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.
| Original language | English |
|---|---|
| Pages (from-to) | 2987-2998 |
| Number of pages | 12 |
| Journal | International Journal of Cancer |
| Volume | 146 |
| Issue number | 11 |
| DOIs | |
| State | Published - 1 Jun 2020 |
Keywords
- African ancestry
- eQTLs
- gene expression
- genome wide association study
- ovarian cancer
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In: International Journal of Cancer, Vol. 146, No. 11, 01.06.2020, p. 2987-2998.
Research output: Contribution to journal › Article › peer-review
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 - Funding Information: The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME‐ON Post‐GWAS Initiative (U19‐CA148112). Our study made use of data generated by the Wellcome Trust Case Control consortium that was funded by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The OCAC OncoArray genotyping project was funded through grants from the U.S. National Institutes of Health (CA1X01HG007491‐01 (C.I.A.), U19‐CA148112 (T.A.S.), R01‐CA149429 (C.M.P.) and R01‐CA058598 (M.T.G.); Canadian Institutes of Health Research (MOP‐86727 (L.E.K.) and the Ovarian Cancer Research Fund (A.B.). The COGS project was funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 ‐ HEALTH‐F2‐2009‐223175). M.E.B. was supported by the National Cancer Institute of the National Institutes of Health (Award Number K00 CA212222). L.C.P. was supported by the National Cancer Institute of the National Institutes of Health (Award Number K99/R00 CA218681). Funding for the eQTL analyses in tissue of high‐grade serous ovarian cancer in African Americans was supported by the National Institutes of Health grant R01‐CA200854 (J.M.S. and J.A.D). P.G.M. has received compensation for work related to litigation in regard to talc and ovarian cancer. Funding Information: Funding for individual studies: AAS: National Institutes of Health (R01‐CA142081); BEL: National Kankerplan; BVU: Vanderbilt University Medical Center's BioVU is supported by the 1S10RR025141‐01 instrumentation award and Vanderbilt CTSA grant from the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) (ULTR000445); CAM: National Institutes of Health Research Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Cancer Centre; DKE: Ovarian Cancer Research Fund; DOV: National Institutes of Health R01‐CA112523 and R01‐CA87538; HAW: U.S. National Institutes of Health (R01‐CA58598, N01‐CN‐55424 and N01‐PC‐67001); HOP: University of Pittsburgh School of Medicine Dean's Faculty Advancement Award (F.M.), Department of Defense (DAMD17‐02‐1‐0669) and NCI (K07‐CA080668, R01‐CA95023, P50‐CA159981 MO1‐RR000056 R01‐CA126841); LAX: American Cancer Society Early Detection Professorship (SIOP‐06‐258‐01‐COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124; MAY: National Institutes of Health (R01‐CA122443, P30‐CA15083, P50‐CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; MEC: NIH (CA54281, CA164973, CA63464); MOF: Moffitt Cancer Center, Merck Pharmaceuticals, the state of Florida, Hillsborough County, and the city of Tampa; NCO: National Institutes of Health (R01‐CA76016) and the Department of Defense (DAMD17‐02‐1‐0666); NEC: National Institutes of Health R01‐CA54419 and P50‐CA105009 and Department of Defense W81XWH‐10‐1‐02802; NHS: UM1 CA186107, P01 CA87969, R01 CA49449, R01‐CA67262, UM1 CA176726; NOR: Helse Vest, The Norwegian Cancer Society, The Research Council of Norway; NTH: Radboud University Medical Centre; ORE: OHSU Foundation; OVA: This work was supported by Canadian Institutes of Health Research grant (MOP‐86727) and by NIH/NCI 1 R01CA160669‐01A1; PLC: Intramural Research Program of the National Cancer Institute; RMH: Cancer Research UK, Royal Marsden Hospital; RPC: National Institute of Health (P50 CA159981, R01CA126841); SEA: Cancer Research UK (C490/A10119 C490/A10124); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; SIS: The Sister Study (SISTER) is supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01‐ES044005 and Z01‐ES049033); STA: NIH grants U01 CA71966 and U01 CA69417; UCI: NIH R01‐CA058860 and the Lon V Smith Foundation grant LVS‐39420; UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre; USC: P01CA17054, P30CA14089, R01CA61132, N01PC67010, R03CA113148, R03CA115195, N01CN025403 and California Cancer Research Program (00‐01389V‐20170, 2II0200); WMH: National Health and Medical Research Council of Australia, Enabling Grants ID 310670 and ID 628903. Cancer Institute NSW Grants 12/RIG/1‐17 and 15/RIG/1‐16. Funding Information: We are grateful to the family and friends of Kathryn Sladek Smith for their generous support of the Ovarian Cancer Association Consortium through their donations to the Ovarian Cancer Research Fund. The OncoArray and COGS genotyping projects would not have been possible without the contributions of the following: Per Hall (COGS); Douglas F. Easton, Paul Pharoah, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang (BCAC), Andrew Berchuck, Marjorie J. Riggan (OCAC), Rosalind A. Eeles, Douglas F. Easton, Ali Amin Al Olama, Zsofia Kote‐Jarai, Sara Benlloch (PRACTICAL), Georgia Chenevix‐Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch and Ken Offit (CIMBA), Joe Dennis, Jonathan P. Tyrer, Siddhartha Kar, Alison M. Dunning, Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez‐Neira and the staff of the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière and Frederic Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. We pay special tribute to the contribution of Professor Brian Henderson to the GAME‐ON consortium; to Olga M. Sinilnikova for her contribution to CIMBA and for her part in the initiation and coordination of GEMO until she sadly passed away on the 30th June 2014 and to Catherine M. Phelan for her contribution to OCAC and coordination of the OncoArray until she passed away on 22 September 2017. Funding Information: National Cancer Institute; Grant numbers: R01-CA142081, R01-CA200854, U19-CA148112; Grant sponsor: European Commission?s Seventh Framework Programme; Grant sponsor: Canadian Institutes of Health Research; Grant sponsor: U.S. National Institutes of Health; Grant sponsor: Wellcome Trust; Grant sponsor: US National Cancer Institute GAME-ON Post-GWAS Initiative; Grant sponsor: Ovarian Cancer Research Fund. 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 - http://www.scopus.com/inward/record.url?scp=85074598427&partnerID=8YFLogxK
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 -