Epigenetic Mechanisms in Lynch Syndrome

Abstract

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.
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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]