title: Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.
abstract: BACKGROUND
  Mutations in genes for hereditary non-polyposis colorectal cancer (HNPCC) in ovarian cancer patients remains poorly defined. We sought to estimate the frequency and characteristics of HNPCC gene mutations in a population-based sample of women with epithelial ovarian cancer.
  
  
  METHODS
  The analysis included 1893 women with epithelial ovarian cancer ascertained from three population-based studies. Full-germline DNA sequencing of the coding regions was performed on three HNPCC genes, MLH1, MSH2 and MSH6. Collection of demographic, clinical and family history information was attempted in all women.
  
  
  RESULTS
  Nine clearly pathogenic mutations were identified, including five in MSH6, two each in MLH1 and MSH2. In addition, 28 unique predicted pathogenic missense variants were identified in 55 patients. Pathogenic mutation carriers had an earlier mean age at diagnosis of ovarian cancer, overrepresentation of cancers with non-serous histologies and a higher number of relatives with HNPCC-related cancers.
  
  
  CONCLUSIONS
  Our findings suggest that fewer than 1% of women with ovarian cancer harbour a germline mutation in the HNPCC genes, with overrepresentation of MSH6 mutations. This represents a lower-range estimate due to the large number of predicted pathogenic variants in which pathogenicity could not definitively be determined. Identification of mismatch repair gene mutations has the potential to impact screening and treatment decisions in these women.
authors.affiliation: Departments of Cancer Epidemiology, Biostatistics, Anatomic Pathology and Experimental Therapeutics, Moffitt Cancer Center, MRC-CANCONT, 12902 Magnolia Drive, Tampa, FL 33612, USA. tuya.pal@moffitt.org
authors.forename: T
authors.initials: T
authors.lastname: Pal
authors.forename: M R
authors.initials: MR
authors.lastname: Akbari
authors.forename: P
authors.initials: P
authors.lastname: Sun
authors.forename: J-H
authors.initials: JH
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Fulp
authors.forename: Z
authors.initials: Z
authors.lastname: Thompson
authors.forename: D
authors.initials: D
authors.lastname: Coppola
authors.forename: S
authors.initials: S
authors.lastname: Nicosia
authors.forename: T A
authors.initials: TA
authors.lastname: Sellers
authors.forename: J
authors.initials: J
authors.lastname: McLaughlin
authors.forename: H A
authors.initials: HA
authors.lastname: Risch
authors.forename: B
authors.initials: B
authors.lastname: Rosen
authors.forename: P
authors.initials: P
authors.lastname: Shaw
authors.forename: J
authors.initials: J
authors.lastname: Schildkraut
authors.forename: S A
authors.initials: SA
authors.lastname: Narod
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D015179:Colorectal Neoplasms / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein