Epigenetic Drivers of Genetic Alterations in Cancer

Abstract

In cancer cells, aberrant deoxyribonucleic acid (DNA) methylation plays key roles in the epigenetic dysregulation of tumour‐related genes, thereby affecting numerous cellular processes. Here we discuss the mechanism by which epigenetic events drive genetic alterations in cancer. Epigenetic inactivation of mutL homolog 1 (MLH1) is a major cause of microsatellite instability, while methylation of O‐6‐methylguanine‐DNA methyltransferase (MGMT) is often associated with specific mutations. In addition, the silencing of breast cancer 1 (BRCA1), Fanconi anemia, complementation group F (FANCF) and checkpoint with forkhead and ring finger domains (CHFR) impairs the machinery involved in maintaining genomic integrity. Conversely, a recently discovered link between isocitrate dehydrogenase 1 (IDH1)/2 or tet methylcytosine dioxygenase 2 (TET2) mutations and genome‐wide aberrant methylation suggests the hypermethylator phenotype may lie downstream of genetic alterations. Dissecting the association between epigenetic and genetic alterations could provide important clues for developing novel approaches to the treatment of cancer.

Key Concepts:

  • Epigenetic alteration of driver genes can lead to genetic alterations in cancer.

  • Epigenetic drivers include genes involved in DNA repair and cell cycle checkpoints.

  • Global hypomethylation may be another epigenetic driver that induces chromosomal instability.

  • Epigenetic alteration of driver genes is often associated with the CpG island methylator phenotype (CIMP).

  • The CIMP may lie downstream of specific gene mutations.

Keywords: DNA methylation; DNA repair; cell cycle checkpoint; chromosomal instability; CIMP

Figure 1.

IGFBP7 methylation and escape from senescence.

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References

Agrelo R, Cheng WH, Setien F et al. (2006) Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. Proceedings of the National Academy of Sciences of the USA 103(23): 8822–8827.

Akino K, Toyota M, Suzuki H et al. (2005) The Ras effector RASSF2 is a novel tumor‐suppressor gene in human colorectal cancer. Gastroenterology 129(1): 156–169.

Alvarez S, Diaz‐Uriarte R, Osorio A et al. (2005) A predictor based on the somatic genomic changes of the BRCA1/BRCA2 breast cancer tumors identifies the non‐BRCA1/BRCA2 tumors with BRCA1 promoter hypermethylation. Clinical Cancer Research 11(3): 1146–1153.

Baylin SB and Jones PA (2011) A decade of exploring the cancer epigenome – biological and translational implications. Nature Reviews Cancer 11(10): 726–734.

Brandes JC, van Engeland M, Wouters KA, Weijenberg MP and Herman JG (2005) CHFR promoter hypermethylation in colon cancer correlates with the microsatellite instability phenotype. Carcinogenesis 26(6): 1152–1156.

Cahill DP, Lengauer C, Yu J et al. (1998) Mutations of mitotic checkpoint genes in human cancers. Nature 392(6673): 300–303.

Chan TL, Yuen ST, Kong CK et al. (2006) Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nature Genetics 38(10): 1178–1183.

Chiang JW, Karlan BY, Cass L and Baldwin RL (2006) BRCA1 promoter methylation predicts adverse ovarian cancer prognosis. Gynecologic Oncology 101(3): 403–410.

Costello JF, Futscher BW, Kroes RA and Pieper RO (1994) Methylation‐related chromatin structure is associated with exclusion of transcription factors from and suppressed expression of the O‐6‐methylguanine DNA methyltransferase gene in human glioma cell lines. Molecular and Cellular Biology 14(10): 6515–6521.

D'Andrea AD and Grompe M (2003) The Fanconi anaemia/BRCA pathway. Nature Reviews Cancer 3(1): 23–34.

Dang L, White DW, Gross S et al. (2009) Cancer‐associated IDH1 mutations produce 2‐hydroxyglutarate. Nature 462(7274): 739–744.

Eden A, Gaudet F, Waghmare A and Jaenisch R (2003) Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300(5618): 455.

Esteller M (2007) Cancer epigenomics: DNA methylomes and histone‐modification maps. Nature Reviews Genetics 8(4): 286–298.

Esteller M, Hamilton SR, Burger PC , Baylin SB and Herman JG (1999) Inactivation of the DNA repair gene O6‐methylguanine‐DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Research 59(4): 793–797.

Esteller M, Silva JM, Dominguez G et al. (2000a) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. Journal of the National Cancer Institute 92(7): 564–569.

Esteller M, Toyota M, Sanchez‐Cespedes M et al. (2000b) Inactivation of the DNA repair gene O6‐methylguanine‐DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K‐ras in colorectal tumorigenesis. Cancer Research 60(9): 2368–2371.

Figueroa ME, Abdel‐Wahab O, Lu C et al. (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18(6): 553–567.

Fu Z, Regan K, Zhang L et al. (2009) Deficiencies in Chfr and Mlh1 synergistically enhance tumor susceptibility in mice. Journal of Clinical Investigation 119(9): 2714–2724.

Futreal PA, Liu Q, Shattuck‐Eidens D et al. (1994) BRCA1 mutations in primary breast and ovarian carcinomas. Science 266(5182): 120–122.

Gudmundsdottir K and Ashworth A (2006) The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene 25(43): 5864–5874.

Hansen RS, Wijmenga C, Luo P et al. (1999) The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proceedings of the National Academy of Sciences of the USA 96(25): 14412–14417.

