title: Germ-line msh6 mutations in colorectal cancer families.
abstract: Hereditary nonpolyposis colorectal carcinoma (HNPCC) is due primarily to inherited mutations in two mismatch repair genes, MSH2 and MLH1, whereas germ-line mutations in other mismatch repair genes are rare. We examined the frequency of germ-line msh6 mutations in a population-based series of 140 colorectal cancer patients, including 45 sporadic cases, 91 familial non-HNPCC cases, and 4 HNPCC cases. Among the 91 population-based familial non-HNPCC cases, germ-line msh6 mutations were found in 6 patients (7.1% of probands analyzed; median age at diagnosis, 61 years). These mutations included a splice site mutation, a frameshift mutation, two missense mutations that were demonstrated to be loss of function mutations, and two missense mutations for which functional studies were not possible. In contrast, germ-line msh6 mutations were not found in any of the 45 sporadic cases and the 4 HNPCC cases in the population-based series or in the second series of 58 clinic-based, primarily HNPCC families. Our data suggest that germ-line msh6 mutations predispose individuals to primarily late-onset, familial colorectal carcinomas that do not fulfill classic criteria for HNPCC.
authors.affiliation: Ludwig Institute for Cancer Research, Department of Medicine and Cancer Center, University of California San Diego Medical School, La Jolla 92093-0660, USA. rkolodner@ucsd.edu
authors.forename: R D
authors.initials: RD
authors.lastname: Kolodner
authors.forename: J D
authors.initials: JD
authors.lastname: Tytell
authors.forename: J L
authors.initials: JL
authors.lastname: Schmeits
authors.forename: M F
authors.initials: MF
authors.lastname: Kane
authors.forename: R D
authors.initials: RD
authors.lastname: Gupta
authors.forename: J
authors.initials: J
authors.lastname: Weger
authors.forename: S
authors.initials: S
authors.lastname: Wahlberg
authors.forename: E A
authors.initials: EA
authors.lastname: Fox
authors.forename: D
authors.initials: D
authors.lastname: Peel
authors.forename: A
authors.initials: A
authors.lastname: Ziogas
authors.forename: J E
authors.initials: JE
authors.lastname: Garber
authors.forename: S
authors.initials: S
authors.lastname: Syngal
authors.forename: H
authors.initials: H
authors.lastname: Anton-Culver
authors.forename: F P
authors.initials: FP
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D004268:DNA-Binding Proteins; D005656:Fungal Proteins / Q000235:genetics*; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C501486:MLH1 protein, human; C098790:MSH6 protein, S cerevisiae; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; D000070957:MutL Protein Homolog 1