Epigenetic Mechanisms in Lynch Syndrome


Lynch syndrome (LS) has been known for a century. The syndrome was originally recognised as a dominant predisposition to cancers of multiple organs, including those of the gastrointestinal tract and female reproductive organs. In 1993–1995, LS was linked to germline mutations in DNA (deoxyribonucleic acid) mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Soon thereafter, promoter methylation as an alternative mechanism of DNA MMR gene inactivation was discovered. Such ‘epigenetic mutations’ (epimutations) may be somatic (e.g. biallelic methylation of MLH1 in sporadic microsatellite‐unstable cancers) or constitutional (monoallelic methylation of MLH1 or MSH2 in normal tissue, involving cells derived from all three germ layers and causing predisposition to LS cancers). To date, epigenetic mechanisms are known to operate at all stages of LS tumourigenesis, from constitutional predisposition to cancer initiation and progression, and involve DNA MMR genes as well as multiple other growth‐regulatory genes. This review discusses the role of epigenetic mechanisms in the pathogenesis of LS and more broadly, LS as a model of epigenetic mechanisms underlying common human cancers.

Key Concepts

  • Lynch syndrome (LS) is caused by mutations in one of the DNA mismatch repair genes; MLH1, MSH2, MSH6 or PMS2.
  • DNA methylation, miRNAs and histone modifications are involved in epigenetic regulation of MMR genes.
  • Epigenetic regulation has been linked to constitutional predisposition, cancer initiation and progression in LS.
  • MLH1 gene may be constitutionally affected by primary epimutation (has no known genetic basis and is usually not inherited) or secondary epimutation (associated with genetic cis‐ or trans‐acting alteration, which can be transmitted to offspring).
  • EPCAM deletions may induce secondary epimutations of the MSH2 gene.
  • MMR genes typically, but not always, require two hit inactivation for tumour initiation.
  • LS spectrum tumours have epigenetic profiles characteristic of tumour type.
  • Environmental factors interact with genetic and epigenetic factors, influencing LS phenotype.

Keywords: epigenetic regulation; Lynch syndrome; DNA methylation; DNA mismatch repair; tumourigenesis; epimutation

Figure 1. Multiple steps in LS tumourigenesis. The maternal (M) and paternal (P) homologues of a chromosome (e.g. #3) containing an MMR gene locus are depicted as bars (left). A mutant MMR gene (e.g., MLH1) that has suffered a genetic or epigenetic event is indicated as a solid circle. Examples of tumour suppressor promoter methylation that may accompany transition from normal to premalignant to malignant tissue in colorectal (Valo et al., ) and endometrial tumourigenesis (Nieminen et al., ; Kaur et al., ) are given at the bottom.
Figure 2. LS tumour spectrum. The estimated lifetime risks of cancer for different organs in LS individuals are indicated (Aarnio et al., ). Selected tumour suppressor genes with hypermethylation reported for both LS and sporadic cases are shown in bold. For some genes, methylation information is predominantly available from LS (underlined) or alternatively, sporadic cases (neither bolded nor underlined).
Figure 3. (a) Density of tumour suppressor gene (TSG) methylator phenotype in different cancers from LS mutation carriers. All tumours originate from the nation‐wide LS registry of one population (Lotsari et al., ; Niskakoski et al., ). The average number of methylated TSGs out of 24 investigated per tumour is indicated, based on the methylation dosage ratio of 0.25 or higher as a cutoff by methylation‐specific multiplex ligation‐dependent probe amplification. (b) Differential promoter methylation of tumour suppressor genes in different LS cancers. The analysis includes those genes (among all 24) that were methylated in at least 10% for at least one tumour type. Gastrointestinal cancers share increased methylation of ESR1, CHFR and RARB, whereas methylation of RASSF1A and CDH13 is typical of cancers of female organs.


Aarnio M, Sankila R, Pukkala E, et al. (1999) Cancer risk in mutation carriers of DNA‐mismatch‐repair genes. International Journal of Cancer 81: 214–218.

Balaguer F, Moreira L, Lozano JJ, et al. (2011) Colorectal cancers with microsatellite instability display unique miRNA profiles. Clinical Cancer Research 17: 6239–6249.

