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 The database was recently reorganized to efficiently gather published and unpublished data and to classify the variants according to a five-tiered scheme linked to clinical recommendations.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.
Highlights
Four main DNA mismatch repair (MMR) genes have been identified, MLH1, MSH2, MSH6, and PMS2, which when mutated cause susceptibility to Lynch syndrome (LS)
Alternative hMutL heterodimers are hMutLc, composed of MLH1 and MLH3, which may predominantly contribute to insertion/deletion loops (IDL) repair, and hMutLb (MLH1 and PMS1), which does not seem to participate in MMR
No LS-associated germline mutations have been detected in MSH4 or MSH5
Summary
MLH1, MSH2, MSH6 and PMS2 account for 40, 34, 18, and 8 %, respectively, of the 3000 unique germline sequence variants of MMR genes deposited to the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) database ([16] and www.insight-group.org, date accessed December 19th, 2015). The different substrate specificities described above may explain why MLH1 and MSH2 are the most important predisposing genes for LS (their protein products are obligatory components in all types of heterodimers, Fig. 1), followed by MSH6 and PMS2, whereas MLH3 mutations are rare (functionally redundant with PMS2), and no LS-predisposing germline mutations are known for MSH3 (functionally redundant with MSH6). No LS-associated germline mutations have been detected in MSH4 or MSH5 (their primary role is in meiotic recombination rather than MMR)
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