Rare mutations in XRCC2 increase the risk of breast cancer

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Park DJ, Lesueur F, Nguyen-Dumont T, Pertesi M, Odefrey F, Hammet F, Neuhausen SL, John EM, Andrulis IL, Terry MB, Daly M, Buys S, Le Calvez-Kelm F, Lonie A, Pope BJ, Tsimiklis H, Voegele C, Hilbers FM, Hoogerbrugge N, Barroso A, Osorio A, Giles GG, Devilee P, Benitez J, Hopper JL, Tavtigian SV, Goldgar DE, Southey MC (2012) Rare mutations in XRCC2 increase the risk of breast cancer. Am J Hum Genet 90:734-739


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="">

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