Cancer Medicine (May 2019)
Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women
- Delores J. Grant,
- Ani Manichaikul,
- Anthony J. Alberg,
- Elisa V. Bandera,
- Jill Barnholtz‐Sloan,
- Melissa Bondy,
- Michele L. Cote,
- Ellen Funkhouser,
- Patricia G. Moorman,
- Lauren C. Peres,
- Edward S. Peters,
- Ann G. Schwartz,
- Paul D. Terry,
- Xin‐Qun Wang,
- Temitope O. Keku,
- Cathrine Hoyo,
- Andrew Berchuck,
- Dale P. Sandler,
- Jack A. Taylor,
- Katie M. O’Brien,
- Digna R. Velez Edwards,
- Todd L. Edwards,
- Alicia Beeghly‐Fadiel,
- Nicolas Wentzensen,
- Celeste Leigh Pearce,
- Anna H. Wu,
- Alice S. Whittemore,
- Valerie McGuire,
- Weiva Sieh,
- Joseph H. Rothstein,
- Francesmary Modugno,
- Roberta Ness,
- Kirsten Moysich,
- Mary Anne Rossing,
- Jennifer A. Doherty,
- Thomas A. Sellers,
- Jennifer B. Permuth‐Way,
- Alvaro N. Monteiro,
- Douglas A. Levine,
- Veronica Wendy Setiawan,
- Christopher A. Haiman,
- Loic LeMarchand,
- Lynne R. Wilkens,
- Beth Y. Karlan,
- Usha Menon,
- Susan Ramus,
- Simon Gayther,
- Aleksandra Gentry‐Maharaj,
- Kathryn L. Terry,
- Daniel W. Cramer,
- Ellen L. Goode,
- Melissa C. Larson,
- Scott H. Kaufmann,
- Rikki Cannioto,
- Kunle Odunsi,
- John L. Etter,
- Ruea‐Yea Huang,
- Marcus Q. Bernardini,
- Alicia A. Tone,
- Taymaa May,
- Marc T. Goodman,
- Pamela J. Thompson,
- Michael E. Carney,
- Shelley S. Tworoger,
- Elizabeth M. Poole,
- Diether Lambrechts,
- Ignace Vergote,
- Adriaan Vanderstichele,
- Els Van Nieuwenhuysen,
- Hoda Anton‐Culver,
- Argyrios Ziogas,
- James D. Brenton,
- Line Bjorge,
- Helga B. Salvensen,
- Lambertus A. Kiemeney,
- Leon F. A. G. Massuger,
- Tanja Pejovic,
- Amanda Bruegl,
- Melissa Moffitt,
- Linda Cook,
- Nhu D. Le,
- Angela Brooks‐Wilson,
- Linda E. Kelemen,
- Paul D.P. Pharoah,
- Honglin Song,
- Ian Campbell,
- Diana Eccles,
- Anna DeFazio,
- Catherine J. Kennedy,
- Joellen M. Schildkraut
Affiliations
- Delores J. Grant
- Department of Biological and Biomedical Sciences, Cancer Research Program JLC‐Biomedical/Biotechnology Research Institute, North Carolina Central University Durham North Carolina
- Ani Manichaikul
- Center for Public Health Genomics University of Virginia Charlottesville Virginia
- Anthony J. Alberg
- Department of Epidemiology and Biostatistics, Arnold School of Public Health University of South Carolina Columbia South Carolina
- Elisa V. Bandera
- Department of Population Science Rutgers Cancer Institute of New Jersey New Brunswick New Jersey
- Jill Barnholtz‐Sloan
- Case Comprehensive Cancer Center Case Western Reserve University School of Medicine Cleveland Ohio
- Melissa Bondy
- Cancer Prevention and Population Sciences Program Baylor College of Medicine Houston Texas
- Michele L. Cote
- Department of Oncology and the Karmanos Cancer Institute Population Studies and Disparities Research Program Wayne State University School of Medicine Detroit Michigan
- Ellen Funkhouser
- Division of Preventive Medicine University of Alabama at Birmingham Birmingham Alabama
- Patricia G. Moorman
- Department of Community and Family Medicine Duke University Medical Center Durham North Carolina
- Lauren C. Peres
- Center for Public Health Genomics University of Virginia Charlottesville Virginia
- Edward S. Peters
- Epidemiology Program Louisiana State University Health Sciences Center School of Public Health New Orleans Louisisana
- Ann G. Schwartz
- Department of Oncology and the Karmanos Cancer Institute Population Studies and Disparities Research Program Wayne State University School of Medicine Detroit Michigan
- Paul D. Terry
- Department of Medicine University of Tennessee Medical Center – Knoxville Knoxville Tennessee
- Xin‐Qun Wang
- Department of Public Health Sciences University of Virginia Charlottesville Virginia
- Temitope O. Keku
- Departments of Medicine and Nutrition, Division of Gastroenterology and Hepatology University of North Carolina at Chapel Hill Chapel Hill North Carolina
- Cathrine Hoyo
- Department of Biological Sciences North Carolina State University Raleigh North Carolina
- Andrew Berchuck
- Department of Obstetrics and Gynecology Duke University Medical Center Durham North Carolina
- Dale P. Sandler
- Epidemiology Branch, Division of Intramural Research National Institute of Environmental Health Sciences, National Institutes of Health Research Triangle Park North Carolina
- Jack A. Taylor
- Epidemiology Branch, Division of Intramural Research National Institute of Environmental Health Sciences, National Institutes of Health Research Triangle Park North Carolina
- Katie M. O’Brien
