Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers.
Christopher HakkaartJohn F PearsonLouise MarquartJoe G DennisGeorge A R WigginsDaniel R BarnesBridget A RobinsonPeter D MaceKristiina AittomäkiIrene L AndrulisBanu K ArunJacopo AzzolliniJudith BalmañaRosa B BarkardottirSami BelhadjLieke BergerMarinus J BlokSusanne E BoonenJulika BordeAngela R BradburyJoan BrunetSaundra S BuysMaria A CaligoIan G CampbellWendy K ChungKathleen B M Claesnull nullnull nullMarie-Agnès Collonge-RameJackie CookCasey CosgroveFergus J CouchMary B DalySita DandikerRosemarie DavidsonMiguel de la HoyaRobin de PutterCapucine DelnatteMallika DhawanOrland DiezYuan Chun DingSusan M DomchekAlan DonaldsonJacqueline EasonDouglas F EastonHans EhrencronaChristoph EngelD Gareth EvansUlrike FaustLidia FeliubadalóFlorentia FostiraEitan FriedmanMegan FroneDebra FrostJudy GarberSimon A GaytherAndrea GehrigPaul GestaAndrew K GodwinDavid E GoldgarMark H GreeneEric HahnenChristopher R HakeUte HamannThomas V O HansenJan HaukeJulia HentschelNatalie HeroldEllen HonischPeter J HulickEvgeny N Imyanitovnull nullnull nullnull nullClaudine IsaacsLouise IzattAngel IzquierdoAnna JakubowskaPaul A JamesRamunas JanaviciusEsther M JohnJoseph VijaiBeth Y KarlanZoe KempJudy KirkIrene KonstantopoulouMarco KoudijsAva KwongYael LaitmanFiona LallooChristine LassetCharlotte LautrupConxi Lazaro GarciaClémentine LegrandGoska LeslieFabienne LesueurPhuong L MaiSiranoush ManoukianVéronique MariJohn W M MartensLesley McGuffogNoura MebiroukAlfons MeindlAustin MillerMarco MontagnaLidia MoserleEmmanuelle Mouret-FourmeHannah MusgraveSophie NambotKatherine L NathansonSusan L NeuhausenHeli NevanlinnaJoanne Ngeow Yuen YieTu Nguyen-DumontLiene Nikitina-ZakeKenneth OffitEdith OlahOlufunmilayo I OlopadeAna OsorioClaus-Eric OttSue-Kyung ParkMichael T ParsonsInge Sokilde PedersenAna PeixotoPedro Perez-SeguraPaolo PeterlongoTimea PoczaPaolo RadiceJuliane RamserJohanna RantalaGustavo C RodriguezKarina RønlundEfraim H RosenbergMaria RossingRita K SchmutzlerPayal D ShahSaba SharifPriyanka SharmaLucy E SideJacques SimardChristian F SingerKatie SnapeDoris SteinemannDominique Stoppa-LyonnetChristian SutterYen Yen TanManuel R TeixeiraSoo-Hwang TeoMads ThomassenDarcy L ThullMarc TischkowitzAmanda Ewart TolandAlison H TrainerVishakha TripathiNadine TungKlaartje van EngelenElizabeth J vanRensburgAna VegaAlessandra VielLisa WalkerJeffrey N WeitzelMarijke R WeversGeorgia Chenevix-TrenchAmanda B SpurdleAntonis C AntoniouLogan C WalkerPublished in: Communications biology (2022)
The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.