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. 2010 Jul 15;19(14):2886-97.
doi: 10.1093/hmg/ddq174. Epub 2010 Apr 23.

Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers

Xianshu Wang  1 , V Shane Pankratz, Zachary Fredericksen, Robert Tarrell, Mary Karaus, Lesley McGuffog, Paul D P Pharaoh, Bruce A J Ponder, Alison M Dunning, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost; EMBRACE; Olga M Sinilnikova, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Claude Houdayer; GEMO; Frans B L Hogervorst, Maartje J Hooning, Marjolijn J Ligtenberg; HEBON; Amanda Spurdle, Georgia Chenevix-Trench; kConFab; Rita K Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Susan M Domchek, Katherine L Nathanson, Timothy R Rebbeck, Christian F Singer, Daphne Gschwantler-Kaulich, Catherina Dressler, Anneliese Fink, Csilla I Szabo, Michal Zikan, Lenka Foretova, Kathleen Claes, Gilles Thomas, Robert N Hoover, David J Hunter, Stephen J Chanock, Douglas F Easton, Antonis C Antoniou, Fergus J Couch
Collaborators, Affiliations

Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers

Xianshu Wang et al. Hum Mol Genet. .

Abstract

Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 x 10(-3)) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (P(trend) < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69-0.90, P(trend) = 3.6 x 10(-4) and HR = 1.25, 95% CI: 1.10-1.41, P(trend) = 4.2 x 10(-4)), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25-1.92, P(trend) = 6 x 10(-5) and HR = 1.37, 95% CI: 1.16-1.62, P(trend) = 1.7 x 10(-4)). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.

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Figures

Figure 1.
Figure 1.
Study-specific per allele hazards ratio estimates for selected SNPs in BRCA1 and BRCA2 mutation carriers. (A) HR estimates for rs6138178 from the SNRPB locus and rs6602595 from the CAMK1D locus. (B) HR estimates for rs12652447 from the FBXL7 locus and rs9393597 from the LOC134997 locus. The area of each square is proportional to the sample size of each study. Horizontal lines represent the 95% CI for each study.
Figure 2.
Figure 2.
Age-related modifying effects of breast cancer risk by selected SNPs in BRCA1 and BRCA2 mutation carriers. Cumulative risk modifying effects of rs6138178 and rs6602595 combined (A), rs6138178 (B) and rs6602595 (C) genotypes in BRCA1 mutation carriers. Cumulative risk modifying effects of rs9393597 and rs12652447 combined (D), rs9393597 (E) and rs12652447 (F) genotypes in BRCA2 mutation carriers. All possible genotypes of the loci and their frequencies in BRCA1 or BRCA2 mutation carriers are shown. ‘Average’ represents the cumulative breast cancer risk over all possible modifying effects among BRCA1 or BRCA2 mutation carriers.
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