DOI QR코드

DOI QR Code

Epigenetic insights into colorectal cancer: comprehensive genome-wide DNA methylation profiling of 294 patients in Korea

  • Soobok Joe (Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology) ;
  • Jinyong Kim (Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Jin-Young Lee (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University) ;
  • Jongbum Jeon (Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology) ;
  • Iksu Byeon (Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology) ;
  • Sae-Won Han (Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Seung-Bum Ryoo (Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Kyu Joo Park (Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Sang-Hyun Song (Cancer Research Institute, Seoul National University College of Medicine) ;
  • Sheehyun Cho (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University) ;
  • Hyeran Shim (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University) ;
  • Hoang Bao Khanh Chu (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University) ;
  • Jisun Kang (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University) ;
  • Hong Seok Lee (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University) ;
  • DongWoo Kim (Cellgentek) ;
  • Young-Joon Kim (Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University) ;
  • Tae-You Kim (Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Seon-Young Kim (Korea Bioinformation Center (KOBIC), Korea Research Institute of Bioscience and Biotechnology)
  • 투고 : 2023.06.12
  • 심사 : 2023.08.14
  • 발행 : 2023.10.31

초록

DNA methylation regulates gene expression and contributes to tumorigenesis in the early stages of cancer. In colorectal cancer (CRC), CpG island methylator phenotype (CIMP) is recognized as a distinct subset that is associated with specific molecular and clinical features. In this study, we investigated the genome-wide DNA methylation patterns among patients with CRC. The methylation data of 1 unmatched normal, 142 adjacent normal, and 294 tumor samples were analyzed. We identified 40,003 differentially methylated positions with 6,933 (79.8%) hypermethylated and 16,145 (51.6%) hypomethylated probes in the genic region. Hypermethylated probes were predominantly found in promoter-like regions, CpG islands, and N shore sites; hypomethylated probes were enriched in open-sea regions. CRC tumors were categorized into three CIMP subgroups, with 90 (30.6%) in the CIMP-high (CIMP-H), 115 (39.1%) in the CIMP-low (CIMP-L), and 89 (30.3%) in the non-CIMP group. The CIMP-H group was associated with microsatellite instability-high tumors, hypermethylation of MLH1, older age, and right-sided tumors. Our results showed that genome-wide methylation analyses classified patients with CRC into three subgroups according to CIMP levels, with clinical and molecular features consistent with previous data.

키워드

과제정보

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT (grant number: NRF-2017M3A9A7050614 and NRF-2017M3A9A7050610). It was additionally supported by a grant from the National Research Foundation of Korea (NRF-2020M3A9I6A01036057).

