Abstract LB-195: The intronic DPYD variant rs75017182 correlates with a modest reduction in DPD enzyme activity

Shikshya Shrestha; Steven M. Offer; Robert B. Diasio

doi:10.1158/1538-7445.AM2016-LB-195

Abstract Nearly one-third of cancer patients that receive the commonly prescribed chemotherapy drug 5-fluorouracil (5-FU) experience severe (grade 3+) adverse toxicity related to treatment. Approximately 1,300 deaths are directly attributed to 5-FU toxicity annually in the U.S. While three deleterious genetic variations in the dihydropyrimidine dehydrogenase (DPD) gene (DPYD) are well-established predictors of severe toxicity (i.e., *2A, p.I560S, p.D949V), they only explain 30-35% of adverse cases of 5-FU toxicity. Recently, an intronic variant (rs75017182) has been suggested to contribute to 5-FU toxicity risk by promoting the alternative splicing of DPYD. However, recent clinical studies are conflicting as to the degree to which rs75017182 affects DPD enzyme function, and it remains unclear as to the extent to which DPYD splicing is affected in carriers. The primary aim of this study was to directly determine correlations between rs75017182, DPD enzyme function, and DPYD splicing. Genotyping for rs75017182, *2A, p.I560S, and p.D949V was performed on DNA obtained from 3950 healthy participants in the Mayo Clinic Biobank. Individuals carrying one or more of the genotyped variants, as well as matched non-carriers, were asked to provide an additional blood sample that was used to measure DPYD expression, DPYD splicing relevant to rs75017182, and DPD enzyme activity (n = 204). A moderate, but significant, reduction was noted in the expression of canonically spliced DPYD in rs75017182 carriers compared to non-carriers. DPD enzyme activity in peripheral blood mononuclear cells was similarly reduced in rs75017182 carriers. The degree to which DPD activity was reduced in rs75017182 carriers was not as severe as was noted for carriers of the toxicity-associated variants *2A, p.I560S, or p.D949V. Collectively, our data support a model in which rs75017182 leads to alternative splicing of a fraction of primary transcripts that harbor the variant, which in turn causes a modest reduction in the levels of functional DPD enzyme. The modest phenotypes noted may partially explain some of the discrepant results noted between various clinical studies that have attempted to evaluate the variant. Citation Format: Shikshya Shrestha, Steven M. Offer, Robert B. Diasio. The intronic DPYD variant rs75017182 correlates with a modest reduction in DPD enzyme activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-195.

Abstract LB-195: The intronic DPYD variant rs75017182 correlates with a modest reduction in DPD enzyme activity

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