Abstract LB-425: Replication of 18 susceptibility loci of breast cancer in women of African ancestry

Abstract

Abstract Background: Numerous novel susceptibility loci for breast cancer have been identified in genome-wide association studies (GWAS). However, all GWAS of breast cancer have been conducted in populations of European and Asian ancestry and array chips optimized for populations of European ancestry have been used. Thus the question remains whether these genetic associations can be generalized more broadly to other racial/ethnic populations. We addressed this question and examined whether common genetic variants identified from prior GWAS are associated with breast cancer risk in women of African ancestry. Methods: We evaluated 24 single nucleotide polymorphisms (SNPs) at 1p11, 2q35, 3p24, 5p12, 5q11, 6q22, 6q25, 8q24, 9p21, 10q21, 10q22, 10q26, 11p15, 11q13, 14q24, 16q12, 17q23, and 19p13, in a pooled case-control study of breast cancer, which included 1,543 cases and 1,416 controls. Cases and controls were enrolled in Nigeria, Barbados, and the United States; all were women of African ancestry by self-report. We also selected 30 ancestral informative markers to estimate and control for population admixture in African Americans and African Barbadians. Logistic regression models were used to estimate odds ratio and 95% confidence intervals (CI) for each SNP, after adjusting for study sites and proportion of European admixture. Results: The mean age (SD) was 47.9 years old (12.1) in cases and 47.0 years old (13.2) in controls; the majority of cases (58.8%) and controls (58.2%) were younger than age 50. The proportion of European admixture was 0.143 in Barbadians and 0.218 in African Americans. Cases and controls had similar proportions of European admixture. Significant associations were observed between two index SNPs (rs10995190 at 10q21 and rs3817198 at 11p15) and breast cancer risk, but the associations were in the opposite direction of the previous studies. The minor allele frequencies for both SNPs were different slightly between this and previous studies but no switch between minor and major alleles. For the remaining 16 loci, no significant associations were observed for the index SNPs from GWAS. We also evaluated two SNPs identified from previous fine-mapping studies in women of African ancestry. We found both SNPs were significantly associated with breast cancer risk in the present study. The allelic odds ratio was 1.24 (95% CI: 1.04-1.47; p=0.018) for the rs2981578-G allele (10q26/FGFR2) and 1.34 (95% CI: 1.10-1.63; p=0.0035) for the rs9397435-G allele (6q25). Conclusion: This study highlights the complexity of applying current GWAS findings across racial/ethnic groups, as none of GWAS-identified index SNPs could be replicated in women of African ancestry. Our successful replication of SNPs from fine-mapping studies suggests that fine-mapping studies and new GWAS in understudied minority population may be promising to reveal additional and causal variants for breast cancer susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-425. doi:10.1158/1538-7445.AM2011-LB-425