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Lynch syndrome (LS) typically arises in the setting of a heterozygous germline mutation in one of the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2). Rarely, LS can also arise due to germline deletion of the 3′ region of the epithelial cell adhesion molecule (EPCAM) gene, an event that results in silencing of the in cis downstream MSH2 gene in epithelial cells.1 ,2 As with other causes of LS, EPCAM mutations have been associated with increased risk of colorectal and endometrial carcinomas.3
Biallelic MMR mutations (ie, the presence of two defective germline copies of the same MMR gene) result in a different cancer syndrome. Malignancy may occur as early as the first decade, and the most common neoplasms are lymphomas, leukaemias and tumours of the central nervous system (CNS).4 Gastrointestinal carcinomas are also common, and usually arise in the colorectum, with a minority occurring in the small bowel.4 ,5 In one review of patients with gastrointestinal carcinoma with biallelic MMR mutations, the mean age of first cancer diagnosis was 16.4 years (range: 5–28 years), with 55% (16 of 29) of cases presenting in the paediatric setting.4 Patients may also have skin lesions typically associated with neurofibromatosis type 1, such as café-au-lait macules and neurofibromas. …
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