Botma A, Vasen HF, van Duijnhoven FJ, et al. (2013) Dietary patterns and colorectal adenomas in lynch syndrome: The GEOLynch cohort study. Cancer 119: 512–521.

Cancer Genome Atlas Network (2012a) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487: 330–337.

Cancer Genome Atlas Network (2012b) Comprehensive molecular portraits of human breast tumours. Nature 490: 61–70.

Cancer Genome Atlas Research Network (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474: 609–615.

Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al. (2013) Integrated genomic characterization of endometrial carcinoma. Nature 497: 67–73.

Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513: 202–209.

Castillejo A, Hernandez‐Illan E, Rodriguez‐Soler M, et al. (2015) Prevalence of MLH1 constitutional epimutations as a cause of lynch syndrome in unselected versus selected consecutive series of patients with colorectal cancer. Journal of Medical Genetics 52: 498–502.

Cejka P, Stojic L, Mojas N, et al. (2003) Methylation‐induced G(2)/M arrest requires a full complement of the mismatch repair protein hMLH1. EMBO Journal 22: 2245–2254.

Fernandez AF, Assenov Y, Martin‐Subero JI, et al. (2012) A DNA methylation fingerprint of 1628 human samples. Genome Research 22: 407–419.

Grindedal EM, Renkonen‐Sinisalo L, Vasen H, et al. (2010) Survival in women with MMR mutations and ovarian cancer: a multicentre study in lynch syndrome kindreds. Journal of Medical Genetics 47: 99–102.

Gylling A, Abdel‐Rahman WM, Juhola M, et al. (2007) Is gastric cancer part of the tumour spectrum of hereditary non‐polyposis colorectal cancer? A molecular genetic study. Gut 56: 926–933.

Gylling AH, Nieminen TT, Abdel‐Rahman WM, et al. (2008) Differential cancer predisposition in lynch syndrome: Insights from molecular analysis of brain and urinary tract tumors. Carcinogenesis 29: 1351–1359.

Gylling A, Ridanpaa M, Vierimaa O, et al. (2009) Large genomic rearrangements and germline epimutations in lynch syndrome. International Journal of Cancer 124: 2333–2340.

Hampel H and de la Chapelle A (2013) How do we approach the goal of identifying everybody with lynch syndrome? Familial Cancer 12: 313–317.

Hitchins MP, Wong JJ, Suthers G, et al. (2007) Inheritance of a cancer‐associated MLH1 germ‐line epimutation. New England Journal of Medicine 356: 697–705.

Joensuu EI, Abdel‐Rahman WM, Ollikainen M, et al. (2008) Epigenetic signatures of familial cancer are characteristic of tumor type and family category. Cancer Research 68: 4597–4605.

Joensuu EI, Nieminen TT, Lotsari JE, et al. (2015) Methyltransferase expression and tumor suppressor gene methylation in sporadic and familial colorectal cancer. Genes, Chromosomes & Cancer 54: 776–787.

Kaur S, Lotsari JE, Al‐Sohaily S, et al. (2015) Identification of subgroup‐specific miRNA patterns by epigenetic profiling of sporadic and lynch syndrome‐associated colorectal and endometrial carcinoma. Clinical Epigenetics 7: 20‐015‐0059‐3.

Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Sciences of the United States of America 68: 820–823.

Kwok CT, Vogelaar IP, van Zelst‐Stams WA, et al. (2014) The MLH1 c.‐27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype. European Journal of Human Genetics 22: 617–624.

Lagerstedt Robinson K, Liu T, Vandrovcova J, et al. (2007) Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. Journal of the National Cancer Institute 99: 291–299.

Li F, Mao G, Tong D, et al. (2013) The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSalpha. Cell 153: 590–600.

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: 112–117.

Lim JP and Brunet A (2013) Bridging the transgenerational gap with epigenetic memory. Trends in Genetics 29: 176–186.

Lotsari JE, Gylling A, Abdel‐Rahman WM, et al. (2012) Breast carcinoma and lynch syndrome: molecular analysis of tumors arising in mutation carriers, non‐carriers, and sporadic cases. Breast Cancer Research 14: R90.

