Abstract
DNA hypermethylation in CpG-rich promoters is now recognized as a common feature of human neoplasia. However, the pathophysiology of hyper-methylation (why, when, where) remains obscure. Cancers can be classified according to their degree of methylation, and those cancers with high degrees of methylation (the CpG island methylator phenotype, or CIMP) represent a clinically and aetiologically distinct group that is characterized by 'epigenetic instability'. Furthermore, CIMP-associated cancers seem to have a distinct epidemiology, a distinct histology, distinct precursor lesions and distinct molecular features.
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References
Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nature Genet. 33 (Suppl.), 245–254 (2003).
Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002).
Li, E., Bestor, T. H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).
Yoder, J. A., Walsh, C. P. & Bestor, T. H. Cytosine methylation and the ecology of intragenomic parasites. Trends Genet. 13, 335–340 (1997).
Egger, G., Liang, G., Aparicio, A. & Jones, P. A. Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457–463 (2004).
Herman, J. G. & Baylin, S. B. Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med. 349, 2042–2054 (2003).
Brinster, R. L. Participation of teratocarcinoma cells in mouse embryo development. Cancer Res. 36, 3412–3414 (1976).
Li, L., Connelly, M. C., Wetmore, C., Curran, T. & Morgan, J. I. Mouse embryos cloned from brain tumors. Cancer Res. 63, 2733–2736 (2003).
Hochedlinger, K. et al. Reprogramming of a melanoma genome by nuclear transplantation. Genes Dev. 18, 1875–1885 (2004).
Santini, V., Kantarjian, H. M. & Issa, J. P. Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann. Intern. Med. 134, 573–586 (2001).
Silverman, L. R. et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J. Clin. Oncol. 20, 2429–2440 (2002).
Jones, P. A. & Baylin, S. B. The fundamental role of epigenetic events in cancer. Nature Rev. Genet. 3, 415–428 (2002).
Sidransky, D. Emerging molecular markers of cancer. Nature Rev. Cancer 2, 210–219 (2002).
Issa, J. P. Methylation and prognosis: of molecular clocks and hypermethylator phenotypes. Clin. Cancer Res. 9, 2879–2881 (2003).
Issa, J. P. et al. Increased cytosine DNA-methyltransferase activity during colon cancer progression. J. Natl Cancer Inst. 85, 1235–1240 (1993).
De Marzo, A. M. et al. Abnormal regulation of DNA methyltransferase expression during colorectal carcinogenesis. Cancer Res. 59, 3855–3860 (1999).
Robertson, K. D., Keyomarsi, K., Gonzales, F. A., Velicescu, M. & Jones, P. A. Differential mRNA expression of the human DNA methyltransferases (DNMTs) 1, 3a and 3b during the G(0)/G(1) to S phase transition in normal and tumor cells. Nucleic Acids Res. 28, 2108–2113 (2000).
Eads, C. A. et al. CpG island hypermethylation in human colorectal tumors is not associated with DNA methyltransferase overexpression. Cancer Res. 59, 2302–2306 (1999).
Shen, L. et al. DNA methylation and environmental exposures in human hepatocellular carcinoma. J. Natl Cancer Inst. 94, 755–761 (2002).
Kim, D. H. et al. p16(INK4a) and histology-specific methylation of CpG islands by exposure to tobacco smoke in non-small cell lung cancer. Cancer Res. 61, 3419–3424 (2001).
Issa, J. P., Baylin, S. B. & Belinsky, S. A. Methylation of the estrogen receptor CpG island in lung tumors is related to the specific type of carcinogen exposure. Cancer Res. 56, 3655–3658 (1996).
Loeb, L. A. A mutator phenotype in cancer. Cancer Res. 61, 3230–3239 (2001).
Baylin, S. B. et al. DNA methylation patterns of the calcitonin gene in human lung cancers and lymphomas. Cancer Res. 46, 2917–2922 (1986).
