Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms

(Background & Aims) under bar: Germline mutations in one of four mismatch r epair genes have been found in the majority of families with hereditary non polyposis colorectal cancer (HNPCC), but only in a small part of families w ith atypical HNPCC. The recently cloned EXO1 gene might be involved in the pathogenesis of HNPCC because the EXO1 protein strongly interacts with the MSH2 protein. To determine its role in HNPCC, EXO1 was scanned for germline mutations, (Methods) under bar: All 14 exons of EXO1 were scanned for muta tions in index patients from 33 families with HNPCC fulfilling the Amsterda m criteria and in 225 index patients suspected of HNPCC. (Results) under ba r: Germline variants of EXO1 were detected in 14 patients, including one sp lice-site mutation in a family with HNPCC and 13 missense mutations in pati ents with atypical HNPCC, These variants did not occur in more than 200 con trol individuals. From 13 of these 14 patients, tumors were available for a nalysis of microsatellite instability and loss of heterozygosity, Six of th e tumors showed microsatellite instability. Heterozygosity analysis showed one case without EXO1 allelic loss and 12 tumors with loss of the mutant al lele and retention of the normal one. (Conclusions) under bar: The results indicate a possible association of germline EXO1 variants with HNPCC and at ypical HNPCC.