TY - JOUR
T1 - Identification of novel epithelial ovarian cancer loci in women of African ancestry
AU - the African American Breast Cancer Consortium (AABC)
AU - the African Ancestry Prostate Cancer Consortium (AAPC)
AU - the African American Cancer Epidemiology Study (AACES) and the Ovarian Cancer Association Consortium (OCAC)
AU - Manichaikul, Ani
AU - Peres, Lauren C.
AU - Wang, Xin Qun
AU - Barnard, Mollie E.
AU - Chyn, Deanna
AU - Sheng, Xin
AU - Du, Zhaohui
AU - Tyrer, Jonathan
AU - Dennis, Joseph
AU - Schwartz, Ann G.
AU - Cote, Michele L.
AU - Peters, Edward
AU - Moorman, Patricia G.
AU - Bondy, Melissa
AU - Barnholtz-Sloan, Jill S.
AU - Terry, Paul
AU - Alberg, Anthony J.
AU - Bandera, Elisa V.
AU - Funkhouser, Ellen
AU - Wu, Anna H.
AU - Pearce, Celeste Leigh
AU - Pike, Malcom
AU - Setiawan, Veronica Wendy
AU - Haiman, Christopher A.
AU - Palmer, Julie R.
AU - LeMarchand, Loic
AU - Wilkens, Lynne R.
AU - Berchuck, Andrew
AU - Doherty, Jennifer A.
AU - Modugno, Francesmary
AU - Ness, Roberta
AU - Moysich, Kirsten
AU - Karlan, Beth Y.
AU - Whittemore, Alice S.
AU - McGuire, Valerie
AU - Sieh, Weiva
AU - Lawrenson, Kate
AU - Gayther, Simon
AU - Sellers, Thomas A.
AU - Pharoah, Paul
AU - Schildkraut, Joellen M.
N1 - Publisher Copyright:
© 2019 UICC
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
KW - African ancestry
KW - eQTLs
KW - gene expression
KW - genome wide association study
KW - ovarian cancer
UR - https://www.scopus.com/pages/publications/85074598427
U2 - 10.1002/ijc.32653
DO - 10.1002/ijc.32653
M3 - Article
C2 - 31469419
AN - SCOPUS:85074598427
SN - 0020-7136
VL - 146
SP - 2987
EP - 2998
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 11
ER -