Ahuja, N. et al. Association between CpG island methylation and microsatellite instability in colorectal cancer. Cancer Res. 57, 3370–3374 (1997).
Kane, M. F. et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 57, 808–811 (1997).
Herman, J. G. et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc. Natl Acad. Sci. USA 95, 6870–6875 (1998).
Shibata, D. M. et al. Hypermethylation of HPP1 is associated with hMLH1 hypermethylation in gastric adenocarcinomas. Cancer Res. 62, 5637–5640 (2002).
Shen, L., Kondo, Y., Hamilton, S. R., Rashid, A. & Issa, J. P. p14 methylation in human colon cancer is associated with microsatellite instability and wild-type p53. Gastroenterology 124, 626–633 (2003).
Yamamoto, H. et al. Differential involvement of the hypermethylator phenotype in hereditary and sporadic colorectal cancers with high-frequency microsatellite instability. Genes Chromosomes Cancer 33, 322–325 (2002).
Toyota, M. et al. Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res. 59, 2307–2312 (1999).
Toyota, M. et al. CpG Island methylator phenotype in colorectal cancer. Proc. Natl Acad. Sci. USA 96, 8681–8686 (1999).
Issa, J. P. Epigenetic variation and human disease. J. Nutr. 132, 2388S–2392S (2002).
Issa, J. P. et al. Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nature Genet. 7, 536–540 (1994).
Toyota, M., Ohe-Toyota, M., Ahuja, N. & Issa, J. P. Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. Proc. Natl Acad. Sci. USA 97, 710–715 (2000).
Kambara, T. et al. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53, 1137–1144 (2004).
Whitehall, V. L. et al. Morphological and molecular heterogeneity within nonmicrosatellite instability-high colorectal cancer. Cancer Res. 62, 6011–6014 (2002).
Yan, P. S. et al. Use of CpG island microarrays to identify colorectal tumors with a high degree of concurrent methylation. Methods 27, 162–169 (2002).
van Rijnsoever, M., Grieu, F., Elsaleh, H., Joseph, D. & Iacopetta, B. Characterisation of colorectal cancers showing hypermethylation at multiple CpG islands. Gut 51, 797–802 (2002).
Li, Q. et al. Concordant methylation of the ER and N33 genes in glioblastoma multiforme. Oncogene 16, 3197–3202 (1998).
Toyota, M. et al. Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. Cancer Res. 59, 5438–5442 (1999).
Kim, H. et al. Concerted promoter hypermethylation of hMLH1, p16INK4A, and E-cadherin in gastric carcinomas with microsatellite instability. J. Pathol. 200, 23–31 (2003).
Ueki, T. et al. Hypermethylation of multiple genes in pancreatic adenocarcinoma. Cancer Res. 60, 1835–1839 (2000).
Strathdee, G. et al. Primary ovarian carcinomas display multiple methylator phenotypes involving known tumor suppressor genes. Am. J. Pathol. 158, 1121–1127 (2001).
Garcia-Manero, G. et al. DNA methylation of multiple promoter-associated CpG islands in adult acute lymphocytic leukemia. Clin. Cancer Res. 8, 2217–2224 (2002).
Toyota, M. et al. Methylation profiling in acute myeloid leukemia. Blood 97, 2823–2829 (2001).
Eads, C. A. et al. Epigenetic patterns in the progression of esophageal adenocarcinoma. Cancer Res. 61, 3410–3418 (2001).
Yamashita, K., Dai, T., Dai, Y., Yamamoto, F. & Perucho, M. Genetics supersedes epigenetics in colon cancer phenotype. Cancer Cell 4, 121–131 (2003).
Bestor, T. H. Unanswered questions about the role of promoter methylation in carcinogenesis. Ann. NY Acad. Sci. 983, 22–27 (2003).
Watanabe, T. et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N. Engl. J. Med. 344, 1196–1206 (2001).
Ward, R. L. et al. Adverse prognostic effect of methylation in colorectal cancer is reversed by microsatellite instability. J. Clin. Oncol. 21, 3729–3736 (2003).
