ASPO Abstracts
A molecular epidemiology study of the reactive oxygen species pathway in risk of melanoma
Category: Molecular Epidemiology & Environment, Early Detection & Risk Prediction
Conference Year: 2018
Abstract Body:
Purpose of the study: UV exposure is the primary environmental risk factor for human melanomas yet the underlying mechanism is not fully understood. Recent studies have shown that UV-induced chemiexcitation of melanin derivatives plays a critical role in inducing DNA mutations. This process requires the participation of reactive oxygen species (ROS) which may be produced and enhanced by cellular NADPH oxidase (NOX) complexes. We hypothesized that ROS producing and metabolizing enzymes were the major contributors in UV- driven melanomas. Method: Using a pathway-driven case-control study that included 170 cases and 152 controls, we genotyped 23 prioritized single nucleotide polymorphisms in NADPH oxidases 1 and 4 (NOX1, NOX4), CYBAp22phox membrane protein, RAC1-GTPase, and ROS metabolizing enzymes superoxide dismutase (SOD) and catalase, to investigate their associations with the risk of melanoma. Result: We first identified 5 SNPs including rs1049255 (CYBA), rs4673 (CYBA), rs10951982 (RAC1), rs8031 (SOD2), and rs2536512 (SOD3) that exhibited significant genotypic frequency differences between melanoma cases and healthy controls. In simple logistic regression models, RAC1 rs10951982 (OR 8.98, 95% CI: 5.08 to 16.44; P<0.001) reached universal significance after Bonferroni correction (P=0.002); and the minor alleles showed an association with increased risk of melanoma. In contrast, minor alleles in SOD2 rs8031 (OR 0.16, 95% CI: 0.06 to 0.39; P<0.001) and SOD3 rs2536512 (OR 0.08, 95% CI: 0.01 to 0.31; P=0.001) were associated with a reduced risk of melanoma. In multivariate logistic regression models, RAC1 rs10951982 (OR 6.15, 95% CI: 2.98 to 13.41; P<0.001) remained significantly associated with an increased risk of melanoma, adjusting for age, sex, lifetime ever sunburned, and family history of melanoma. Conclusion: Our result highlighted the importance of RAC1, SOD2 and SOD3 variants in the risk of melanoma. Out next step is to replicate the findings. Once the results are validated, these SNPs may be useful for screening high-risk individuals for a better prevention plan in melanoma.
Keywords: Melanoma, reactive oxygen species, single nucleotide polymorphisms, superoxide dismutase, RAC1-GTPase