Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

Introduction: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. less thanbrgreater than less thanbrgreater thanMethods: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. less thanbrgreater than less thanbrgreater thanResults: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 x 10(-6)). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. less thanbrgreater than less thanbrgreater thanConclusions: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of
Funding Agencies|Breast Cancer Research Foundation||MacDonald Family Foundation||Komen Foundation||NIH, NCI|P50 CA 058207|Avon Foundation||UCSF Helen Diller Family Comprehensive Cancer Center UK||CRUK||Russian Federation for Basic Research|10-04-9260110-04-9211011-04-00227|Federal Agency for Science and Innovations|02.740.11.0780|Commission of the European Communities|PITN-GA-2009-238132|Royal Society|JP090615|US National Cancer Institute||Westat, Inc., Rockville, MD||Starr Cancer Consortium||Norman and Carol Stone Genetic Research Fund||Robert and Kate Niehaus Clinical Genetics Initiative at MSKCC||NIH|CA116167CA128978|Research Excellence (SPORE) in Breast Cancer|CA116201|Ministero della Salute|RFPS 2006-5-341353ACC2/R6.9|Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab)||Icelandic Association||Landspitali University Hospital||NEYE Foundation||Deutsches Krebsforschungszentrum (DKFZ)||Associazione Italiana per la Ricerca sul Cancro|4017|Italian citizens||Fondazione Italiana per la Ricerca sul Cancro||Cancer Research UK|C12292/A11174C1287/A10118C1287/A11990C5047/A8385|NIHR||Eileen Stein Jacoby Fund||University of Kansas Cancer Center||Kansas Bioscience Authority Eminent Scholar Program||Familial Cancer Registry (CI)||Tissue Culture Shared Registry at Georgetown University (NIH/NCI)|P30-CA051008|Cancer Genetics Network|HHSN261200744000C|Swing Fore the Cure||German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) GC-HBOC||German Cancer Aid|109076|Centre of Molecular Medicine Cologne (CMMC)||Ligue National Contre le Cancer||Association for International Cancer|AICR-07-0454|Association "Le cancer du sein, parlons-en!" Award||European Community|223175 (HEALTH-F2-2009-223175)|National Cancer Institute, National Institutes of Health|RFA-CA-06-503|Liepajas municipal council|||NO2-CP-11019-50||N02-CP-65504||U01CA69631||5U01CA113916