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

Ani Manichaikul; Lauren C Peres; Xin-Qun Wang; Mollie E Barnard; Deanna Chyn; Xin Sheng; Zhaohui Du; Jonathan Tyrer; Joseph Dennis; Ann G Schwartz; Michele L Cote; Edward Peters; Patricia G Moorman; Melissa Bondy; Jill S Barnholtz-Sloan; Paul Terry; Anthony J Alberg; Elisa V Bandera; Ellen Funkhouser; Anna H Wu; Celeste Leigh Pearce; Malcom Pike; Veronica Wendy Setiawan; Christopher A Haiman; African American Breast Cancer Consortium (AABC); African Ancestry Prostate Cancer Consortium (AAPC); Julie R Palmer; Loic LeMarchand; Lynne R Wilkens; Andrew Berchuck; Jennifer A Doherty; Francesmary Modugno; Roberta Ness; Kirsten Moysich; Beth Y Karlan; Alice S Whittemore; Valerie McGuire; Weiva Sieh; Kate Lawrenson; Simon Gayther; Thomas A Sellers; Paul Pharoah; Joellen M Schildkraut; African American Cancer Epidemiology Study (AACES) and the Ovarian Cancer Association Consortium (OCAC)

doi:10.1002/ijc.32653

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.

Authors

Ani Manichaikul^{1

2}, Lauren C Peres^{2

3}, Xin-Qun Wang², Mollie E Barnard⁴, Deanna Chyn², Xin Sheng⁵, Zhaohui Du⁵, Jonathan Tyrer⁶, Joseph Dennis⁶, Ann G Schwartz⁷, Michele L Cote⁷, Edward Peters⁸, Patricia G Moorman⁹, Melissa Bondy¹⁰, Jill S Barnholtz-Sloan¹¹, Paul Terry¹², Anthony J Alberg¹³, Elisa V Bandera¹⁴, Ellen Funkhouser¹⁵, Anna H Wu⁵, Celeste Leigh Pearce^{16

17}, Malcom Pike^{17

18}, Veronica Wendy Setiawan⁵, Christopher A Haiman⁵; African American Breast Cancer Consortium (AABC); African Ancestry Prostate Cancer Consortium (AAPC); Julie R Palmer¹⁹, Loic LeMarchand²⁰, Lynne R Wilkens²⁰, Andrew Berchuck²¹, Jennifer A Doherty⁴, Francesmary Modugno^{22

23

24}, Roberta Ness²⁵, Kirsten Moysich²⁶, Beth Y Karlan²⁷, Alice S Whittemore^{28

29}, Valerie McGuire²⁹, Weiva Sieh^{30

31}, Kate Lawrenson³², Simon Gayther³³, Thomas A Sellers³, Paul Pharoah⁶, Joellen M Schildkraut²; African American Cancer Epidemiology Study (AACES) and the Ovarian Cancer Association Consortium (OCAC)

Affiliations

¹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
² Department of Public Health Sciences, University of Virginia, Charlottesville, VA.
³ Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
⁴ Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT.
⁵ Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA.
⁶ Strangeways Research Laboratory, University of Cambridge, Cambridge, United Kingdom.
⁷ Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI.
⁸ Epidemiology Program, Louisiana State University Health Sciences Center School of Public Health, New Orleans, LA.
⁹ Department of Community and Family Medicine, Duke University Medical Center, Durham, NC.
¹⁰ Cancer Prevention and Population Sciences Program, Baylor College of Medicine, Houston, TX.
¹¹ Department of Population and Quantitative Health Sciences and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH.
¹² Department of Medicine, University of Tennessee Medical Center - Knoxville, Knoxville, TN.
¹³ Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC.
¹⁴ Department of Population Science, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
¹⁵ Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL.
¹⁶ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI.
¹⁷ Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA.
¹⁸ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
¹⁹ Slone Epidemiology Center at Boston University, Boston, MA.
²⁰ University of Hawaii Cancer Center, Honolulu, HI.
²¹ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC.
²² Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA.
²³ Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA.
²⁴ Ovarian Cancer Center of Excellence, Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA.
²⁵ The University of Texas School of Public Health, Houston, TX.
²⁶ Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY.
²⁷ Department of Obstetrics and Gynecology, Ronald Regan UCLA Medical Center, Los Angeles, CA.
²⁸ Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA.
²⁹ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA.
³⁰ Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, NY, New York.
³¹ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY, New York.
³² Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA.
³³ Center for Bioinformatics and Functional Genomics and the Cedars-Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA.

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

Aldo-Keto Reductase Family 1 Member C3 / genetics
Antigens, Neoplasm / genetics
Black People / genetics*
Black or African American / 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
White People / genetics*

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding