liver cancer
cpg island
island region
methylation
sort1 gene
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Korean (ko)
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조효정
은정우
정재연
김순선
안혜리
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Ajou University Industry Academic Cooperation Foundation
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Ajou University Industry Academic Cooperation Foundation
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    • 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
    • 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
    • C12Q2600/118—Prognosis of disease development
    • 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
    • C12Q2600/154—Methylation markers

Definitions

  • the present invention relates to a composition for diagnosing liver cancer using methylation changes in the SORT1 (Sortilin 1) gene promoter and its use.
  • Liver cancer is the fifth most common cancer worldwide, and according to statistics released by the National Cancer Center, it has the sixth highest incidence rate and an extremely low survival rate of 37%, making it a fatal disease.
  • liver cancer in particular is one of the major causes of death, and is characterized by high incidence, low early diagnosis rate, and low survival rate.
  • the reason for the high mortality rate of liver cancer patients is that there is no biomarker for early diagnosis, and liver cancer is often diagnosed at an advanced stage where it is impossible to cure.
  • Tumor development involves complex molecular mechanisms, and proliferation, metastasis, and angiogenesis occur through interactions with various cell types in the tumor microenvironment. Based on this, the development of safe and effective technologies for early diagnosis and treatment of tumors is urgent. Accordingly, the discovery of liver cancer biomarkers for early diagnosis, prognosis, and treatment response prediction is also urgently needed in liver cancer.
  • the purpose of the present invention is to provide a biomarker composition for diagnosing liver cancer or predicting the prognosis of liver cancer metastasis, which comprises a methylated CpG island region of the SORT1 gene promoter.
  • another object of the present invention is to provide a composition for diagnosing liver cancer, which comprises as an active ingredient an agent capable of measuring the methylation level of a CpG island region of the SORT1 gene promoter, and a kit for diagnosing liver cancer comprising the same.
  • another object of the present invention is to provide a composition for predicting the prognosis of liver cancer metastasis, comprising as an active ingredient an agent capable of measuring the methylation level of the CpG island region of the SORT1 gene promoter, and a kit for predicting the prognosis of liver cancer metastasis comprising the same.
  • another object of the present invention is to provide a method for providing information necessary for diagnosing liver cancer or predicting the prognosis of liver cancer metastasis, comprising a step of measuring the methylation level of a CpG island region of the SORT1 gene promoter.
  • the present invention provides a biomarker composition for diagnosing liver cancer comprising a methylated CpG island region of the SORT1 gene promoter.
  • the present invention provides a biomarker composition for predicting the prognosis of liver cancer metastasis, which comprises a methylated CpG island region of the SORT1 gene promoter.
  • the present invention provides a composition for diagnosing liver cancer, comprising as an active ingredient an agent capable of measuring the methylation level of a CpG island region of the SORT1 gene promoter.
  • the present invention provides a kit for diagnosing liver cancer comprising the composition.
  • the present invention provides a composition for predicting the prognosis of liver cancer, comprising as an active ingredient an agent capable of measuring the methylation level of a CpG island region of the SORT1 gene promoter.
  • the present invention provides a kit for predicting liver cancer prognosis comprising the composition.
  • the present invention provides a method for providing information necessary for diagnosing liver cancer, comprising the steps of: (1) obtaining genomic DNA from a sample isolated from a patient; (2) measuring the methylation level of a CpG island region of a SORT1 gene promoter in the obtained genomic DNA; (3) comparing the measured methylation level of the CpG island region of the SORT1 gene promoter with a control sample; and (4) determining that the sample is liver cancer if the measured methylation level of the CpG island region of the SORT1 gene promoter is decreased compared to the control sample.
  • the present invention provides a method for providing information necessary for predicting the prognosis of liver cancer metastasis, comprising the steps of: (1) obtaining genomic DNA from a sample isolated from a patient; (2) measuring the methylation level of a CpG island region of a SORT1 gene promoter in the obtained genomic DNA; (3) comparing the measured methylation level of the CpG island region of the SORT1 gene promoter with a control sample; and (4) predicting and determining that the possibility of liver cancer metastasis is high if the measured methylation level of the CpG island region of the SORT1 gene promoter is decreased compared to the control sample.
