Fine-mapping of Breast Cancer Genome-wide Association Studies Loci in Women of African Ancestry Identifies Novel Susceptibility Markers
Menée sur 1 502 cas de cancer du sein et 1 378 témoins en population d'origine africaine, cette étude évalue l'association entre 22 polymorphismes à simple nucléotide, précédemment identifiés dans des études en population d'origine européenne ou asiatique, et le risque de cancer du sein, puis identifie de nouveaux loci de susceptibilité
Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified by genome-wide association studies (GWAS). However, these SNPs were primarily discovered and validated in women of European and Asian ancestry. Because linkage disequilibrium (LD) is ancestry-dependent and heterogeneous among racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378 controls of African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer risk variants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry were identified in regions including 5p12 (odds ratio [OR] = 1.40, 95% confidence interval [CI]: 1.11-1.76; P = 0.004), 5q11.2 (OR = 1.22, 95% CI: 1.09-1.36; P = 0.00053), and 10p15.1 (OR = 1.22, 95% CI: 1.08-1.38; P = 0.0015). We also found positive association signals in three regions (6q25.1, 10q26.13, and 16q12.1-q12.2) previously confirmed by fine-mapping in women of African ancestry. In addition, polygenic model indicated that 8 best markers in this study, compared to 22 GWAS-identified SNPs, could better predict breast cancer risk in Black women (per allele OR = 1.21, 95% CI: 1.16-1.27; P = 9.7×10-16). Our results demonstrate that fine-mapping is a powerful approach to better characterizing breast cancer risk alleles in diverse populations. Future studies in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility with clinical implications throughout the African Diaspora.
http://carcin.oxfordjournals.org/content/early/2013/03/07/carcin.bgt090.abstract 2013