Update on Lynch syndrome genomics

Abstract

Four main DNA mismatch repair (MMR) genes have been identified, MLH1, MSH2, MSH6, and PMS2, which when mutated cause susceptibility to Lynch syndrome (LS). LS is one of the most prevalent hereditary cancer syndromes in man and accounts for 1–3 % of unselected colorectal carcinomas and some 15 % of those with microsatellite instability and/or absent MMR protein. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) maintains a database for LS-associated mutations since 1996. The database was recently reorganized to efficiently gather published and unpublished data and to classify the variants according to a five-tiered scheme linked to clinical recommendations. This review provides an update of germline mutations causing susceptibility to LS based on information available in the InSiGHT database and the latest literature. MMR gene mutation profiles, correlations between genotype and phenotype, and possible mechanisms leading to the characteristic spectrum of tumors in LS are discussed in light of the different functions of MMR proteins, many of which directly serve cancer avoidance.

Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibility

“…Secondly, because of the functional impact of MSH6 mutations: Experimental studies in MSH6-deficient yeast, mice or human cells demonstrate that MSH6 mutations results in partial MMR deficiency (mild mutator phenotype, characterized by weak microsatellite instability, MSI-L) and increased cancer susceptibility in animal models (27). And finally because, in the clinical context, MSH6 mutations are associated with cancer syndromes (and TC, possibly): Inherited MSH6 germline mutations are responsible for 7-10% of LS cases, patients presenting an atypical phenotype (lower CRC incidence-with later onset-high incidence of endometrial cancer and lower degree or absence of MSI), compared to the more frequent MSH2 and MLH1-mutant LS cases (27,31,39,62). TC-despite not part of the usual LS spectrum-has been sporadically observed in LS patients harbouring MSH2 and MLH1 mutations (36,(38)(39)(40) and, more recently, also in a MSH6-mutant LS case (37).…”

“…MMR also participates, among other cellular processes (e.g., mitotic and meiotic recombination, immunoglobulin class switching), in the recognition of DNA damage induced by genotoxic chemicals, UV light, IR or oxidative stress (e.g., oxidative lesions, double strand breaks, pyrimidine dimers and inter-strand crosslinks) and subsequent repair (in cooperation with other repair pathways) or damage-induced cytotoxicity (downstream signalling for cell cycle arrest and apoptosis) (28)(29)(30). MMR's role is therefore critical to carcinogenesis: loss of MMR (e.g., inactivating mutation) greatly increases the rate of spontaneous mutation, leading to a mutator phenotype, and results in microsatellite instability (MSI), a hallmark of MMR defects (27,29,31). Not surprisingly, heterozygous germline MMR mutations (e.g., MLH1, MSH2, MSH6 or PMS2) give rise to Lynch syndrome (LS), an autosomal dominant condition (hereditary nonpolyposis colorectal cancer, HNPCC) which strongly predisposes to early-onset colorectal cancer (CRC) and several extracolonic tumours, all typically presenting MSI.…”

“…Not surprisingly, heterozygous germline MMR mutations (e.g., MLH1, MSH2, MSH6 or PMS2) give rise to Lynch syndrome (LS), an autosomal dominant condition (hereditary nonpolyposis colorectal cancer, HNPCC) which strongly predisposes to early-onset colorectal cancer (CRC) and several extracolonic tumours, all typically presenting MSI. MMR mutations and epigenetic silencing (e.g., MLH1 promoter methylation) are also being increasingly implicated in a growing range of tumours (27,31,32).…”

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

“…Molecular diagnoses of LS would contribute to the early diagnosis of cancers in multiple organs, and are critical for the treatment of cancers in patients with LS. MSH2 and MLH1 are the major susceptible genes for LS; around 70% of the reported mutations for LS were found in these genes [35]. Most of the reported susceptible variants of LS are nonsense mutations, out-of-frame indels, or splicing error-causing variants.…”

“…Most of the reported susceptible variants of LS are nonsense mutations, out-of-frame indels, or splicing error-causing variants. One important feature of the mutations found in LS-susceptible variants is that most of them are unique for each family [35]. There are six RP variants in MSH2 in 2KJPN (Table 3).…”