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Eight novel MSH6 germline mutations in patients with familial and nonfamilial colorectal cancer selected by loss of protein expression in tumor tissue
Author(s) -
Plaschke Jens,
Krüger Stefan,
Dietmaier Wolfgang,
Gebert Johannes,
Sutter Christian,
Mangold Elisabeth,
Pagenstecher Constanze,
HolinskiFeder Elke,
Schulmann Karsten,
Möslein Gabriela,
Rüschoff Josef,
Engel Christoph,
Evans Gareth,
Schackert Hans K.
Publication year - 2004
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.9217
Subject(s) - msh6 , msh2 , mlh1 , germline mutation , biology , penetrance , microsatellite instability , germline , genetics , cancer research , dna mismatch repair , point mutation , mutation , colorectal cancer , cancer , gene , phenotype , allele , microsatellite
Germline mutations in mismatch repair (MMR) genes, predominantly in MLH1 and MSH2 , are responsible for hereditary nonpolyposis colorectal cancer (HNPCC), a cancer‐susceptibility syndrome with high penetrance. In addition, MSH6 mutations have been reported to account for about 10% of all germline mismatch repair (MMR) gene mutations in HNPCC patients, and have been associated with a later age of onset of the disease compared to MLH1 and MSH2 mutations. Here, we report eight novel germline mutations in MSH6 . The patients were selected by having developed tumors with loss of MSH6 protein expression. All tumors showed high‐level microsatellite instability (MSI‐H). Seven mutations resulted in premature stop codons, comprised of two nonsense mutations (c.426G>A [p.W142X], c.2105C>A [p.S702X]), two insertions (c.2611_2614dupATTA [p.I872fsX10], c.3324dupT [p.I1109fsX3]) and three deletions (c.1190_1191delAT [p.Y397fsX3], c.1632_1635delAAAA [p.E544fsX26], c.3513_3514delTA [p.1171fsX5]). In addition, an amino acid substitution of an arginine residue (c.2314C>T [p.R772W]) conserved throughout a wide variety of mutS homologs has been found in a patient not fulfilling the Bethesda criteria for HNPCC. Our results emphasize the suitability of IHC as a pre‐selection tool for MSH6 mutation analysis and the high frequency of germline mutation detection in patients with MSH6 ‐deficient tumors. In addition, our findings point towards a broad variability regarding penetrance associated with MSH6 germline mutations. © 2004 Wiley‐Liss, Inc.