title: Splice site mutations in mismatch repair genes and risk of cancer in the general population.
abstract: We tested the hypothesis that splice site variations in MSH2 and MLH1 are associated with increased risk of hereditary non-polyposis colorectal cancer (HNPCC) and of cancer in general in the general population. In a cohort of 154 HNPCC patients with sequenced MSH2 and MLH1, we identified four possible splice-site mutations, which we subsequently genotyped in more than 9,000 individuals from the general population. Allele frequencies in the general population were 0 % for 942+3A>T in MSH2, 0.05 % for 307-19A>G, 0.005 % for 1,667+(2-8)del(taaatca);ins(attt), and 4.4 % for 1039-8T>A in MLH1. Odds ratios for HNPCC in a case-control design were 419 (95 % CI: 53-18,900) for 942+3A>T in MSH2, 19 (5-72) for 307-19A>G, 194 (21-1,768) for 1,667+(2-8)del(taaatca); ins(attt), and 0.3 (0.1-0.7) for 1,039-8T>A in MLH1. In the general population, incidence rate ratios for 1,039-8T>A carriers versus noncarriers were 0.70 (0.51-0.96) for HNPCC-related cancers combined and 0.82 (0.71-0.94) for all cancers combined in a prospective design. The three rare mutations were associated with increased risk of HNPCC. In contrast, the more common 1,039-8T>A associated with a decreased risk of HNPCC, of HNPCC-related cancers and of all cancers combined in the general population. These findings are novel and important in the counseling of HNPCC patients and their relatives.
authors: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, 2730, Herlev, Denmark.
authors: Mette
authors: M
authors: Thomsen
authors: Børge G
authors: BG
authors: Nordestgaard
authors: Anne
authors: A
authors: Tybjærg-Hansen
authors: Stig E
authors: SE
authors: Bojesen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000209:etiology* / Q000473:pathology; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D022821:RNA Splice Sites / Q000235:genetics*; D012307:Risk Factors; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D022821:RNA Splice Sites; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein