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.
2019-05
Citation
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. (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.
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 customâ designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 highâ 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 ORÂ =Â 1.4, 95% CIÂ =Â 1.2â 1.7, PÂ =Â 1.2Â Ã Â 10â 6, BFDPÂ =Â 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele ORÂ =Â 2.3, 95% CIÂ =Â 1.6â 3.4, PÂ =Â 1.6Â Ã Â 10â 5, BFDPÂ =Â 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele ORÂ =Â 1.4, 95% CIÂ =Â 1.2â 1.7, PÂ =Â 2.3Â Ã Â 10â 5, BFDPÂ =Â 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 ORÂ =Â 1.4, 95% CIÂ =Â 1.2â 1.7, PÂ =Â 1.2Â Ã Â 10â 6, BFDPÂ =Â 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele ORÂ =Â 2.3, 95% CIÂ =Â 1.6â 3.4, PÂ =Â 1.6Â Ã Â 10â 5, BFDPÂ =Â 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele ORÂ =Â 1.4, 95% CIÂ =Â 1.2â 1.7, PÂ =Â 2.3Â Ã Â 10â 5, BFDPÂ =Â 0.23). Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.Publisher
Wiley Periodicals, Inc.
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2045-7634 2045-7634
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