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Cancer Med. 2019 May;8(5):2503-2513. doi: 10.1002/cam4.1996. Epub 2019 Apr 18.

Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women.

Author information

1
Department of Biological and Biomedical Sciences, Cancer Research Program, JLC-Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina.
2
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
3
Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, South Carolina.
4
Department of Population Science, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
5
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
6
Cancer Prevention and Population Sciences Program, Baylor College of Medicine, Houston, Texas.
7
Department of Oncology and the Karmanos Cancer Institute Population Studies and Disparities Research Program, Wayne State University School of Medicine, Detroit, Michigan.
8
Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
9
Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina.
10
Epidemiology Program, Louisiana State University Health Sciences Center School of Public Health, New Orleans, Louisisana.
11
Department of Medicine, University of Tennessee Medical Center - Knoxville, Knoxville, Tennessee.
12
Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.
13
Departments of Medicine and Nutrition, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
14
Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina.
15
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina.
16
Epidemiology Branch, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
17
Vanderbilt Epidemiology Center, Center for Human Genetics Research, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee.
18
Division of Epidemiology, Center for Human Genetics Research, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
19
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, Tennessee.
20
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
21
Department of Epidemiology, University of Michigan School of, Public Health, Ann Arbor, Michigan.
22
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
23
Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California.
24
Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, California.
25
Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York.
26
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
27
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
28
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania.
29
Ovarian Cancer Center of Excellence, Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
30
The University of Texas School of Public Health, Houston, Texas.
31
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York.
32
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
33
Department of Epidemiology, University of Washington, Seattle, Washington.
34
Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
35
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.
36
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
37
Gynecologic Oncology, Laura and Isaac Pearlmutter Cancer Center, New York University Langone Medical Center, New York, New York.
38
University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California.
39
University of Hawaii Cancer Center, Honolulu, Hawaii.
40
Cancer Epidemiology Program, University of Hawaii Cancer Center, Hawaii.
41
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
42
MRC CTU at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK.
43
School of Women's and Children's Health, University of New South Wales, New South Wales, Australia.
44
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
45
Center for Cancer Prevention and Translational Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
46
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
47
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, Massachusetts.
48
Harvard T. H. Chan School of Public Health, Boston, Massauchusetts.
49
Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota.
50
Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.
51
Departments of Medicine and Pharmacology, Mayo Clinic, Rochester, Minnesota.
52
Cancer Pathology & Prevention, Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, New York.
53
Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, New York.
54
Center For Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York.
55
Division of Gynecologic Oncology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.
56
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
57
Department of Biomedical Sciences, Community and Population Health Research Institute, Cedars-Sinai Medical Center, Los Angeles, California.
58
Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii.
59
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
60
Biostatistics, Sanofi Genzyme, Boston, Massachusetts.
61
Vesalius Research Center, VIB, Leuven, Belgium.
62
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Belgium.
63
Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
64
Department of Epidemiology, Director of Genetic Epidemiology Research Institute, Center for Cancer Genetics Research & Prevention, School of Medicine, University of California Irvine, Irvine, California.
65
Department of Epidemiology, University of California Irvine, Irvine, California.
66
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
67
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
68
Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.
69
Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, Netherlands.
70
Department of Gynaecology, Radboud University Medical Center, Radboud Institute for Molecular Life sciences, Nijmegen, The Netherlands.
71
Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, Oregon.
72
Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
73
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico.
74
Cancer Control Research, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
75
Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
76
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.
77
Hollings Cancer Center and Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina.
78
Strangeways Research laboratory, Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
79
Strangeways Research Laboratory, Department of Oncology, University of Cambridge, Cambridge, UK.
80
Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Victoria, Australia.
81
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
82
Faculty of Medicine, University of Southampton, Southampton, UK.
83
Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia.
84
Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.

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.

KEYWORDS:

African ancestry risk; genetic association; ovarian cancer; vitamin D pathway

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