American Journal of Human Genetics: Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

Antonis C Antoniou 1Amanda B SpurdleOlga M SinilnikovaSue HealeyKaren A PooleyRita K SchmutzlerBeatrix VersmoldChristoph EngelAlfons MeindlNorbert ArnoldWera HofmannChristian SutterDieter NiederacherHelmut DeisslerTrinidad CaldesKati KämpjärviHeli NevanlinnaJacques SimardJonathan BeesleyXiaoqing ChenKathleen Cuningham Consortium for Research into Familial Breast CancerSusan L NeuhausenTimothy R RebbeckTheresa WagnerHenry T LynchClaudine IsaacsJeffrey WeitzelPatricia A GanzMary B DalyGail TomlinsonOlufunmilayo I OlopadeJoanne L BlumFergus J CouchPaolo PeterlongoSiranoush ManoukianMonica BarilePaolo RadiceCsilla I SzaboLutecia H Mateus PereiraMark H GreeneGad RennertFlavio LejbkowiczOfra Barnett-GrinessIrene L AndrulisHilmi OzcelikOCGNAnne-Marie GerdesMaria A CaligoYael LaitmanBella KaufmanRoni MilgromEitan FriedmanSwedish BRCA1 and BRCA2 study collaboratorsSusan M DomchekKatherine L NathansonAna OsorioGemma LlortRoger L MilneJavier BenítezUte HamannFrans B L HogervorstPeggy MandersMarjolijn J L LigtenbergAns M W van den OuwelandDNA-HEBON collaboratorsSusan PeockMargaret CookRadka PlatteD Gareth EvansRosalind EelesGabriella PichertCarol ChuDiana EcclesRosemarie DavidsonFiona DouglasEMBRACEAndrew K GodwinLaure BarjhouxSylvie MazoyerHagay SobolViolaine BourdonFrançois EisingerAgnès ChompretCorinne CapouladeBrigitte Bressac-de PailleretsGilbert M LenoirMarion Gauthier-VillarsClaude HoudayerDominique Stoppa-LyonnetGEMOGeorgia Chenevix-TrenchDouglas F EastonCIMBA

Abstract

Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p(trend) = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

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