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.

Genome-wide DNA copy number profiling and bioinformatics analysis of ovarian cancer reveals key genes and pathways associated with distinct invasive/migratory capabilities

“…Davies found that AKT1 (E17K) mutations were effective therapeutic targets for AKT inhibitors [53], although combinations with other targeted agents may be required where activating oncogenic mutations of other proteins were present in the same tumour [54]. Furthermore, alterations in EGFR have been found to perturb enzyme efficacy and proliferation in ovaries and impact susceptibility to OC [55]. COL6A3 was shown to be upregulated in ovarian cancer [56].…”

Vitamin D and Ovarian Cancer: Systematic Review of the Literature with a Focus on Molecular Mechanisms

“…A study on 170 cases of epithelial ovarian cancer compared to healthy controls found no association between the ApaI polymorphism and ovarian cancer risk [33]. In another case control study, the ApaI polymorphism was associated with increased risk of ovarian cancer in African-American women [81]. Other researchers reported that the ApaI polymorphism seems to be associated with ovarian cancer in women with higher predicted 25(OH)D levels but not in women with lower predicted levels [82].…”

“…The ApaI polymorphism has also been investigated and case control studies have provided mixed results [12,33,37,81]. A study on 170 cases of epithelial ovarian cancer compared to healthy controls found no association between the ApaI polymorphism and ovarian cancer risk [33].…”

The Role Of “Il 10 (-2 1082 A/G)” Promoter Polymorphism In Ovarian Epithelial Cancer Pathogenesis

“…The status of excess nutrition called obesity has been proven in many studies as a risk factor for cancer, and physical activity is a factor in reducing obesity because it is the primary determinant in energy expenditure so that it can reduce the risk of cancer caused by obesity (11)(12)(13)(14). That is stated in a study related to risk factors that predict cancer cell growth: smoking, diet, alcohol consumption, reproduction (pregnancy, breastfeeding, age at first menstruation, menopause), obesity, and lack of physical activity (8,10,15,16). ).…”