Abstract
The microRNA miR-27a was recently shown to directly regulate dihydropyrimidine dehydrogenase (DPD), the key enzyme in fluoropyrimidine catabolism. A common polymorphism (rs895819A>G) in the miR-27a genomic region (MIR27A) was associated with reduced DPD activity in healthy volunteers, but the clinical relevance of this effect is still unknown. Here, we assessed the association of MIR27A germline variants with early-onset fluoropyrimidine toxicity. MIR27A was sequenced in 514 patients with cancer receiving fluoropyrimidine-based chemotherapy. Associations of MIR27A polymorphisms with early-onset (cycles 1-2) fluoropyrimidine toxicity were assessed in the context of known risk variants in the DPD gene (DPYD) and additional covariates associated with toxicity. The association of rs895819A>G with early-onset fluoropyrimidine toxicity was strongly dependent on DPYD risk variant carrier status (Pinteraction = 0.0025). In patients carrying DPYD risk variants, rs895819G was associated with a strongly increased toxicity risk [OR, 7.6; 95% confidence interval (CI), 1.7-34.7; P = 0.0085]. Overall, 71% (12/17) of patients who carried both rs895819G and a DPYD risk variant experienced severe toxicity. In patients without DPYD risk variants, rs895819G was associated with a modest decrease in toxicity risk (OR, 0.62; 95% CI, 0.43-0.9; P = 0.012). These results indicate that miR-27a and rs895819A>G may be clinically relevant for further toxicity risk stratification in carriers of DPYD risk variants. Our data suggest that direct suppression of DPD by miR-27a is primarily relevant in the context of fluoropyrimidine toxicity in patients with reduced DPD activity. However, miR-27a regulation of additional targets may outweigh its effect on DPD in patients without DPYD risk variants.
Highlights
Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the catabolism of the fluoropyrimidines 5-fluorouracil (5FU) and capecitabine and, as such, is a key determinant of adverse effects from fluoropyrimidine-based chemotherapy [1, 2]
In patients without DPYD risk variants, rs895819G was associated with a modest decrease in toxicity risk (OR, 0.62; 95% confidence interval (CI), 0.43–0.9; P 1⁄4 0.012)
These results indicate that miR-27a and rs895819A>G may be clinically relevant for further toxicity risk stratification in carriers of DPYD risk variants
Summary
Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the catabolism of the fluoropyrimidines 5-fluorouracil (5FU) and capecitabine and, as such, is a key determinant of adverse effects from fluoropyrimidine-based chemotherapy [1, 2]. Deleterious genetic variants in the gene encoding DPD (DPYD) are known to increase the risk of severe and potentially fatal toxicity due to increased fluoropyrimidine exposure [1, 3, 4]. Not all severe fluoropyrimidine toxicity episodes can be explained by currently known DPYD risk variants, and some DPYD risk variant carriers tolerate standard doses of fluoropyrimidine-based chemotherapy without major toxicity [3, 5]. Dine catabolism and toxicity both in patients with and without DPYD risk variants Identification of such modulating factors may prevent life-threatening toxicity episodes by improving the sensitivity and positive predictive value of pharmacogenetic testing to identify patients at increased risk of severe fluoropyrimidine toxicity
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