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

Abstract

Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome‐wide association study in African ancestry women with 755 EOC cases, including 537 high‐grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p < 1 × 10−6), including rs4525119 (intronic to AKR1C3), rs7643459 (intronic to LOC101927394), rs4286604 (12 kb 3′ of UGT2A2) and rs142091544 (5 kb 5′ of WWC1). For HGSOC, we identified six loci with suggestive evidence of association including rs37792 (132 kb 5′ of follistatin [FST]), rs57403204 (81 kb 3′ of MAGEC1), rs79079890 (LOC105376360 intronic), rs66459581 (5 kb 5′ of PRPSAP1), rs116046250 (GABRG3 intronic) and rs192876988 (32 kb 3′ of GK2). Among the identified variants, two are near genes known to regulate hormones and diseases of the ovary (AKR1C3 and FST), and two are linked to cancer (AKR1C3 and MAGEC1). In follow‐up studies of the 10 identified variants, the GK2 region SNP, rs192876988, showed an inverse association with EOC in European ancestry women (p = 0.002), increased risk of ER positive breast cancer in African ancestry women (p = 0.027) and decreased expression of GK2 in HGSOC tissue from African ancestry women (p = 0.004). A European ancestry‐derived polygenic risk score showed positive associations with EOC and HGSOC in women of African ancestry suggesting shared genetic architecture. Our investigation presents evidence of variants for EOC shared among European and African ancestry women and identifies novel EOC risk loci in women of African ancestry.

Polygenic Risk Modelling for Prediction of Epithelial Ovarian Cancer Risk

“…We observed greater attenuation of discriminative ability in East Asian populations than African populations. This finding is in contrast to what one would expect given human demographic history, and results from genome wide association studies for EOC (18,19,33,34). One possible explanation for this disparity is the small sample size and imprecise effect estimates for women of African ancestry in this study, due to the larger differences in allele frequency between this population and that of the cohort used to develop the model.…”

“…One possible explanation for this disparity is the small sample size and imprecise effect estimates for women of African ancestry in this study, due to the larger differences in allele frequency between this population and that of the cohort used to develop the model. Although the model development data for this analysis was predominantly women of European ancestry, the models developed using our approach performed substantially better in women of African ancestry than a PRS model developed by combining 24 published GWAS SNPS associated with non-mucinous EOC, for which the odds of EOC risk was 1.20 fold per standard deviation of PRS (19).…”

“…We investigated transferability of the best-fitting PRS models to populations of non-European ancestry using genotype data from females of East Asian and African ancestries that had been genotyped as part of the OCAC OncoArray Project (18,19). Women of East Asian ancestry - 2,841 non-mucinous invasive EOC (1,960 high-grade serous, 136 low-grade serous, 400 endometrioid, 271 clear cell, 74 other histotypes) and 4,828 controls - were identified using a criterion of >80% Asian ancestry.…”

“…Details of these data have been previously described (18). Similarly, women of African ancestry - 368 cases of non-mucinous invasive EOC (261 high-grade serous, 35 low-grade serous, 47 endometrioid, 7 clear cell, 53 other histoptypes) and 704 controls, mainly from studies conducted in the US, were identified using a criterion of >80% African ancestry.as described previously (19).…”

Race and Ethnicity Influence Survival Outcomes in Women of Caribbean Nativity With Epithelial Ovarian Cancer

“…Recent analyses of The Cancer Genome Atlas (TCGA) determined that tumors from African Americans, across a number of cancer types, demonstrated enriched chromosomal instability compared to tumors from people of European descent (5). In populations of West African descent, distinct genetic loci, not observed in women of European ancestry, have been associated with epithelial ovarian cancer risk (6). These findings suggest that nativity and ancestry are also contributing to disease etiology and outcomes, independent of social determinants.…”