title: Penetrance and expressivity of MSH6 germline mutations in seven kindreds not ascertained by family history.
abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by inherited mutations in DNA mismatch-repair genes, most commonly MLH1 or MSH2. The role MSH6 plays in inherited cancer susceptibility is less well defined. The aim of this study was to investigate the penetrance and expressivity of MSH6 mutations in kindreds ascertained through endometrial cancer probands unselected for family history. Detailed pedigrees were constructed for six MSH6 mutation carriers. All reported cancers and precancers were confirmed, and tissues were obtained when available. Tumors were analyzed for microsatellite instability (MSI) and for expression of MSH2, MLH1, and MSH6. MSH6 mutation status was determined for 59 family members. Of these 59 individuals, 19 (32%) had confirmed cancers and precancers. There was an excess of mutation carriers among the 19 affected family members (11 [58%] of 19) compared with those among the 40 unaffecteds (8 [20%] of 40, P=.0065, odds ratio = 5.5, 95% CI = 1.66-18.19). In four of the seven tumors analyzed from mutation carriers other than the probands, MSI and/or MMR protein expression was consistent with the involvement of MSH6. Overall estimated penetrance of the MHS6 mutations was 57.7%. Of the tumors in mutation carriers, 78% were part of the extended HNPCC spectrum. This study demonstrates that MSH6 germline mutations are, indeed, associated with increased cancer risk and that the penetrance of mutations may be higher than appreciated elsewhere. A combination of MSI and immunohistochemistry analyses may be helpful in screening for MSH6 mutation carriers.
authors.affiliation: Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Buttin
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Powell
authors.forename: David G
authors.initials: DG
authors.lastname: Mutch
authors.forename: Sheri A
authors.initials: SA
authors.lastname: Babb
authors.forename: Phyllis C
authors.initials: PC
authors.lastname: Huettner
authors.forename: Tina Bocker
authors.initials: TB
authors.lastname: Edmonston
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Herzog
authors.forename: Janet S
authors.initials: JS
authors.lastname: Rader
authors.forename: Randall K
authors.initials: RK
authors.lastname: Gibb
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Whelan
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Goodfellow
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D042822:Genomic Instability; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D010375:Pedigree; D019683:Penetrance; D011518:Proto-Oncogene Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein