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

Int J Cancer. 2020 Jun 1;146(11):2987-2998. doi: 10.1002/ijc.32653. Epub 2019 Oct 8.

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.

Keywords: African ancestry; eQTLs; gene expression; genome wide association study; ovarian cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • African Americans / genetics*
  • Aldo-Keto Reductase Family 1 Member C3 / genetics
  • Antigens, Neoplasm / genetics
  • Blacks / genetics*
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / genetics*
  • Carcinoma, Ovarian Epithelial / epidemiology
  • Carcinoma, Ovarian Epithelial / genetics*
  • Female
  • Follistatin / genetics
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study
  • Humans
  • Neoplasm Proteins / genetics
  • Polymorphism, Single Nucleotide / genetics
  • United States / epidemiology
  • Whites / genetics*

Substances

  • Antigens, Neoplasm
  • FST protein, human
  • Follistatin
  • MAGEC1 protein, human
  • Neoplasm Proteins
  • AKR1C3 protein, human
  • Aldo-Keto Reductase Family 1 Member C3

Grant support