Lynch HT and Krush AJ (1971) Cancer family “G” revisited: 1895–1970. Cancer 27: 1505–1511.

Morak M, Schackert HK, Rahner N, et al. (2008) Further evidence for heritability of an epimutation in one of 12 cases with MLH1 promoter methylation in blood cells clinically displaying HNPCC. European Journal of Human Genetics 16: 804–811.

Moreira L, Munoz J, Cuatrecasas M, et al. (2015) Prevalence of somatic mutl homolog 1 promoter hypermethylation in lynch syndrome colorectal cancer. Cancer 121: 1395–1404.

Nagasaka T, Rhees J, Kloor M, et al. (2010) Somatic hypermethylation of MSH2 is a frequent event in lynch syndrome colorectal cancers. Cancer Research 70: 3098–3108.

Nieminen TT, Gylling A, Abdel‐Rahman WM, et al. (2009) Molecular analysis of endometrial tumorigenesis: importance of complex hyperplasia regardless of atypia. Clinical Cancer Research 15: 5772–5783.

Niessen RC, Hofstra RM, Westers H, et al. (2009) Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of lynch syndrome. Genes, Chromosomes & Cancer 48: 737–744.

Niskakoski A, Kaur S, Renkonen‐Sinisalo L, et al. (2013) Distinct molecular profiles in lynch syndrome‐associated and sporadic ovarian carcinomas. International Journal of Cancer 133: 2596–2608.

Niskakoski A, Kaur S, Staff S, et al. (2014) Epigenetic analysis of sporadic and lynch‐associated ovarian cancers reveals histology‐specific patterns of DNA methylation. Epigenetics 9: 1577–1587.

Park JG, Park YJ, Wijnen JT, et al. (1999) Gene‐environment interaction in hereditary nonpolyposis colorectal cancer with implications for diagnosis and genetic testing. International Journal of Cancer 82: 516–519.

Paul B, Barnes S, Demark‐Wahnefried W, et al. (2015) Influences of diet and the gut microbiome on epigenetic modulation in cancer and other diseases. Clinical Epigenetics 7: 112‐015‐0144‐7.

Pavicic W, Perkio E, Kaur S, et al. (2011) Altered methylation at microRNA‐associated CpG islands in hereditary and sporadic carcinomas: a methylation‐specific multiplex ligation‐dependent probe amplification (MS‐MLPA)‐based approach. Molecular Medicine 17: 726–735.

Peltomaki P, Gao X and Mecklin JP (2001) Genotype and phenotype in hereditary nonpolyposis colon cancer: a study of families with different vs. shared predisposing mutations. Familial Cancer 1: 9–15.

Roadmap Epigenomics Consortium, Kundaje A, Meuleman W, et al. (2015) Integrative analysis of 111 reference human epigenomes. Nature 518: 317–330.

Roy DM, Walsh LA and Chan TA (2014) Driver mutations of cancer epigenomes. Protein & Cell 5: 265–296.

Sahnane N, Magnoli F, Bernasconi B, et al. (2015) Aberrant DNA methylation profiles of inherited and sporadic colorectal cancer. Clinical Epigenetics 7: 131‐015‐0165‐2.

Sloane MA, Hesson LB and Ward RL (2014) Epimutations and cancer susceptibility. In: eLS. Chichester: John Wiley Sons, Ltd. DOI: 10.1002/9780470015902.a0024615.

Sloane MA, Nunez AC, Packham D, et al. (2015) Mosaic epigenetic inheritance as a cause of early‐onset colorectal cancer. JAMA Oncology 1: 953–957.

Thompson BA, Spurdle AB, Plazzer JP, et al. (2014) Application of a 5‐tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus‐specific database. Nature Genetics 46: 107–115.

Tobi EW, Lumey LH, Talens RP, et al. (2009) DNA methylation differences after exposure to prenatal famine are common and timing‐ and sex‐specific. Human Molecular Genetics 18: 4046–4053.

Toyota M, Ahuja N, Ohe‐Toyota M, et al. (1999) CpG island methylator phenotype in colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America 96: 8681–8686.