  • the present invention relates to a composition for diagnosing liver cancer using methylation changes in the SORT1 gene promoter and a use thereof, and establishes systematic research methods and techniques for elucidating growth and proliferation, cell death and metastasis inhibition of liver cancer and signal transduction pathways, and confirms whether the target gene SORT1 shows clinical significance based on basic experiments, and can predict or diagnose liver cancer with high accuracy by measuring the methylation level of the SORT1 gene, specifically, cg16988986 in the promoter region of the SORT1 gene. Therefore, the methylation change in the SORT1 gene promoter is highly likely to be utilized as a target for diagnosing liver cancer.
  • Figure 1 shows the association between SORT1 expression and copy number in the TCGA_LIHC dataset.
  • Figure 2 shows the results of correlation analysis between SORT1 activation and methylation in the TCGA_LIHC data set.
  • Figure 3 shows the results of identifying a specific probe region that regulates the activation of SORT1.
  • Figure 4 shows the beta-value analysis results of the four selected probe regions.
  • Figure 5 shows the results of overall survival, disease-free survival, and disease-specific survival curves according to cg16988986 methylation level.
  • Figure 6 shows the results of measuring methylation levels in liver cancer patient tissues using qMSP analysis.
  • Figure 7 shows the results of evaluating the diagnostic ability of liver cancer using the methylation level of SORT1.
  • Figure 8 shows the results of confirming the clinical correlation between the methylation level of SORT1 and liver cancer.
  • Figure 9 shows the results of confirming the correlation between the expression of SORT1 and the methylation level in qRT-PCR and qMSP data.
  • the present invention provides a biomarker composition for diagnosing liver cancer comprising a methylated CpG island region of the SORT1 gene promoter.
  • the present invention provides a biomarker composition for predicting the prognosis of liver cancer metastasis, which comprises a methylated CpG island region of the SORT1 gene promoter.
  • diagnosis includes determining the susceptibility of a subject to a particular disease or condition, determining whether a subject currently has a particular disease or condition, determining the prognosis of a subject having a particular disease or condition, or therametrics (e.g., monitoring the condition of a subject to provide information about the efficacy of a treatment).
  • prognosis prediction means the process of predicting the treatment outcome of a pathological condition by collecting data on the progress of the pathological condition and the treatment process.
  • the prognosis prediction may be interpreted as determining the possibility of metastasis after liver cancer treatment or the possibility of death due to it, but is not limited thereto.
  • methylation in the present invention refers to a phenomenon that occurs at a cytosine in a CpG island in the promoter region of a specific gene, thereby blocking the binding of a transcription factor and thereby blocking the expression of the specific gene.
  • methylation refers to methylation in a CpG island in the promoter region of the SORT1 gene.
  • CpG island refers to a genomic region where CpGs are gathered at an exceptionally high frequency, and refers to a region of 0.2 to 3 kb in length where the C+G content is 50% or more and the CpG ratio is 3.75% or more.
  • C represents cytosine
  • G represents guanine
  • p represents a phosphodiester bond between cytosine and guanine.
  • CpG islands There are about 45,000 CpG islands in the human genome, and most of them are found in promoter regions that regulate gene expression. In fact, the CpG islands are found in the promoters of housekeeping genes, which account for about 50% of human genes (Cross, S. and Bird, A., Curr. Opin.
  • 5-methylcytosine which has a methyl group attached to the fifth carbon of the cytosine ring (5-mC).
  • 5-mC is attached only to the C of the CG dinucleotide (5'-mCG-3'), called CpG.
  • the C of CpG is mostly methylated by contact with the methyl group.
  • Methylation of CpG suppresses the expression of transposons and repetitive sequences in the genome.
  • CpG is the site where most epigenetic changes frequently occur in mammalian cells. This is because the 5-mC of CpG is easily deaminated naturally to become thymine (T).
  • the present invention provides a composition for diagnosing liver cancer, comprising as an active ingredient an agent capable of measuring the methylation level of a CpG island region of the SORT1 gene promoter.
  • the present invention provides a composition for predicting the prognosis of liver cancer metastasis, comprising as an active ingredient an agent capable of measuring the methylation level of a CpG island region of the SORT1 gene promoter.
