Abstract 4613: Cross-ancestry genome-wide association study identifies six new loci for breast cancer in women of African and european ancestry
Authors: Adedokun Babatunde , Du Zhaohui , Gao Guimin , Ahearn Thomas , Lunetta Kathryn L. , Zirpoli Gary , Figueroa Jonine , John Esther M. , Bernstein Leslie , Zheng Wei , Hu Jennifer J. , Ziegler Regina G. , Nyante Sarah , Bandera Elisa V. , Ingles Sue A. , Press Michael F. , Deming Sandra L. , Rodriguez-Gil Jorge L. , Yao Song , Ogundiran Temidayo O. , Ojengbede Oladosu , Blot William , Troester Melissa , Nathanson Katherine L. , Hennis Anselm , Nemesure Barbara , Ambs Stefan , Sucheston-Campbell Lara E. , Bensen Jeannette T. , Chanock Stephen J. , Olshan Andrew F. , Ambrosone Christine B. , Conti David V. , Olopade Olufunmilayo I. , Garcia-Closas Montserrat , Palmer Julie R. , Haiman Christopher A. , Huo Dezheng 
Published: September 2020

Background: Over 180 genetic variants have been identified as risk loci for breast cancer. However, most loci were discovered using European ancestry populations. As some common susceptibility loci are shared across populations, we aim to discover new risk loci for breast cancer using a cross-ancestry genome-wide association study (GWAS) approach.

Methods: Data from five GWAS studies in women of African ancestry with a combined sample size of 9241 cases and 10192 controls were used to generate pooled breast cancer risk estimates in a fixed effect meta-analysis, and this served as the discovery dataset. Summary statistics from the GWAS conducted in European ancestry populations (Breast Cancer Association Consortium, 122977 cases and 105974 controls) served as the validation dataset. The variants that were associated with breast cancer risk at P &lt; 0.01 in the GWAS of African ancestry were meta-analyzed with the GWAS in European ancestry. A locus was considered novel if the lead index variant was genome-wide significant (5 × 10−8) in the cross-ancestry meta-analysis and &gt;500kb away from known breast cancer risk loci. Conditional on the lead index variants, we searched for additional signals in each locus using multivariable logistic regression. Analyses were done separately for ER-positive, ER-negative and overall breast cancer risk.

Results: We discovered four novel loci for overall breast cancer risk (1p13.3, 5q31.1, 15q24, and 15q26.3) and two novel loci for ER-negative breast cancer (1q41 and 7q11.23) at the genome-wide significance level of P &lt; 5 × 10−8. Three index single nucleotide polymorphism (SNPs) lie within introns of genes (KCNK2, C5orf56, and SIN3A) and the other index SNPs are located in intergenic regions (close to GSTM4 and AMPD2, CASTOR2, and the antisense DNA RP11-168G16.2). The direction of the associations was consistent between the GWASs of African and European descendants. At the 15q24 locus, we found an additional SNP (in the intron of the SCAMP2 gene) to be independently associated with overall breast cancer risk.

Conclusions: We have identified six new risk loci that may contribute to better prediction of breast cancer risk in African ancestry populations and provide new insights into mechanisms of breast cancer carcinogenesis. Replication of these loci in multiple populations and functional studies can help to identify causal variants.

Citation Format: Babatunde Adedokun, Zhaohui Du, Guimin Gao, Thomas Ahearn, Kathryn L. Lunetta, Gary Zirpoli, Jonine Figueroa, Esther M. John, Leslie Bernstein, Wei Zheng, Jennifer J. Hu, Regina G. Ziegler, Sarah Nyante, Elisa V. Bandera, Sue A. Ingles, Michael F. Press, Sandra L. Deming, Jorge L. Rodriguez-Gil, Song Yao, Temidayo O. Ogundiran, Oladosu Ojengbede, William Blot, Melissa Troester, Katherine L. Nathanson, Anselm Hennis, Barbara Nemesure, Stefan Ambs, Lara E. Sucheston-Campbell, Jeannette T. Bensen, Stephen J. Chanock, Andrew F. Olshan, Christine B. Ambrosone, David V. Conti, Olufunmilayo I. Olopade, Montserrat Garcia-Closas, Julie R. Palmer, Christopher A. Haiman, Dezheng Huo. Cross-ancestry genome-wide association study identifies six new loci for breast cancer in women of African and european ancestry [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4613.