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.
Original language | English |
---|---|
Pages (from-to) | 2503-2513 |
Number of pages | 11 |
Journal | Cancer Medicine |
Volume | 8 |
Issue number | 5 |
DOIs | |
State | Published - May 2019 |
Keywords
- African ancestry risk
- genetic association
- ovarian cancer
- vitamin D pathway
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In: Cancer Medicine, Vol. 8, No. 5, 05.2019, p. 2503-2513.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women
AU - Grant, Delores J.
AU - Manichaikul, Ani
AU - Alberg, Anthony J.
AU - Bandera, Elisa V.
AU - Barnholtz-Sloan, Jill
AU - Bondy, Melissa
AU - Cote, Michele L.
AU - Funkhouser, Ellen
AU - Moorman, Patricia G.
AU - Peres, Lauren C.
AU - Peters, Edward S.
AU - Schwartz, Ann G.
AU - Terry, Paul D.
AU - Wang, Xin Qun
AU - Keku, Temitope O.
AU - Hoyo, Cathrine
AU - Berchuck, Andrew
AU - Sandler, Dale P.
AU - Taylor, Jack A.
AU - O’Brien, Katie M.
AU - Velez Edwards, Digna R.
AU - Edwards, Todd L.
AU - Beeghly-Fadiel, Alicia
AU - Wentzensen, Nicolas
AU - Pearce, Celeste Leigh
AU - Wu, Anna H.
AU - Whittemore, Alice S.
AU - McGuire, Valerie
AU - Sieh, Weiva
AU - Rothstein, Joseph H.
AU - Modugno, Francesmary
AU - Ness, Roberta
AU - Moysich, Kirsten
AU - Rossing, Mary Anne
AU - Doherty, Jennifer A.
AU - Sellers, Thomas A.
AU - Permuth-Way, Jennifer B.
AU - Monteiro, Alvaro N.
AU - Levine, Douglas A.
AU - Setiawan, Veronica Wendy
AU - Haiman, Christopher A.
AU - LeMarchand, Loic
AU - Wilkens, Lynne R.
AU - Karlan, Beth Y.
AU - Menon, Usha
AU - Ramus, Susan
AU - Gayther, Simon
AU - Gentry-Maharaj, Aleksandra
AU - Terry, Kathryn L.
AU - Cramer, Daniel W.
AU - Goode, Ellen L.
AU - Larson, Melissa C.
AU - Kaufmann, Scott H.
AU - Cannioto, Rikki
AU - Odunsi, Kunle
AU - Etter, John L.
AU - Huang, Ruea Yea
AU - Bernardini, Marcus Q.
AU - Tone, Alicia A.
AU - May, Taymaa
AU - Goodman, Marc T.
AU - Thompson, Pamela J.
AU - Carney, Michael E.
AU - Tworoger, Shelley S.
AU - Poole, Elizabeth M.
AU - Lambrechts, Diether
AU - Vergote, Ignace
AU - Vanderstichele, Adriaan
AU - Van Nieuwenhuysen, Els
AU - Anton-Culver, Hoda
AU - Ziogas, Argyrios
AU - Brenton, James D.
AU - Bjorge, Line
AU - Salvensen, Helga B.
AU - Kiemeney, Lambertus A.
AU - Massuger, Leon F.A.G.
AU - Pejovic, Tanja
AU - Bruegl, Amanda
AU - Moffitt, Melissa
AU - Cook, Linda
AU - Le, Nhu D.
AU - Brooks-Wilson, Angela
AU - Kelemen, Linda E.
AU - Pharoah, Paul D.P.
AU - Song, Honglin
AU - Campbell, Ian
AU - Eccles, Diana
AU - DeFazio, Anna
AU - Kennedy, Catherine J.
AU - Schildkraut, Joellen M.
