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

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

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.

African ancestry risk, genetic association, ovarian cancer, vitamin D pathway
2045-7634
2503-2513
Grant, Delores J.
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Manichaikul, Ani
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Alberg, Anthony J.
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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. and Schildkraut, Joellen 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. (doi:10.1002/cam4.1996).

Record type: Article

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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Accepted/In Press date: 8 January 2019
e-pub ahead of print date: 18 April 2019
Keywords: African ancestry risk, genetic association, ovarian cancer, vitamin D pathway

Identifiers

Local EPrints ID: 431795
URI: http://eprints.soton.ac.uk/id/eprint/431795
ISSN: 2045-7634
PURE UUID: 02cc56cf-d0ab-465e-bbd7-bab0919f961e
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

Catalogue record

Date deposited: 17 Jun 2019 16:30
Last modified: 22 Nov 2021 02:35

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Contributors

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

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