title: The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population.
abstract: The aim of this study was to estimate the contribution of deleterious mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6 and PMS2 to invasive epithelial ovarian cancer (EOC) in the population. The coding sequence and splice site boundaries of all six genes were amplified in germline DNA from 2240 invasive EOC cases and 1535 controls. Barcoded fragment libraries were sequenced using the Illumina GAII or HiSeq and sequence data for each subject de-multiplexed prior to interpretation. GATK and Annovar were used for variant detection and annotation. After quality control 2222 cases (99.2%) and 1528 controls (99.5%) were included in the final analysis. We identified 193 EOC cases (8.7%) carrying a deleterious mutation in at least one gene compared with 10 controls (0.65%). Mutations were most frequent in BRCA1 and BRCA2, with 84 EOC cases (3.8%) carrying a BRCA1 mutation and 94 EOC cases (4.2%) carrying a BRCA2 mutation. The combined BRCA1 and BRCA2 mutation prevalence was 11% in high-grade serous disease. Seventeen EOC cases carried a mutation in a mismatch repair gene, including 10 MSH6 mutation carriers (0.45%) and 4 MSH2 mutation carriers (0.18%). At least 1 in 10 women with high-grade serous EOC has a BRCA1 or BRCA2 mutation. The development of next generation sequencing technologies enables rapid mutation screening for multiple susceptibility genes at once, suggesting that routine clinical testing of all incidence cases should be considered.
authors.affiliation: CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK, hs310@medschl.cam.ac.uk.
authors.forename: Honglin
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Mine S
authors.initials: MS
authors.lastname: Cicek
authors.affiliation: CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
authors.forename: Ed
authors.initials: E
authors.lastname: Dicks
authors.affiliation: CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Harrington
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, CA, USA.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Ramus
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.affiliation: Department of Biostatistics, University of Kansas Medical Center, Kansas, USA and.
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.affiliation: CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Tyrer
authors.affiliation: CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Alsop
authors.affiliation: Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Jimenez-Linan
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, CA, USA.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Gayther
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.affiliation: CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein
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