Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
Department of Public Health Sciences, University of Virginia, Charlottesville, VA.
Int J Cancer. 2020 Jun 1;146(11):2987-2998. doi: 10.1002/ijc.32653. Epub 2019 Oct 8.
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 ), 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.
非裔女性的上皮性卵巢癌 (EOC) 发病率较低，但与欧洲裔女性相比，生存预后更差。我们在非洲裔女性中进行了一项全基因组关联研究，其中包括 755 例 EOC 病例，包括 537 例高级别浆液性卵巢癌 (HGSOC) 和 1235 例对照。我们发现了四个与 EOC 有提示性关联的新位点（p<1×10-8），包括 rs4525119（AKR1C3 内含子）、rs7643459（LOC101927394 内含子）、rs4286604（UGT2A2 下游 12kb）和 rs142091544（WWC1 上游 5kb）。对于 HGSOC，我们发现了六个具有提示性关联的位点，包括 rs37792（卵泡抑素 [FST] 上游 132kb）、rs57403204（MAGEC1 下游 81kb）、rs79079890（LOC105376360 内含子）、rs66459581（PRPSAP1 上游 5kb）、rs116046250（GABRG3 内含子）和 rs192876988（GK2 下游 32kb）。在所鉴定的变体中，有两个位于已知调节卵巢激素和疾病的基因附近（AKR1C3 和 FST），还有两个与癌症有关（AKR1C3 和 MAGEC1）。在对 10 个鉴定变体的后续研究中，GK2 区域 SNP rs192876988 与欧洲裔女性的 EOC 呈负相关（p=0.002），与非洲裔女性的 ER 阳性乳腺癌风险增加相关（p=0.027），并降低了非洲裔女性 HGSOC 组织中 GK2 的表达（p=0.004）。一个源于欧洲裔的多基因风险评分与非洲裔女性的 EOC 和 HGSOC 呈正相关，表明存在共同的遗传结构。我们的研究提供了证据表明，欧洲裔和非洲裔女性之间存在上皮性卵巢癌的共同变体，并确定了非洲裔女性上皮性卵巢癌的新风险位点。
