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

• Published in: Cancer medicine (Malden, MA) Vol. 8; no. 5; pp. 2503 - 2513
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.05.2019; John Wiley and Sons Inc; Wiley
• Subjects: African Americans; African ancestry risk; Alleles; Bayes Theorem; Bayesian analysis; Bioavailability; Biosynthesis; Black or African American - genetics; Cancer Prevention; Carcinoma, Ovarian Epithelial - genetics; Carcinoma, Ovarian Epithelial - metabolism; Carcinoma, Ovarian Epithelial - pathology; Consortia; Epidermal growth factor receptors; ErbB Receptors - genetics; Female; Genes; genetic association; Genetic Association Studies; Genetic diversity; Genomes; Genotyping; Glucuronosyltransferase - genetics; Humans; Logistic Models; Medical research; Metabolism; Middle Aged; Neoplasm Grading; Oncology; Original Research; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Polymorphism, Single Nucleotide; Quality control; Receptors, Calcitriol - genetics; Single-nucleotide polymorphism; Studies; Vitamin D; Vitamin D - biosynthesis; vitamin D pathway; Vitamin D receptors; Womens health; genetic association; ovarian cancer; vitamin D pathway; African ancestry risk
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.1996

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. We sought to examine associations 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). 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). Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.