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

2 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 (US)
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

ASJC Scopus subject areas

Oncology
Radiology Nuclear Medicine and imaging
Cancer Research

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10.1002/cam4.1996

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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

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

@article{4e9239b2d7e349b7af81a7b86323e93b,

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 = "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 (US)",

volume = "8",

pages = "2503--2513",

journal = "Cancer medicine",

issn = "2045-7634",

publisher = "John Wiley and Sons Ltd",

number = "5",

}

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.

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

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U2 - 10.1002/cam4.1996

DO - 10.1002/cam4.1996

M3 - Article

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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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