참고문헌

  1. Siegel RL, Miller KD, Fuchs HE and Jemal A (2022) Cancer statistics, 2022. CA Cancer J Clin 72, 7-33 https://doi.org/10.3322/caac.21708
  2. O'Connell JB, Maggard MA and Ko CY (2004) Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. J Natl Cancer Inst 96, 1420-1425 https://doi.org/10.1093/jnci/djh275
  3. Chang GJ, Hu CY, Eng C, Skibber JM and Rodriguez-Bigas MA (2009) Practical application of a calculator for conditional survival in colon cancer. J Clin Oncol 27, 5938-5943 https://doi.org/10.1200/JCO.2009.23.1860
  4. Fearon ER and Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61, 759-767 https://doi.org/10.1016/0092-8674(90)90186-I
  5. Smith G, Carey FA, Beattie J et al (2002) Mutations in APC, Kirsten-ras, and p53--alternative genetic pathways to colorectal cancer. Proc Natl Acad Sci USA 99, 9433-9438 https://doi.org/10.1073/pnas.122612899
  6. Okugawa Y, Grady WM and Goel A (2015) Epigenetic alterations in colorectal cancer: emerging biomarkers. Gastroenterology 149, 1204-1225 e12
  7. Lakshminarasimhan R and Liang G (2016) The role of DNA methylation in cancer. Adv Exp Med Biol 945, 151-172 https://doi.org/10.1007/978-3-319-43624-1_7
  8. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB and Issa JP (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A 96, 8681-8686 https://doi.org/10.1073/pnas.96.15.8681
  9. Weisenberger DJ, Siegmund KD, Campan M et al (2006) CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38, 787-793 https://doi.org/10.1038/ng1834
  10. Aryee MJ, Jaffe AE, Corrada-Bravo H et al (2014) Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics 30, 1363-1369 https://doi.org/10.1093/bioinformatics/btu049
  11. Maksimovic J, Gordon L and Oshlack A (2012) SWAN: Subset-quantile within array normalization for illumina infinium HumanMethylation450 BeadChips. Genome Biol 13, R44
  12. McInnes T, Zou D, Rao DS et al (2017) Genome-wide methylation analysis identifies a core set of hypermethylated genes in CIMP-H colorectal cancer. BMC Cancer 17, 228
  13. Lao VV and Grady WM (2011) Epigenetics and colorectal cancer. Nat Rev Gastroenterol Hepatol 8, 686-700 https://doi.org/10.1038/nrgastro.2011.173
  14. Gu S, Lin S, Ye D et al (2019) Genome-wide methylation profiling identified novel differentially hypermethylated biomarker MPPED2 in colorectal cancer. Clin Epigenetics 11, 41
  15. Herman JG and Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349, 2042-2054 https://doi.org/10.1056/NEJMra023075
  16. Jia M, Jansen L, Walter V et al (2016) No association of CpG island methylator phenotype and colorectal cancer survival: population-based study. Br J Cancer 115, 1359-1366 https://doi.org/10.1038/bjc.2016.361
  17. Cha Y, Kim KJ, Han SW et al (2016) Adverse prognostic impact of the CpG island methylator phenotype in metastatic colorectal cancer. Br J Cancer 115, 164-171 https://doi.org/10.1038/bjc.2016.176
  18. Hinoue T, Weisenberger DJ, Lange CP et al (2012) Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res 22, 271-282 https://doi.org/10.1101/gr.117523.110
  19. Dobre M, Salvi A, Pelisenco IA et al (2021) Crosstalk between DNA methylation and gene mutations in colorectal cancer. Front Oncol 11, 697409
  20. Kambara T, Simms LA, Whitehall VL et al (2004) BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53, 1137-1144 https://doi.org/10.1136/gut.2003.037671
  21. Toyota M, Ohe-Toyota M, Ahuja N and Issa JP (2000) Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. Proc Natl Acad Sci U S A 97, 710-715 https://doi.org/10.1073/pnas.97.2.710
  22. Kim JH, Rhee YY, Bae JM et al (2013) Subsets of microsatellite-unstable colorectal cancers exhibit discordance between the CpG island methylator phenotype and MLH1 methylation status. Mod Pathol 26, 1013-1022 https://doi.org/10.1038/modpathol.2012.241
  23. Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50, 113-130 https://doi.org/10.1111/j.1365-2559.2006.02549.x
  24. Ogino S, Nosho K, Kirkner GJ et al (2009) CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut 58, 90-96 https://doi.org/10.1136/gut.2008.155473
  25. Rawson J, Mrkonjic M, Daftary D et al (2011) Promoter methylation of Wnt5a is associated with microsatellite instability and BRAF V600E mutation in two large populations of colorectal cancer patients. Br J Cancer 104, 1906-1912 https://doi.org/10.1038/bjc.2011.165
  26. Rawson JB, Manno M, Mrkonjic M et al (2011) Promoter methylation of Wnt antagonists DKK1 and SFRP1 is associated with opposing tumor subtypes in two large populations of colorectal cancer patients. Carcinogenesis 32, 741-747 https://doi.org/10.1093/carcin/bgr020
  27. Silva AL, Dawson SN, Arends MJ et al (2014) Boosting Wnt activity during colorectal cancer progression through selective hypermethylation of Wnt signaling antagonists. BMC Cancer 14, 1-10 https://doi.org/10.1186/1471-2407-14-1
  28. Wi DH, Cha JH and Jung YS (2021) Mucin in cancer: a stealth cloak for cancer cells. BMB Rep 54, 344-355 https://doi.org/10.5483/BMBRep.2021.54.7.064
  29. Kim SC, Kim J, Kim DW et al (2022) Methylation-sensitive high-resolution melting analysis of the USP44 promoter can detect early-stage hepatocellular carcinoma in blood samples. BMB Rep 55, 553-558 https://doi.org/10.5483/BMBRep.2022.55.11.110
  30. Lee B, Hwang S, Kim PG et al (2023) Introduction of the Korea BioData Station (K-BDS) for sharing biological data. Genomics Inform 21, e12