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 & 70 others 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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)2503-2513
Number of pages11
JournalCancer medicine
Volume8
Issue number5
DOIs
StatePublished - May 1 2019

Fingerprint

Vitamin D
African Americans
Single Nucleotide Polymorphism
Odds Ratio
Confidence Intervals
Calcitriol Receptors
Genes
Alleles
25-Hydroxyvitamin D3 1-alpha-Hydroxylase
Cholesterol Side-Chain Cleavage Enzyme
Cytochrome P-450 CYP3A
Ovary
Logistic Models
Ovarian epithelial cancer
Genome
Enzymes

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Grant, D. J., Manichaikul, A., Alberg, A. J., Bandera, E. V., Barnholtz-Sloan, J., Bondy, M., ... 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

Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women. / Grant, Delores J.; Manichaikul, Ani; Alberg, Anthony J.; Bandera, Elisa V.; Barnholtz-Sloan, Jill; Bondy, Melissa; Cote, Michele L.; Funkhouser, Ellen; Moorman, Patricia G.; Peres, Lauren C.; Peters, Edward S.; Schwartz, Ann G.; Terry, Paul D.; Wang, Xin Qun; Keku, Temitope O.; Hoyo, Cathrine; Berchuck, Andrew; Sandler, Dale P.; Taylor, Jack A.; O’Brien, Katie M.; Velez Edwards, Digna R.; Edwards, Todd L.; Beeghly-Fadiel, Alicia; Wentzensen, Nicolas; Pearce, Celeste Leigh; Wu, Anna H.; Whittemore, Alice S.; McGuire, Valerie; Sieh, Weiva; Rothstein, Joseph H.; Modugno, Francesmary; Ness, Roberta; Moysich, Kirsten; Rossing, Mary Anne; Doherty, Jennifer A.; Sellers, Thomas A.; Permuth-Way, Jennifer B.; Monteiro, Alvaro N.; Levine, Douglas A.; Setiawan, Veronica Wendy; Haiman, Christopher A.; LeMarchand, Loic; Wilkens, Lynne R.; Karlan, Beth Y.; Menon, Usha; Ramus, Susan; Gayther, Simon; Gentry-Maharaj, Aleksandra; Terry, Kathryn L.; Cramer, Daniel W.; Goode, Ellen L; Larson, Melissa C.; Kaufmann, Scott H; Cannioto, Rikki; Odunsi, Kunle; Etter, John L.; Huang, Ruea Yea; Bernardini, Marcus Q.; Tone, Alicia A.; May, Taymaa; Goodman, Marc T.; Thompson, Pamela J.; Carney, Michael E.; Tworoger, Shelley S.; Poole, Elizabeth M.; Lambrechts, Diether; Vergote, Ignace; Vanderstichele, Adriaan; Van Nieuwenhuysen, Els; Anton-Culver, Hoda; Ziogas, Argyrios; Brenton, James D.; Bjorge, Line; Salvensen, Helga B.; Kiemeney, Lambertus A.; Massuger, Leon F.A.G.; Pejovic, Tanja; Bruegl, Amanda; Moffitt, Melissa; Cook, Linda; Le, Nhu D.; Brooks-Wilson, Angela; Kelemen, Linda E.; Pharoah, Paul D.P.; Song, Honglin; Campbell, Ian; Eccles, Diana; DeFazio, Anna; Kennedy, Catherine J.; Schildkraut, Joellen M.

In: Cancer medicine, Vol. 8, No. 5, 01.05.2019, p. 2503-2513.

Research output: Contribution to journalArticle

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
Grant, Delores J. ; Manichaikul, Ani ; Alberg, Anthony J. ; Bandera, Elisa V. ; Barnholtz-Sloan, Jill ; Bondy, Melissa ; Cote, Michele L. ; Funkhouser, Ellen ; Moorman, Patricia G. ; Peres, Lauren C. ; Peters, Edward S. ; Schwartz, Ann G. ; Terry, Paul D. ; Wang, Xin Qun ; Keku, Temitope O. ; Hoyo, Cathrine ; Berchuck, Andrew ; Sandler, Dale P. ; Taylor, Jack A. ; O’Brien, Katie M. ; Velez Edwards, Digna R. ; Edwards, Todd L. ; Beeghly-Fadiel, Alicia ; Wentzensen, Nicolas ; Pearce, Celeste Leigh ; Wu, Anna H. ; Whittemore, Alice S. ; McGuire, Valerie ; Sieh, Weiva ; Rothstein, Joseph H. ; Modugno, Francesmary ; Ness, Roberta ; Moysich, Kirsten ; Rossing, Mary Anne ; Doherty, Jennifer A. ; Sellers, Thomas A. ; Permuth-Way, Jennifer B. ; Monteiro, Alvaro N. ; Levine, Douglas A. ; Setiawan, Veronica Wendy ; Haiman, Christopher A. ; LeMarchand, Loic ; Wilkens, Lynne R. ; Karlan, Beth Y. ; Menon, Usha ; Ramus, Susan ; Gayther, Simon ; Gentry-Maharaj, Aleksandra ; Terry, Kathryn L. ; Cramer, Daniel W. ; Goode, Ellen L ; Larson, Melissa C. ; Kaufmann, Scott H ; Cannioto, Rikki ; Odunsi, Kunle ; Etter, John L. ; Huang, Ruea Yea ; Bernardini, Marcus Q. ; Tone, Alicia A. ; May, Taymaa ; Goodman, Marc T. ; Thompson, Pamela J. ; Carney, Michael E. ; Tworoger, Shelley S. ; Poole, Elizabeth M. ; Lambrechts, Diether ; Vergote, Ignace ; Vanderstichele, Adriaan ; Van Nieuwenhuysen, Els ; Anton-Culver, Hoda ; Ziogas, Argyrios ; Brenton, James D. ; Bjorge, Line ; Salvensen, Helga B. ; Kiemeney, Lambertus A. ; Massuger, Leon F.A.G. ; Pejovic, Tanja ; Bruegl, Amanda ; Moffitt, Melissa ; Cook, Linda ; Le, Nhu D. ; Brooks-Wilson, Angela ; Kelemen, Linda E. ; Pharoah, Paul D.P. ; Song, Honglin ; Campbell, Ian ; Eccles, Diana ; DeFazio, Anna ; Kennedy, Catherine J. ; Schildkraut, Joellen M. / Evaluation of vitamin D biosynthesis and pathway target genes reveals UGT2A1/2 and EGFR polymorphisms associated with epithelial ovarian cancer in African American Women. In: Cancer medicine. 2019 ; Vol. 8, No. 5. pp. 2503-2513.
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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.",
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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 - 2019/5/1

Y1 - 2019/5/1

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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EP - 2513

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SN - 2045-7634

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