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A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population

Abstract

Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (Ptrend = 2.3 × 10−9 to Ptrend = 3.9 × 10−7), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17–1.35; rs2363956 HR = 0.84, 95% CI 0.80–0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor–negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75–0.92, Ptrend = 0.0003) and an association with estrogen receptor–positive disease in the opposite direction (OR = 1.07, 95% CI 1.01–1.14, Ptrend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 × 10−7 to Ptrend = 8 × 10−5; rs2363956 per-allele OR = 0.80, 95% CI 0.74–0.87, Ptrend = 1.1 × 10−7).

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Figure 1: Forest plots of the associations by country of residence of BRCA1 mutation carriers in the combined stage 1 and stage 2 samples.
Figure 2: Above, results of the kinship-adjusted score test statistic (1 d.f.) by position (kb) in stage 1 and 2 samples combined for genotyped and imputed SNPs in the associated region (chromosome 19, positions 17,100–17,400 kb).

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Acknowledgements

Financial support for this study was provided by the Breast Cancer Research Foundation (BCRF), Susan G. Komen for the Cure and US National Institutes of Health grant CA128978 to F.J.C. and by Cancer Research UK to D.F.E. and A.C.A. A.C.A. is a Cancer Research UK Senior Cancer Research Fellow and D.F.E. is a Cancer Research UK Principal Research Fellow. The authors thank Cancer Genetic Markers of Susceptability (CGEMS) and Wellcome Trust Case Control Consortium (WTCCC) for provision of genotype data from controls. Study specific acknowledgments listed in Supplementary Note.

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F.J.C., A.C.A. and D.F.E. designed the study and obtained financial support. G.C.-T. founded CIMBA in order to provide the infrastructure for the BRCA1 GWAS. F.J.C. and X.W. coordinated collection of samples. A.C.A. directed the statistical analysis. D.F.E. advised on the statistical analysis. C.K., Z.S.F. and T.L. carried out analyses. Z.S.F., R.T., J.M., L.M. and D.B. provided bioinformatics and database support. F.J.C., H. Hakonarson and X.W. directed the genotyping of the BRCA1 carrier and triple-negative samples. M.G. directed the genotyping of the UK case-control samples. A.C.A., F.J.C. and D.F.E. drafted the manuscript. F.J.C. was the overall project leader.

O.M.S. and S.H. coordinated the BRCA1 mutation classification. T.K., J.V., M.M.G., D.A. and C.G. were involved in the BRCA2 GWAS genotyping and coordination. K.O. led the BRCA2 GWAS.

S.P., M.C., C.O., D.F., D.E., D.G.E., R.E., L.I., C.C., F.D., J.P., O.M.S., D.S.-L., C.H., S.M., S.G., C.L., A.R., O.C., A.H., P.B., F.B.L.H., M.A.R., A.J., A.v.d.O., N.H., R.B.v.d.L., H.M.-H., E.B.G.G., P.D., M.P.G.V., J.L., A.J., J.G., T.H., T.B., B.G., C.C., A.B.S., H.H., D.E., E.M.J., J.L.H., M.S., S.S.B., M.B.D., M.-B.T., R.K.S., B.W., C.E., A.M., S.P.-A., N.A., D.N., C.S., S.M.D., K.L.N., T.R., J.L.B., M.P., G.C.R., K.W., J.F.B., J.B., S.V.B., E.F., B.K., Y.L., R.M., I.L.A., G.G., H.O., N.L., K.H., J.R., H.E., A.-M.G., M.T., L.S., P.P., S.M., B.B., A.V., P.R., T.C., M.d.l.H., C.F.S., A.F.-R., M.H.G., P.L.M., J.T.L., L.G., N.M.L., T.V.O.H., F.C.N., I.B., C.L., J.G., S.J.R., S.A.G., C.P., S.N., C.I.S., J.B., A.O., H.N., T.H., M.A.C., M.S.B., U.H., A.K.G., M.M., C.C., S.L.N., B.Y.K., N.T., A.E.T., J.W., O.O., J.S., P.S., W.S.R., A.A. and G.R. collected data and samples on BRCA1 and or BRCA2 mutation carriers.

N.G.M., G.W.M., J.C.-C., D.F.-J., H.B., G.S., L.B., A.C., S.S.C., P.M., S.M.G., W.T., D.Y., G.F., P.A.F., M.W.B., I.d.S.S., J.P., D.L., R.P., T.R., A.F., R.W., K.P., R.B.D., A.M.L., J.E.-P., C.V., F.B., K.D., A.D. and P.P.D.P. collected data and samples for the TNBCC case-control and/or the SEARCH studies.

All authors provided critical review of the manuscript.

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Correspondence to Fergus J Couch.

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The authors declare no competing financial interests.

Additional information

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

Supplementary information

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Supplementary Figures 1 and 2, Supplementary Tables 1–5 and Supplementary Note (PDF 875 kb)

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Antoniou, A., Wang, X., Fredericksen, Z. et al. A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population. Nat Genet 42, 885–892 (2010). https://doi.org/10.1038/ng.669

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