- Epidemiology Branch, Division of Intramural Research National Institute of Environmental Health Sciences, National Institutes of Health Research Triangle Park North Carolina
- Digna R. Velez Edwards
- Vanderbilt Epidemiology Center, Center for Human Genetics Research, Department of Obstetrics and Gynecology Vanderbilt University Medical Center Nashville Tennessee
- Todd L. Edwards
- Division of Epidemiology, Center for Human Genetics Research, Department of Medicine Vanderbilt University Medical Center Nashville Tennessee
- Alicia Beeghly‐Fadiel
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center Institute for Medicine and Public Health, Vanderbilt University Medical Center Nashville Tennessee
- Nicolas Wentzensen
- Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda Maryland
- Celeste Leigh Pearce
- Department of Epidemiology University of Michigan School of Public Health Ann Arbor Michigan
- Anna H. Wu
- Department of Preventive Medicine, Keck School of Medicine University of Southern California Norris Comprehensive Cancer Center Los Angeles California
- Alice S. Whittemore
- Department of Health Research and Policy Stanford University School of Medicine Stanford California
- Valerie McGuire
- Department of Health Research and Policy Stanford University School of Medicine Stanford California
- Weiva Sieh
- Department of Population Health Science and Policy Icahn School of Medicine at Mount Sinai New York New York
- Joseph H. Rothstein
- Department of Population Health Science and Policy Icahn School of Medicine at Mount Sinai New York New York
- Francesmary Modugno
- Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences University of Pittsburgh School of Medicine Pittsburgh Pennsylvania
- Roberta Ness
- The University of Texas School of Public Health Houston Texas
- Kirsten Moysich
- Department of Cancer Prevention and Control Roswell Park Cancer Institute Buffalo New York
- Mary Anne Rossing
- Program in Epidemiology, Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle Washington
- Jennifer A. Doherty
- Department of Population Health Sciences Huntsman Cancer Institute, University of Utah Salt Lake City, Utah
- Thomas A. Sellers
- Department of Cancer Epidemiology Moffitt Cancer Center Tampa Florida
- Jennifer B. Permuth‐Way
- Department of Cancer Epidemiology Moffitt Cancer Center Tampa Florida
- Alvaro N. Monteiro
- Department of Cancer Epidemiology Moffitt Cancer Center Tampa Florida
- Douglas A. Levine
- Gynecology Service, Department of Surgery Memorial Sloan Kettering Cancer Center New York New York
- Veronica Wendy Setiawan
- University of Southern California Norris Comprehensive Cancer Center Los Angeles California
- Christopher A. Haiman
- University of Southern California Norris Comprehensive Cancer Center Los Angeles California
- Loic LeMarchand
- University of Hawaii Cancer Center Honolulu Hawaii
- Lynne R. Wilkens
- Cancer Epidemiology Program University of Hawaii Cancer Center Hawaii
- Beth Y. Karlan
- Women's Cancer Program Samuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical Center Los Angeles California
- Usha Menon
- MRC CTU at UCL, Institute of Clinical Trials and Methodology University College London London UK
- Susan Ramus
- School of Women's and Children's Health University of New South Wales New South Wales Australia
- Simon Gayther
- Center for Cancer Prevention and Translational Genomics Samuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical Center Los Angeles California
- Aleksandra Gentry‐Maharaj
- MRC CTU at UCL, Institute of Clinical Trials and Methodology University College London London UK
- Kathryn L. Terry
- Obstetrics and Gynecology Epidemiology Center Brigham and Women's Hospital Boston Massachusetts
- Daniel W. Cramer
- Obstetrics and Gynecology Epidemiology Center Brigham and Women's Hospital Boston Massachusetts
- Ellen L. Goode
- Department of Health Science Research, Division of Epidemiology Mayo Clinic Rochester Minnesota
- Melissa C. Larson
- Department of Health Science Research, Division of Biomedical Statistics and Informatics Mayo Clinic Rochester Minnesota
- Scott H. Kaufmann
- Departments of Medicine and Pharmacology Mayo Clinic Rochester Minnesota
- Rikki Cannioto
- Cancer Pathology & Prevention, Division of Cancer Prevention and Population Sciences Roswell Park Cancer Institute Buffalo New York
- Kunle Odunsi
- Department of Gynecological Oncology Roswell Park Cancer Institute Buffalo New York
- John L. Etter
- Department of Cancer Prevention and Control Roswell Park Cancer Institute Buffalo New York
- Ruea‐Yea Huang
- Center For Immunotherapy Roswell Park Cancer Institute Buffalo New York