  • the agent capable of measuring the methylation level of the CpG island region of the SORT1 gene promoter may be at least one selected from the group consisting of a primer pair capable of amplifying a fragment within the methylated CpG island region of the SORT1 gene, a probe capable of hybridizing with the methylated CpG island region of the SORT1 gene, a methylation-specific binding protein capable of binding to the methylated CpG island region of the SORT1 gene, a methylation-specific binding antibody or aptamer of the SORT1 gene; and a methylation-sensitive restriction enzyme, but is not limited thereto.
  • the CpG island region of the SORT1 gene promoter may be cg16988986, but is not limited thereto.
  • primer refers to a short nucleic acid sequence having a short free 3' hydroxyl group, which can form base pairs with a complementary template and serves as a starting point for copying the template strand.
  • the primer can initiate DNA synthesis in the presence of a reagent for polymerization reaction (i.e., DNA polymerase or reverse transcriptase) and four different nucleoside triphosphates in an appropriate buffer and temperature.
  • a reagent for polymerization reaction i.e., DNA polymerase or reverse transcriptase
  • the lengths of the sense and antisense primers can be appropriately selected according to techniques known in the art.
  • the primers of the present invention can be preferably designed according to the sequence of the CpG island to be analyzed for methylation, and can be a primer pair that can specifically amplify a cytosine that is methylated and not modified by bisulfite, and a primer pair that can specifically amplify a cytosine that is not methylated and modified by bisulfite.
  • probe in this specification refers to a nucleic acid fragment such as RNA or DNA, which is short, a few bases or long, several hundred bases, and can specifically bind to mRNA, and is labeled so that the presence or absence of a specific mRNA and the expression level can be confirmed.
  • the probe can be produced in the form of an oligonucleotide probe, a single strand DNA probe, a double strand DNA probe, an RNA probe, etc.
  • the selection of an appropriate probe and hybridization conditions can be appropriately selected according to techniques known in the art.
  • antibody as used herein is a term known in the art, and refers to a specific immunoglobulin directed against an antigenic site.
  • the antibody in the present invention refers to an antibody that specifically binds to the PMVK of the present invention, and the antibody can be prepared according to a conventional method in the art.
  • the form of the antibody includes a polyclonal antibody or a monoclonal antibody, and includes all immunoglobulin antibodies.
  • the antibody refers to a complete form having two full-length light chains and two full-length heavy chains.
  • the antibody also includes special antibodies such as humanized antibodies.
  • aptamer refers to a type of polynucleotide composed of a special type of single-stranded nucleic acid (DNA, RNA or modified nucleic acid) that has a stable tertiary structure in itself and has the characteristics of being able to bind to a target molecule with high affinity and specificity.
  • DNA DNA, RNA or modified nucleic acid
  • an aptamer is composed of a polynucleotide that can specifically bind to an antigenic substance in the same way as an antibody, but is more stable than a protein, has a simple structure, and is easy to synthesize, and therefore can be used as a substitute for an antibody.
  • methylation-sensitive restriction enzyme refers to a restriction enzyme that can specifically detect methylation of a CpG island and contains CG as a recognition site of the restriction enzyme. Examples thereof include, but are not limited to, SmaI, SacII, EagI, HpaII, MspI, BssHII, BstUI, NotI, etc. Depending on methylation or unmethylation at C of the restriction enzyme recognition site, whether or not the restriction enzyme cuts is different and this can be detected through PCR or Southern Blot analysis. Other methylation-sensitive restriction enzymes other than the above restriction enzymes are well known in the art.
  • the present invention provides a kit for diagnosing liver cancer comprising the composition.
  • the present invention provides a composition for predicting the prognosis of liver cancer metastasis comprising the composition.
  • the kit may be any one selected from the group consisting of an RT-PCR kit, a microarray chip kit, a DNA kit, and a protein chip kit, but is not limited thereto.
  • the present invention provides a method for providing information necessary for diagnosing liver cancer, comprising the steps of: (1) obtaining genomic DNA from a sample isolated from a patient; (2) measuring the methylation level of a CpG island region of a SORT1 gene promoter in the obtained genomic DNA; (3) comparing the measured methylation level of the CpG island region of the SORT1 gene promoter with a control sample; and (4) determining that the sample is liver cancer if the measured methylation level of the CpG island region of the SORT1 gene promoter is decreased compared to the control sample.