Umar A, Boland CR, Terdiman JP, et al. (2004) Revised bethesda guidelines for hereditary nonpolyposis colorectal cancer (lynch syndrome) and microsatellite instability. Journal of the National Cancer Institute 96: 261–268.

Valeri N, Gasparini P, Fabbri M, et al. (2010) Modulation of mismatch repair and genomic stability by miR‐155. Proceedings of the National Academy of Sciences of the United States of America 107: 6982–6987.

Valo S, Kaur S, Ristimaki A, et al. (2015) DNA hypermethylation appears early and shows increased frequency with dysplasia in lynch syndrome‐associated colorectal adenomas and carcinomas. Clinical Epigenetics 7: 71‐015‐0102‐4.

Vasen HF, Mecklin JP, Khan PM, et al. (1991) The international collaborative group on hereditary non‐polyposis colorectal cancer (ICG‐HNPCC). Diseases of the Colon & Rectum 34: 424–425.

Vasen HF, Watson P, Mecklin JP, et al. (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, lynch syndrome) proposed by the international collaborative group on HNPCC. Gastroenterology 116: 1453–1456.

Veigl ML, Kasturi L, Olechnowicz J, et al. (1998) Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proceedings of the National Academy of Sciences of the United States of America 95: 8698–8702.

Ward RL, Dobbins T, Lindor NM, et al. (2013) Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the colon cancer family registry. Genetics in Medicine 15: 25–35.

Wijnen J, Khan PM, Vasen H, et al. (1997) Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch‐repair‐gene mutations. American Journal of Human Genetics 61: 329–335.

Yamamoto H and Imai K (2015) Microsatellite instability: an update. Archives of Toxicology 89: 899–921.

Yurgelun MB, Goel A, Hornick JL, et al. (2012) Microsatellite instability and DNA mismatch repair protein deficiency in lynch syndrome colorectal polyps. Cancer Prevention Research (Philadelphia, Pa.) 5: 574–582.

www.insight‐group.org (2015) International Society for Gastrointestinal Hereditary Tumours.

Further Reading

Alegria‐Torres JA, Baccarelli A and Bollati V (2011) Epigenetics and lifestyle. Epigenomics 3: 267–277.

Bak ST, Sakellariou D and Pena‐Diaz J (2014) The dual nature of mismatch repair as antitumor and mutator: for better or for worse. Frontiers in Genetics 5: 287.

Cini G, Carnevali I, Quaia M, et al. (2015) Concomitant mutation and epimutation of the MLH1 gene in a lynch syndrome family. Carcinogenesis 36: 452–458.

Earle JS, Luthra R, Romans A, et al. (2010) Association of microRNA expression with microsatellite instability status in colorectal adenocarcinoma. Journal of Molecular Diagnostics 12: 433–440.

Heijink DM, de Vries EGE, Koornstra JJ, et al. (2011) Perspectives for tailored chemoprevention and treatment of colorectal cancer in lynch syndrome. Critical Reviews in Oncology/Hematology 80: 264–277.

Luo Y, Wong C‐J, Kaz AM, et al. (2014) Differences in methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer. Gastroenterology 147: 418–429.

Morak M, Koehler U, Schackert HK, et al. (2011) Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing lynch syndrome. Journal of Medical Genetics 48: 513–519.

Svrcek M, Buhard O, Colas C, et al. (2010) Methylation tolerance due to an O6‐methylguanine DNA methyltransferase (MGMT) field defect in the colonic mucosa: an initiating step in the development of mismatch repair‐deficient colorectal cancers. Gut 59: 1516–1526.

Tutlewska K, Lubinski J and Kurzawski G (2013) Germline deletions in the EPCAM gene as a cause of lynch syndrome – literature review. Hereditary Cancer in Clinical Practice 11: 9.

Winkels RM, Botma A, van Duijnhoven FJB, et al. (2012) Smoking increases the risk of colorectal adenomas in patients with lynch syndrome. Gastroenterology 142: 241–247.

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Nieminen, Taina T, Niskakoski, Anni, and Peltomäki, Päivi(Apr 2016) Epigenetic Mechanisms in Lynch Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026560]