Suter CM, Martin DI, Ward RLGermline epimutation of MLH1 in individuals with multiple cancers. Nat Genet 36: 497-501

Department of Medical Oncology, St Vincent's Hospital, Sydney, New South Wales, Australia.
Nature Genetics (Impact Factor: 29.35). 06/2004; 36(5):497-501. DOI: 10.1038/ng1342
Source: PubMed


Epigenetic silencing can mimic genetic mutation by abolishing expression of a gene. We hypothesized that an epimutation could occur in any gene as a germline event that predisposes to disease and looked for examples in tumor suppressor genes in individuals with cancer. Here we report two individuals with soma-wide, allele-specific and mosaic hypermethylation of the DNA mismatch repair gene MLH1. Both individuals lack evidence of genetic mutation in any mismatch repair gene but have had multiple primary tumors that show mismatch repair deficiency, and both meet clinical criteria for hereditary nonpolyposis colorectal cancer. The epimutation was also present in spermatozoa of one of the individuals, indicating a germline defect and the potential for transmission to offspring. Germline epimutation provides a mechanism for phenocopying of genetic disease. The mosaicism and nonmendelian inheritance that are characteristic of epigenetic states could produce patterns of disease risk that resemble those of polygenic or complex traits.

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Available from: Robyn Ward, Apr 14, 2014
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    • "The instability of SSRs was identified to be a pathway to lead to colorectal cancer [27]. It is now accepted that unstable maintenance of microsatellites occurs in about 15% of sporadic colorectal cancers [28,29]. Microsatellite instability is also frequently associated with other diseases such as ovarian cancers, malignant tumors of endometrium [30], small intestine [29], stomach [31], skin [32] and brain, etc. "
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    BMC Genomics 08/2012; 13(1):435. DOI:10.1186/1471-2164-13-435 · 3.99 Impact Factor
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    • "These tumors are MMR deficient, due to a second hit to the MMR gene, and show microsatellite instability and loss of expression of the relevant MMR protein.2 Germline sequence mutations in the MMR genes are not found in 25–30% of patients with suspected Lynch syndrome, and a proportion of these mutation-negative individuals have been shown to carry constitutional epimutations of the MLH1 or MSH2 genes.3,4,5,6,7,8 Constitutional epimutations manifest as promoter methylation and loss of transcription from one genetic allele within normal somatic tissues.9 "
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    ABSTRACT: Purpose: Constitutional MLH1 epimutations manifest as promoter methylation and silencing of the affected allele in normal tissues, predisposing to Lynch syndrome–associated cancers. This study investigated their frequency and inheritance. Methods: A total of 416 individuals with a colorectal cancer showing loss of MLH1 expression and without deleterious germline mutations in MLH1 were ascertained from the Colon Cancer Family Registry (C-CFR). Constitutive DNA samples were screened for MLH1 methylation in all 416 subjects and for promoter sequence changes in 357 individuals. Results: Constitutional MLH1 epimutations were identified in 16 subjects. Of these, seven (1.7%) had mono- or hemi-allelic methylation and eight had low-level methylation (2%). In one subject the epimutation was linked to the c.-27C>A promoter variant. Testing of 37 relatives from nine probands revealed paternal transmission of low-level methylation segregating with a c.+27G>A variant in one case. Five additional probands had a promoter variant without an MLH1 epimutation, with three showing diminished promoter activity in functional assays. Conclusion: Although rare, sequence changes in the regulatory region of MLH1 and aberrant methylation may alone or together predispose to the development of cancer. Screening for these changes is warranted in individuals who have a negative germline sequence screen of MLH1 and loss of MLH1 expression in their tumor.
    Genetics in medicine: official journal of the American College of Medical Genetics 08/2012; 15(1). DOI:10.1038/gim.2012.91 · 7.33 Impact Factor
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    • "Such ASM events have yet to be characterized in large populationbased studies, but more modest studies addressing heterozygous non-imprinted loci have identified widespread ASMs associated with nearby genotypic polymorphisms in DNA from multiple tissue types (Kerkel et al. 2008; Tycko 2010; Schalkwyk et al. 2010), as well as allele-specific chromatin structure and transcription factor binding in lymphoblastoid cell DNA (McDaniell et al. 2010, reviewed in Birney et al. 2010). Presumed transgenerational inheritance of epigenetic changes (''epimutations'') in the MLH1 (Suter et al. 2004) and MSH2 (Chan et al. 2006) mismatch repair genes, both associated with colorectal cancer, were also traced to germline genetic variation. In the case of the MSH2 epimutation, deletion of a gene immediately upstream of the MSH2 gene causes transcription to run through the MSH2 promoter, causing somatic hypermethylation and gene silencing (Ligtenberg et al. 2009). "
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