  • the present invention provides a method for providing information necessary for predicting the prognosis of liver cancer metastasis, comprising the steps of: (1) obtaining genomic DNA from a sample isolated from a patient; (2) measuring the methylation level of a CpG island region of a SORT1 gene promoter in the obtained genomic DNA; (3) comparing the measured methylation level of the CpG island region of the SORT1 gene promoter with a control sample; and (4) predicting and determining that the possibility of liver cancer metastasis is high if the measured methylation level of the CpG island region of the SORT1 gene promoter is decreased compared to the control sample.
  • the measurement of the methylation level of the CpG island region of the SORT1 gene promoter can be performed by a method selected from the group consisting of, but not limited to, PCR, methylation specific PCR, real time methylation specific PCR, PCR using a methylated DNA-specific binding protein, ChIP analysis using a methylated DNA-specific binding antibody or aptamer, DNA chip, pyrosequencing, and bisulfite sequencing.
  • the CpG island region of the SORT1 gene promoter may be cg16988986, but is not limited thereto.
  • the step (4) is performed by a cut-off value, and the cut-off value may be 0.0885 when the relative methylation level of the SORT1 gene promoter is log10 substituted, but is not limited thereto.
  • the isolated sample may be, but is not limited to, isolated cells, tissues, blood, saliva or urine.
  • liver cancer tissue samples were used for methylation analysis, including non-tumor (NT) and liver cancer tissue (Tumor, T) surrounding non-liver cancer tissues from 58 patients who underwent hepatectomy.
  • NT non-tumor
  • T liver cancer tissue
  • TCGA LIHC data were used to validate methylation, expression, and survival analyses.
  • Genomic DNA of the tissue was extracted using the DNeasy Blood & Tissue kit (Qiagen, #69504) according to the kit's manual.
  • Tissues measuring approximately 8 mm 3 in size were frozen in liquid nitrogen, ground with a sterilized mortar and pestle, and 180 ul of Buffer ATL and 20 ul of proteinase K were added, vortexed, and reacted in a shaking incubator at 56°C for more than 12 hours.
  • DNA adsorbed to the column was separated using elution buffer, and the amount and purity of the separated genomic DNA were measured using a NanoPhotometer (Implen).
  • DNA bisulfite conversion was performed by combining 1 ug DNA and DW to make 20 ul, adding 130 ul of CT conversion reagent, and making a total of 150 ul.
  • the sample and 600 ⁇ l of binding buffer were added to the Zymo-Spin IC column, and centrifuged at 12,000 g for 30 seconds to allow DNA to be adsorbed to the column.
  • the bisulfite-converted genomic DNA was separated from the column using M-elution buffer.
  • the information of the probe derived from the methylation analysis of the gene is as follows.
  • target probes were identified in the UCSC genome brower (https:/genome.ucsc.edu/index.html), and primers for qMSP were designed using MethPrimer (https:/www.urogene.org/cgi-bin/methprimer/methprimer.cgi) for the chr1:109,397,301-109,399,000 (1700 bp) sequence containing the target probes and CpG islands.
  • qMSP was performed using a total of 10 ul of reaction mixture containing 2X qPCR master mix (Gendepot, Q5602), 10 uM primer, and bisulfite-modified DNA under the conditions below.
  • cDNA was synthesized from 500 ng of RNA in a total volume of 10 ⁇ l using 5X PrimeScriptTMRT Master Mix (Takara) and AmfiSure qGreen Q-PCR Master Mix (GenDEPOT) was used at 95°C for 2 min, followed by 40 cycles of 95°C for 15 sec, 60°C for 34 sec, and 72°C for 30 sec, followed by a dissociation stage of 95°C for 10 sec, 65°C for 5 sec, and 95°C for 5 sec.
  • Real-time monitoring was confirmed using a CFX Connect Real-Time PCR Detection System (Bio-Rad).
  • the primer NM number of SORT1 is NM_001205228.1, the product size is 198 bp, and the sequence is as follows.
  • Gene copy number variation is one of the genetic structural variations existing in the human genome and is closely related to gene expression. It affects the final activity of the gene, the increase or decrease of the transcript, which is the gene product, and the expression of protein.
