Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry

Abstract

Background Genome-wide association studies have identified ~100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Due to different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry. Methods We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER and ROOT). Results Fifty-four of the 74 variants (73%) were found to have odds ratios that were directionally consistent with those previously reported, of which twelve were nominally statistically significant (P < 0.05). Through fine-mapping, in six regions (3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13) we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (11q13, 16q12/TOX3) we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality. Conclusions Through fine-mapping of known susceptibility regions we have revealed alleles that better characterize breast cancer risk in women of African ancestry. Impact The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry.

Identification of novel epithelial ovarian cancer loci in women of African ancestry

“…Therefore, we examined the association of the 10 SNPs identified in the present African ancestry GWAS of EOC or HGSOC at p < 1 × 10 −6 (Table ) with previously completed studies of breast cancer (overall, ER positive and ER negative) and prostate cancer in populations of African descent. Genetic associations in breast cancer were determined from 3,007 cases, of which 987 are ER negative and 1,518 are ER positive, and 2,720 African ancestry controls from the African American Breast Cancer Consortium (AABC), using the Illumina Human 1M‐Duo BeadChip . The genotype associations for prostate cancer were from 4,853 cases and 4,678 controls in the African American Prostate Cancer Consortium (AAPC), using the Illumina Infinium 1M‐Duo .…”

“…Genetic associations in breast cancer were determined from 3,007 cases, of which 987 are ER negative and 1,518 are ER positive, and 2,720 African ancestry controls from the African American Breast Cancer Consortium (AABC), using the Illumina Human 1M-Duo BeadChip. 15 The genotype associations for prostate cancer were from 4,853 cases and 4,678 controls in the African American Prostate Cancer Consortium (AAPC), using the Illumina Infinium 1M-Duo. 16 For the selected SNPs, evidence of association from the studies of breast and prostate cancer is reported at a nominal level (p < 0.05) without adjustment for multiple comparisons.…”

Validation of a genetic risk score for Arkansas women of color

“…Several studies have shown that combining risk estimates based on SNP genotypes with risk estimates from conventional breast cancer risk prediction tools, such as the BCRAT, can improve individual risk estimates for certain ethnic populations [ 13 – 16 ]. Larger studies have also made efforts to identify SNPs specifically associated with breast cancer risk in African American populations through consortium including the AMBER, ROOT, and AABC [ 17 , 18 ]. This approach clearly has important implications under current National Comprehensive Cancer Network guidelines for breast cancer screening and risk reduction.…”

Genetic variation in the Hippo pathway and breast cancer risk in women of African ancestry

“…Overall, the correlations between the significant SNPs in our study and those in the GAME‐ON/DRIVE were very low ( r 2 < 0.1). Actually, it is common to identify different disease‐associated index SNPs between European‐ and African‐descent populations, and this phenomenon has been frequently reported in diseases including prostate cancer and breast cancer . This inconsistency of association may be due to the different genetic backgrounds, such as LD patterns between African and European ancestries.…”

“…Actually, it is common to identify different disease-associated index SNPs between European-and African-descent populations, and this phenomenon has been frequently reported in diseases including prostate cancer [37][38][39][40] and breast cancer. 7,14,15,41 This inconsistency of association may be due to the different genetic backgrounds, such as LD patterns between African and European ancestries. In addition, although we undertook our GWAS using dense genotyping array with ∼2.5 million markers and imputation using the 1000 Genomes Project data, it is worth noting that rare variants (especially very rare ones) were not particularly targeted in array development or reliably imputed, and therefore not included in the analyses.…”