Herman JG, Umar A, Polyak K et al. (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proceedings of the National Academy of Sciences of the USA 95(12): 6870–6875.

Hinoue T, Weisenberger DJ, Pan F et al. (2009) Analysis of the association between CIMP and BRAF in colorectal cancer by DNA methylation profiling. PLoS ONE 4(12): e8357.

Hitchins MP, Rapkins RW, Kwok CT et al. (2011) Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer‐affected family is linked to a single nucleotide variant within the 5′UTR. Cancer Cell 20(2): 200–213.

Imai K and Yamamoto H (2008) Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics. Carcinogenesis 29(4): 673–680.

Issa JP (2004) CpG island methylator phenotype in cancer. Nature Reviews Cancer 4(12): 988–993.

Kane MF, Loda M, Gaida GM et al. (1997) 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 Research 57(5): 808–811.

Kinzler KW and Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87(2): 159–170.

Ligtenberg MJ, Kuiper RP, Chan TL et al. (2009) Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nature Genetics 41(1): 112–117.

Lim SL, Smith P, Syed N et al. (2008) Promoter hypermethylation of FANCF and outcome in advanced ovarian cancer. British Journal of Cancer 98(8): 1452–1456.

Marsit CJ, Liu M, Nelson HH et al. (2004) Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival. Oncogene 23(4): 1000–1004.

Michaloglou C, Vredeveld LC, Soengas MS et al. (2005) BRAFE600‐associated senescence‐like cell cycle arrest of human naevi. Nature 436(7051): 720–724.

Mizuno K, Osada H, Konishi H et al. (2002) Aberrant hypermethylation of the CHFR prophase checkpoint gene in human lung cancers. Oncogene 21(15): 2328–2333.

Narayan G, Arias‐Pulido H, Nandula SV et al. (2004) Promoter hypermethylation of FANCF: disruption of Fanconi anemia‐BRCA pathway in cervical cancer. Cancer Research 64(9): 2994–2997.

Noushmehr H, Weisenberger DJ, Diefes K et al. (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17(5): 510–522.

Pegg AE (1990) Mammalian O6‐alkylguanine‐DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Research 50(19): 6119–6129.

Rodriguez J, Frigola J, Vendrell E et al. (2006) Chromosomal instability correlates with genome‐wide DNA demethylation in human primary colorectal cancers. Cancer Research 66(17): 8462–9468.

Satoh A, Toyota M, Itoh F et al. (2003) Epigenetic inactivation of CHFR and sensitivity to microtubule inhibitors in gastric cancer. Cancer Research 63(24): 8606–8613.

Strohmaier H, Spruck CH, Kaiser P et al. (2001) Human F‐box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature 413(6853): 316–322.

Suter CM, Martin DI and Ward RL (2004) Germline epimutation of MLH1 in individuals with multiple cancers. Nature Genetics 36(5): 497–501.

Suzuki H, Igarashi S, Nojima M et al. (2010) IGFBP7 is a p53‐responsive gene specifically silenced in colorectal cancer with CpG island methylator phenotype. Carcinogenesis 31(3): 342–349.

Taniguchi T, Tischkowitz M, Ameziane N et al. (2003) Disruption of the Fanconi anemia‐BRCA pathway in cisplatin‐sensitive ovarian tumors. Nature Medicine 9(5): 568–574.

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. Proceedings of the National Academy of Sciences of the United States of America 97(2): 710–715.

Toyota M, Sasaki Y, Satoh A et al. (2003) Epigenetic inactivation of CHFR in human tumors. Proceedings of the National Academy of Sciences of the USA 100(13): 7818–7823.

Wajapeyee N, Serra RW, Zhu X, Mahalingam M and Green MR (2008) Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132(3): 363–374.

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. Nature Genetics 38(7): 787–793.

Xu X, Gammon MD, Zhang Y et al. (2009) BRCA1 promoter methylation is associated with increased mortality among women with breast cancer. Breast Cancer Research and Treatment 115(2): 397–404.

Yamada Y, Jackson‐Grusby L, Linhart H et al. (2005) Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proceedings of the National Academy of Sciences of the USA 102(38): 13580–13585.

Yang AS, Estecio MR, Doshi K et al. (2004) A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Research 32(3): e38.

Yu X, Minter‐Dykhouse K, Malureanu L et al. (2005) Chfr is required for tumor suppression and Aurora A regulation. Nature Genetics 37(4): 401–406.

Further Reading

Feinberg AP and Tycko B (2004) The history of cancer epigenetics. Nature Reviews Cancer 4(2): 143–153.

Jones PA and Baylin SB (2007) The epigenomics of cancer. Cell 128(4): 683–692.

Lu C, Ward PS, Kapoor GS et al. (2012) IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483(7390): 474–478.

Suzuki H, Tokino T, Shinomura Y, Imai K and Toyota M (2008) DNA methylation and cancer pathways in gastrointestinal tumors. Pharmacogenomics 9(12): 1917–1928.

Toyota M, Suzuki H, Yamashita T et al. (2009) Cancer epigenomics: implications of DNA methylation in personalized cancer therapy. Cancer Science 100(5): 787–791.

Turcan S, Rohle D, Goenka A et al. (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483(7390): 479–483.

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How to Cite close
Suzuki, Hiromu(Jul 2012) Epigenetic Drivers of Genetic Alterations in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023867]