  • the beta value was checked in the liver cancer and non-liver cancer tissues of the same 50 liver cancer patients, the beta value was concentrated at 0 in the liver cancer tissues compared to the non-liver cancer tissues, confirming that the methylation of SORT1 was relatively low (Fig. 2).

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Abstract

La présente invention concerne une composition pour diagnostiquer le cancer hépatique sur la base d'un changement de méthylation d'un promoteur du gène SORT1 et son utilisation, et la présente invention a permis : l'établissement d'un procédé et d'une technique de recherche systématique pour étudier la croissance et la prolifération du cancer hépatique, l'apoptose, l'inhibition des métastases et une voie de signalisation ; la confirmation du fait que SORT1, qui est un gène cible, présente une signification clinique, sur la base d'une expérience fondamentale ; et la prédiction ou le diagnostic du cancer hépatique avec une grande précision en mesurant le degré de méthylation du gène SORT1, particulièrement cg16988986 dans une région promotrice du gène SORT1. Par conséquent, un changement de méthylation du promoteur du gène SORT1 a de fortes chances d'être utilisé comme cible pour diagnostiquer le cancer hépatique.
PCT/KR2024/009723 2023-07-12 2024-07-09 Composition pour le diagnostic du cancer hépatique par l'utilisation du changement de méthylation du promoteur du gène sort1 et son utilisation Pending WO2025014239A1 (fr)

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KR10-2023-0090455 2023-07-12
KR1020230090455A KR20250010344A (ko) 2023-07-12 2023-07-12 Sort1 유전자 프로모터의 메틸화 변화를 이용한 간암 진단용 조성물 및 이의 용도

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KR101596359B1 (ko) 2014-12-01 2016-02-22 이화여자대학교 산학협력단 SORT1 유전자 프로모터의 CpG 메틸화 변화를 이용한 모야모야병 진단용 조성물 및 이의 이용

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
AHN H R, SON J A, WEON J H, BAEK G O, YOON M G, HAN J E, KIM S S, CHEONG J Y, KWON M, EUN J W, CHO H J: "SORT1 with oncogenic potential associated hypomethylation and promotes tumor progression in hepatocellular carcinoma", CANCER GENOMICS 258 (PB038), 1 May 2023 (2023-05-01), pages S94, XP093260212 *
AHN, H. R. et al. Hypomethylation-mediated upregulation of the SORT1 promotes tumor progression in hepatocellular carcinoma. In: KSBMB International conference 2023. May 2023, Poster D-44. *
GAO YAN, LI YAN, SONG ZIYAN, JIN ZHENXING, LI XIAO, YUAN CHUNLUAN: "Sortilin 1 Promotes Hepatocellular Carcinoma Cell Proliferation and Migration by Regulating Immune Cell Infiltration", JOURNAL OF ONCOLOGY, HINDAWI PUBLISHING CORPORATION, US, vol. 2022, 8 July 2022 (2022-07-08), US , pages 1 - 13, XP093260252, ISSN: 1687-8450, DOI: 10.1155/2022/6509028 *
LIN MINJIE, ZHU MENGYING, GE TINGQIU, LU NAIYING, FU XILING, CHANG JIABAO: "and its co‐expressed genes in hepatocellular carcinoma based on integrative analysis of multiple database", PRECISION MEDICAL SCIENCES, vol. 11, no. 4, 1 December 2022 (2022-12-01), pages 161 - 173, XP093260248, ISSN: 2642-2514, DOI: 10.1002/prm2.12084 *
LIN XIA-HUI, LI DONG-PING, LIU ZHI-YONG, ZHANG SI, TANG WEN-QING, CHEN RONG-XIN, WENG SHU-QIANG, TSENG YU-JEN, XUE RU-YI, DONG LIN: "Six immune-related promising biomarkers may promote hepatocellular carcinoma prognosis: a bioinformatics analysis and experimental validation", CANCER CELL INTERNATIONAL, BIOMED CENTRAL, LONDON, GB, vol. 23, no. 1, GB , XP093260243, ISSN: 1475-2867, DOI: 10.1186/s12935-023-02888-9 *

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