Jass, J. R. Serrated route to colorectal cancer: back street or super highway? J. Pathol. 193, 283–285 (2001).
Chan, A. O., Issa, J. P., Morris, J. S., Hamilton, S. R. & Rashid, A. Concordant CpG island methylation in hyperplastic polyposis. Am. J. Pathol. 160, 529–536 (2002).
Park, S. J. et al. Frequent CpG island methylation in serrated adenomas of the colorectum. Am. J. Pathol. 162, 815–822 (2003).
Chan, T. L., Zhao, W., Leung, S. Y. & Yuen, S. T. BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res. 63, 4878–4881 (2003).
Cunningham, J. M. et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 58, 3455–3460 (1998).
Ji, X., Woodard, A. S., Rimm, D. L. & Fearon, E. R. Transcriptional defects underlie loss of e-cadherin expression in breast cancer. Cell Growth Differ. 8, 773–778 (1997).
Song, J. Z., Stirzaker, C., Harrison, J., Melki, J. R. & Clark, S. J. Hypermethylation trigger of the glutathione-S-transferase gene (GSTP1) in prostate cancer cells. Oncogene 21, 1048–1061 (2002).
Toyota, M. et al. Aberrant methylation of the cyclooxygenase 2 CpG island in colorectal tumors. Cancer Res. 60, 4044–4048 (2000).
Issa, J. P. The epigenetics of colorectal cancer. Ann. NY Acad. Sci. 910, 140–153 (2000).
Turker, M. S. Gene silencing in mammalian cells and the spread of DNA methylation. Oncogene 21, 5388–5393 (2002).
Velicescu, M. et al. Cell division is required for de novo methylation of CpG islands in bladder cancer cells. Cancer Res. 62, 2378–2384 (2002).
Kang, G. H. et al. Epstein-barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma. Am. J. Pathol. 160, 787–794 (2002).
Waterland, R. A. & Jirtle, R. L. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol. Cell Biol. 23, 5293–5300 (2003).
Issa, J. P., Ahuja, N., Toyota, M., Bronner, M. P. & Brentnall, T. A. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res. 61, 3573–3577 (2001).
Eads, C. A. et al. Fields of aberrant CpG island hypermethylation in Barrett's esophagus and associated adenocarcinoma. Cancer Res. 60, 5021–5026 (2000).
Zochbauer-Muller, S. et al. Aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Res. 61, 249–255 (2001).
Fleisher, A. S. et al. Microsatellite instability in inflammatory bowel disease-associated neoplastic lesions is associated with hypermethylation and diminished expression of the DNA mismatch repair gene, hMLH1. Cancer Res. 60, 4864–4868 (2000).
Frazier, M. L. et al. Association of the CpG island methylator phenotype with family history of cancer in patients with colorectal cancer. Cancer Res. 63, 4805–4808 (2003).
Ricciardiello, L. et al. Frequent loss of hMLH1 by promoter hypermethylation leads to microsatellite instability in adenomatous polyps of patients with a single first-degree member affected by colon cancer. Cancer Res. 63, 787–792 (2003).
Laird, P. W. The power and the promise of DNA methylation markers. Nature Rev. Cancer 3, 253–266 (2003).
Leung, Y. F. & Cavalieri, D. Fundamentals of cDNA microarray data analysis. Trends Genet. 19, 649–659 (2003).
Kinzler, K. W. & Vogelstein, B. Lessons form hereditary colorectal cancer. Cell 87, 159–170 (1996).
Jass, J. R. Limitations of the adenoma-carcinoma sequence in colorectum. Clin. Cancer Res. 10, 5969–5970 (2004).
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MD Anderson Cancer Center resource on CpG island methylation
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Issa, JP. CpG island methylator phenotype in cancer. Nat Rev Cancer 4, 988–993 (2004). https://doi.org/10.1038/nrc1507
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DOI: https://doi.org/10.1038/nrc1507
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