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Hereditary non-polyposis colorectal cancer (HNPCC), or Lynch syndrome, is an autosomal dominant condition predisposing to tumours of the large bowel and other sites. In HNPCC, cancer predisposition is usually inherited as a highly penetrant trait, with a tendency to the development of multiple tumours. Clinical diagnosis of HNPCC is based on the so-called modified “Amsterdam criteria”,1 which include: (a) the presence of at least three family members—one of whom must be a first degree relative to two other members—affected with carcinoma of the colon, rectum, endometrium, small bowel, or urothelium; (b) a direct transmission of the disease from parent to child; (c) the occurrence of at least one tumour before the patient reaches 50 years of age; and (d) the exclusion of a diagnosis of familial adenomatous polyposis.
The genetic defects underlying most HNPCC cases are represented by constitutional point mutations of one of several genes encoding for proteins of the DNA mismatch repair complex. The vast majority of mutations are located in the major mismatch repair genes MSH2 and MLH1 (International Collaborative Group on HNPCC Mutation Database). The constitutional defects most commonly identified are nonsense, splice-site, or frameshift alterations, which all predict the synthesis of shorter, non-functional proteins. Tumours arising in carriers of mismatch repair gene mutations are characterised by a high frequency of insertion or deletion type somatic mutations within microsatellite repeats.2 These are the expression of mismatch repair deficiency, which arises when a second somatic mutation affecting the wild-type allele fully inactivates the gene locus already altered in the germline.3 Inactivation of a specific mismatch repair locus in a HNPCC tumour is often revealed by immunohistochemical methods, which show absence of nuclear staining following incubation with antibodies against the mismatch repair protein encoded by the mutant gene.4
In addition to genetic heterogeneity, HNPCC …
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