- Marcus Q. Bernardini
- Division of Gynecologic Oncology Princess Margaret Hospital, University Health Network Toronto Ontario Canada
- Alicia A. Tone
- Division of Gynecologic Oncology Princess Margaret Hospital, University Health Network Toronto Ontario Canada
- Taymaa May
- Division of Gynecologic Oncology Princess Margaret Hospital, University Health Network Toronto Ontario Canada
- Marc T. Goodman
- Cancer Prevention and Control Samuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical Center Los Angeles California
- Pamela J. Thompson
- Cancer Prevention and Control Samuel Oschin Comprehensive Cancer Institute, Cedars‐Sinai Medical Center Los Angeles California
- Michael E. Carney
- Department of Obstetrics and Gynecology John A. Burns School of Medicine, University of Hawaii Honolulu Hawaii
- Shelley S. Tworoger
- Channing Division of Network Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts
- Elizabeth M. Poole
- Biostatistics, Sanofi Genzyme Boston Massachusetts
- Diether Lambrechts
- Vesalius Research Center, VIB Leuven Belgium
- Ignace Vergote
- Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute University Hospitals Leuven Leuven Belgium
- Adriaan Vanderstichele
- Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute University Hospitals Leuven Leuven Belgium
- Els Van Nieuwenhuysen
- Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute University Hospitals Leuven Leuven Belgium
- Hoda Anton‐Culver
- Department of Epidemiology, Director of Genetic Epidemiology Research Institute, Center for Cancer Genetics Research & Prevention, School of Medicine University of California Irvine Irvine California
- Argyrios Ziogas
- Department of Epidemiology University of California Irvine Irvine California
- James D. Brenton
- Cancer Research UK Cambridge Institute University of Cambridge Cambridge UK
- Line Bjorge
- Department of Gynecology and Obstetrics Haukeland University Hospital Bergen Norway
- Helga B. Salvensen
- Department of Gynecology and Obstetrics Haukeland University Hospital Bergen Norway
- Lambertus A. Kiemeney
- Radboud University Medical Center Radboud Institute for Health Sciences Nijmegen Netherlands
- Leon F. A. G. Massuger
- Department of Gynaecology, Radboud University Medical Center Radboud Institute for Molecular Life sciences Nijmegen The Netherlands
- Tanja Pejovic
- Department of Obstetrics & Gynecology Oregon Health & Science University Portland Oregon
- Amanda Bruegl
- Department of Obstetrics & Gynecology Oregon Health & Science University Portland Oregon
- Melissa Moffitt
- Department of Obstetrics & Gynecology Oregon Health & Science University Portland Oregon
- Linda Cook
- Division of Epidemiology and Biostatistics, Department of Internal Medicine University of New Mexico Albuquerque New Mexico
- Nhu D. Le
- Cancer Control Research, British Columbia Cancer Agency Vancouver British Columbia Canada
- Angela Brooks‐Wilson
- Canada's Michael Smith Genome Sciences Centre British Columbia Cancer Agency Vancouver British Columbia Canada
- Linda E. Kelemen
- Hollings Cancer Center and Department of Public Health Sciences Medical University of South Carolina Charleston South Carolina
- Paul D.P. Pharoah
- Strangeways Research laboratory, Department of Oncology, Department of Public Health and Primary Care University of Cambridge Cambridge UK
- Honglin Song
- Strangeways Research Laboratory, Department of Oncology University of Cambridge Cambridge UK
- Ian Campbell
- Cancer Genetics Laboratory, Research Division Peter MacCallum Cancer Centre Victoria Australia
- Diana Eccles
- Faculty of Medicine University of Southampton Southampton UK
- Anna DeFazio
- Centre for Cancer Research The Westmead Institute for Medical Research, The University of Sydney Sydney New South Wales Australia
- Catherine J. Kennedy
- Centre for Cancer Research The Westmead Institute for Medical Research, The University of Sydney Sydney New South Wales Australia
- Joellen M. Schildkraut
- Department of Public Health Sciences University of Virginia Charlottesville Virginia
- DOI
- https://doi.org/10.1002/cam4.1996
- Journal volume & issue
-
Vol. 8,
no. 5
pp. 2503 – 2513
Abstract
Abstract An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom‐designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high‐grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 1.2 × 10−6, BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6‐3.4, P = 1.6 × 10−5, BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 2.3 × 10−5, BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.
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