Sistema Gastrointestinal e Digestivo

Abstrato

An Update on the Pathogenesis of Lynch Syndrome: Recently Described Novel Molecular Mechanisms

Aaron R. Huber, D.O., Christa L. Whitney-Miller, Jennifer and J. Findeis-Hosey

Lynch syndrome, originally described in 1913 and previously known as hereditary nonpolyposis colorectal carcinoma syndrome, is the most common hereditary cancer syndrome. This syndrome is classically due to germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2. The cancer risk for patients with Lynch syndrome is not limited to the colorectum; women with Lynch syndrome are at risk for endometrial cancer, and Lynch patients of both genders are at risk for other cancers as well. There are cases of cancers in families that meet the clinical criteria (Amsterdam and Bethesda criteria) for Lynch syndrome but do not have a mutation in the one of the four classic mismatch repair genes. For some time, there has been speculation that other mutations or mechanisms were responsible for a subset of Lynch syndrome patients; much research has gone into identifying those alternative mutations and mechanisms. Recently, EPCAM deletion, CHEK2 mutations, and germline MLH1 hypermethylation have been identified as alternative mutations that cause Lynch syndrome in mismatch repair-negative patients. This article reviews these novel mechanisms and mutations, their clinical significance, and the pathogenesis of these Lynch causing mutations.