N1 - Funding Information: This work was supported by the National Institues of Health (Genetic Associations and Mechanisms in Oncology (GAME‐ON) (U19‐CA148112); R01‐CA114343 and R01‐CA114343‐S1 for the genotyping, bioinformatics, and biostatistical analysis for MAY, NCO, TBO, and TOR; P30‐CA15083 for the Mayo Clinic Genotyping Shared Resource; R01‐CA142081 for AACES; R01‐CA112523 and R01‐CA87538 for DOV; R01‐CA58598, N01‐CN‐55424 and N01‐PC‐67001 for HAW; K07‐ CA080668, R01‐CA95023, P50‐CA159981 and MO1‐RR000056 for HOP; R01‐CA122443, P30‐CA15083, and P50‐CA136393 for MAY; CA54281, CA164973, and CA63464 for MEC; R01‐CA76016 for NCO; R01‐CA54419 and P50‐CA105009 for NEC; UM1‐CA186107, P01‐CA87969, R01‐CA49449, UM1‐CA176726, and R01‐CA67262 for NHS; R01CA160669‐01A1 for OVA; P50‐CA159981 and R01‐CA126841 for RPC; Z01‐ES044005 and Z01‐ES049033 for SIS and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences for SIS; U01‐CA71966 and U01‐CA69417 for STA; R01‐CA058860 for UCI; P01‐CA17054, P30‐CA14089, R01‐CA61132, N01‐PC67010, R03‐CA113148, R03‐CA115195, and N01‐CN025403 for USC; the Intramural Research Program of the National Cancer Institute for PLC); Nationaal Kankerplan (BEL), a Vanderbilt CTSA grant from the National Institutes of Health/National Center for Advancing Translational Sciences (ULTR000445 for BVU); the National Institutes of Health Research Cambridge Biomedical Research Centre and Cancer Research UK (for RMH; C490/A10119 and C490/A10124 for SEA; and Cambridge Cancer Centre for CAM); the Ovarian Cancer Research Fund (DKE); the Department of Defense (DAMD17‐02‐1‐0669 for HOP; DAMD17‐02‐1‐0666 for NCO; W81XWH‐10‐1‐02802 for NEC); the American Cancer Society Early Detection Professorship (SIOP‐06‐258‐01‐COUN) and the National Center for Advancing Translational Sciences (UL1TR000124) for LAX; the Mayo Foundation, the Minnesota Ovarian Cancer Alliance and the Katherine B. Andersen Foundation (for MAY); the Moffitt Cancer Center (P30‐CA076292), Merck Pharmaceuticals, the state of Florida, Hillsborough County and the city of Tampa (for MOF); Helse Vest, the Norwegian Cancer Society, and the Research Council of Norway (for NOR); Radboud University Medical Centre (for NTH); the OHSU Foundation (for ORE); the Canadian Institiues of Health (MOP‐86727 for OVA); Royal Marsden Hospital (for RMH); the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge (SEA); the Lon V Smith Foundation (LVS‐39420 for UCI); Princess Margaret Cancer Centre Foundation‐Bridge for the Cure (for UHN); The Eve Appeal (The Oak Foundation) and the National Institute for Health Research University College London Hospitals Biomedical Research Centre (for UKO); the California Cancer Research Program (00‐01389 V‐20170, 2II0200 for USC); the National Health and Medical Research Council of Australia (310670 and 628903 for WMH); Cancer Institute NSW (12/RIG/1‐17 and 15/RIG/1‐16 for WMH); Research Centers in Minority Institutes (RCMI), National Institute of Minority Health and Health Disparities; North Carolina Central University/University of North Carolina at Chapel Hill, U54 Cooperative Agreement Grant, National Cancer Institute (1U54MD012393‐02 DJG; 1U54CA156735‐01 for DJG, TOK, CH, JMS) Funding Information: De Roover for technical assistance. The CAM study was supported by Cancer Research UK, the University of Cambridge, and the National Institute for Health Research Cambridge Biomedical Research Centre. The MOF study would like to thank the Total Cancer Care™ Protocol and the Collaborative Data Services and Tissue Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute, an NCI designated Comprehensive Cancer Center, Merck Pharmaceuticals and the state of Florida (MOF). The NHS/ NHSII studies thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The SEA study thanks the SEARCH team, Craig Luccarini, Caroline Baynes, Don Conroy. The UKO study thanks I. Jacobs, M. Widschwendter, E. Wozniak, A. Ryan, J. Ford and N. Balogun for their contribution to the study. The WMH study thanks the Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network‐Oncology group. Publisher Copyright: © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
KW - African ancestry risk
KW - genetic association
KW - ovarian cancer
KW - vitamin D pathway
UR - http://www.scopus.com/inward/record.url?scp=85066414259&partnerID=8YFLogxK
U2 - 10.1002/cam4.1996
DO - 10.1002/cam4.1996
M3 - Article
C2 - 31001917
AN - SCOPUS:85066414259
SN - 2045-7634
VL - 8
SP - 2503
EP - 2513
JO - Cancer Medicine
JF - Cancer Medicine
IS - 5
ER -