title: Rare mutations in XRCC2 increase the risk of breast cancer.
abstract: An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p < 0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases.
authors.affiliation: Genetic Epidemiology Laboratory, The University of Melbourne, Victoria, Australia.
authors.forename: D J
authors.initials: DJ
authors.lastname: Park
authors.forename: F
authors.initials: F
authors.lastname: Lesueur
authors.forename: T
authors.initials: T
authors.lastname: Nguyen-Dumont
authors.forename: M
authors.initials: M
authors.lastname: Pertesi
authors.forename: F
authors.initials: F
authors.lastname: Odefrey
authors.forename: F
authors.initials: F
authors.lastname: Hammet
authors.forename: S L
authors.initials: SL
authors.lastname: Neuhausen
authors.forename: E M
authors.initials: EM
authors.lastname: John
authors.forename: I L
authors.initials: IL
authors.lastname: Andrulis
authors.forename: M B
authors.initials: MB
authors.lastname: Terry
authors.forename: M
authors.initials: M
authors.lastname: Daly
authors.forename: S
authors.initials: S
authors.lastname: Buys
authors.forename: F
authors.initials: F
authors.lastname: Le Calvez-Kelm
authors.forename: A
authors.initials: A
authors.lastname: Lonie
authors.forename: B J
authors.initials: BJ
authors.lastname: Pope
authors.forename: H
authors.initials: H
authors.lastname: Tsimiklis
authors.forename: C
authors.initials: C
authors.lastname: Voegele
authors.forename: F M
authors.initials: FM
authors.lastname: Hilbers
authors.forename: N
authors.initials: N
authors.lastname: Hoogerbrugge
authors.forename: A
authors.initials: A
authors.lastname: Barroso
authors.forename: A
authors.initials: A
authors.lastname: Osorio
authors.forename: G G
authors.initials: GG
authors.lastname: Giles
authors.forename: P
authors.initials: P
authors.lastname: Devilee
authors.forename: J
authors.initials: J
authors.lastname: Benitez
authors.forename: J L
authors.initials: JL
authors.lastname: Hopper
authors.forename: S V
authors.initials: SV
authors.lastname: Tavtigian
authors.forename: D E
authors.initials: DE
authors.lastname: Goldgar
authors.forename: M C
authors.initials: MC
authors.lastname: Southey
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D012306:Risk
chemical_list: D004268:DNA-Binding Proteins; C113187:XRCC2 protein, human