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

doi:10.1002/cam4.1996

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’BrienDigna 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

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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	https://doi.org/10.1002/cam4.1996
State	Published - May 2019

Keywords

African ancestry risk
genetic association
ovarian cancer
vitamin D pathway

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10.1002/cam4.1996

Cite this

Grant, D. J., Manichaikul, A., Alberg, A. J., Bandera, E. V., Barnholtz-Sloan, J., Bondy, M., Cote, M. L., Funkhouser, E., Moorman, P. G., Peres, L. C., Peters, E. S., Schwartz, A. G., Terry, P. D., Wang, X. Q., Keku, T. O., Hoyo, C., Berchuck, A., Sandler, D. P., Taylor, J. A., ... Schildkraut, J. M. (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. Cancer Medicine, 8(5), 2503-2513. https://doi.org/10.1002/cam4.1996

@article{a62d1b9565a14fce9421fd089a80560e,

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

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",

author = "Grant, {Delores J.} and Ani Manichaikul and Alberg, {Anthony J.} and Bandera, {Elisa V.} and Jill Barnholtz-Sloan and Melissa Bondy and Cote, {Michele L.} and Ellen Funkhouser and Moorman, {Patricia G.} and Peres, {Lauren C.} and Peters, {Edward S.} and Schwartz, {Ann G.} and Terry, {Paul D.} and Wang, {Xin Qun} and Keku, {Temitope O.} and Cathrine Hoyo and Andrew Berchuck and Sandler, {Dale P.} and Taylor, {Jack A.} and O{\textquoteright}Brien, {Katie M.} and {Velez Edwards}, {Digna R.} and Edwards, {Todd L.} and Alicia Beeghly-Fadiel and Nicolas Wentzensen and Pearce, {Celeste Leigh} and Wu, {Anna H.} and Whittemore, {Alice S.} and Valerie McGuire and Weiva Sieh and Rothstein, {Joseph H.} and Francesmary Modugno and Roberta Ness and Kirsten Moysich and Rossing, {Mary Anne} and Doherty, {Jennifer A.} and Sellers, {Thomas A.} and Permuth-Way, {Jennifer B.} and Monteiro, {Alvaro N.} and Levine, {Douglas A.} and Setiawan, {Veronica Wendy} and Haiman, {Christopher A.} and Loic LeMarchand and Wilkens, {Lynne R.} and Karlan, {Beth Y.} and Usha Menon and Susan Ramus and Simon Gayther and Aleksandra Gentry-Maharaj and Terry, {Kathryn L.} and Cramer, {Daniel W.} and Goode, {Ellen L.} and Larson, {Melissa C.} and Kaufmann, {Scott H.} and Rikki Cannioto and Kunle Odunsi and Etter, {John L.} and Huang, {Ruea Yea} and Bernardini, {Marcus Q.} and Tone, {Alicia A.} and Taymaa May and Goodman, {Marc T.} and Thompson, {Pamela J.} and Carney, {Michael E.} and Tworoger, {Shelley S.} and Poole, {Elizabeth M.} and Diether Lambrechts and Ignace Vergote and Adriaan Vanderstichele and {Van Nieuwenhuysen}, Els and Hoda Anton-Culver and Argyrios Ziogas and Brenton, {James D.} and Line Bjorge and Salvensen, {Helga B.} and Kiemeney, {Lambertus A.} and Massuger, {Leon F.A.G.} and Tanja Pejovic and Amanda Bruegl and Melissa Moffitt and Linda Cook and Le, {Nhu D.} and Angela Brooks-Wilson and Kelemen, {Linda E.} and Pharoah, {Paul D.P.} and Honglin Song and Ian Campbell and Diana Eccles and Anna DeFazio and Kennedy, {Catherine J.} and Schildkraut, {Joellen M.}",

note = "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{\texttrademark} 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: {\textcopyright} 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.",

year = "2019",

month = may,

doi = "10.1002/cam4.1996",

language = "English",

volume = "8",

pages = "2503--2513",

journal = "Cancer Medicine",

issn = "2045-7634",

publisher = "John Wiley and Sons Ltd",

number = "5",

}

Grant, DJ, Manichaikul, A, Alberg, AJ, Bandera, EV, Barnholtz-Sloan, J, Bondy, M, Cote, ML, Funkhouser, E, Moorman, PG, Peres, LC, Peters, ES, Schwartz, AG, Terry, PD, Wang, XQ, Keku, TO, Hoyo, C, Berchuck, A, Sandler, DP, Taylor, JA, O’Brien, KM, Velez Edwards, DR, Edwards, TL, Beeghly-Fadiel, A, Wentzensen, N, Pearce, CL, Wu, AH, Whittemore, AS, McGuire, V, Sieh, W , Rothstein, JH, Modugno, F, Ness, R, Moysich, K, Rossing, MA, Doherty, JA, Sellers, TA, Permuth-Way, JB, Monteiro, AN, Levine, DA, Setiawan, VW, Haiman, CA, LeMarchand, L, Wilkens, LR, Karlan, BY, Menon, U, Ramus, S, Gayther, S, Gentry-Maharaj, A, Terry, KL, Cramer, DW, Goode, EL, Larson, MC, Kaufmann, SH, Cannioto, R, Odunsi, K, Etter, JL, Huang, RY, Bernardini, MQ, Tone, AA, May, T, Goodman, MT, Thompson, PJ, Carney, ME, Tworoger, SS, Poole, EM, Lambrechts, D, Vergote, I, Vanderstichele, A, Van Nieuwenhuysen, E, Anton-Culver, H, Ziogas, A, Brenton, JD, Bjorge, L, Salvensen, HB, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bruegl, A, Moffitt, M, Cook, L, Le, ND, Brooks-Wilson, A, Kelemen, LE, Pharoah, PDP, Song, H, Campbell, I, Eccles, D, DeFazio, A, Kennedy, CJ & Schildkraut, JM 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', Cancer Medicine, vol. 8, no. 5, pp. 2503-2513. https://doi.org/10.1002/cam4.1996

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 -

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

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