Abstract
<div>Abstract<p><b>Purpose:</b> 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 (<i>MIR27A</i>) 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 <i>MIR27A</i> germline variants with early-onset fluoropyrimidine toxicity.</p><p><b>Experimental Design:</b> <i>MIR27A</i> was sequenced in 514 patients with cancer receiving fluoropyrimidine-based chemotherapy. Associations of <i>MIR27A</i> polymorphisms with early-onset (cycles 1–2) fluoropyrimidine toxicity were assessed in the context of known risk variants in the DPD gene (<i>DPYD</i>) and additional covariates associated with toxicity.</p><p><b>Results:</b> The association of rs895819A>G with early-onset fluoropyrimidine toxicity was strongly dependent on <i>DPYD</i> risk variant carrier status (<i>P</i><sub>interaction</sub> = 0.0025). In patients carrying <i>DPYD</i> risk variants, rs895819G was associated with a strongly increased toxicity risk [OR, 7.6; 95% confidence interval (CI), 1.7–34.7; <i>P</i> = 0.0085]. Overall, 71% (12/17) of patients who carried both rs895819G and a <i>DPYD</i> risk variant experienced severe toxicity. In patients without <i>DPYD</i> risk variants, rs895819G was associated with a modest decrease in toxicity risk (OR, 0.62; 95% CI, 0.43–0.9; <i>P</i> = 0.012).</p><p><b>Conclusions:</b> These results indicate that miR-27a and rs895819A>G may be clinically relevant for further toxicity risk stratification in carriers of <i>DPYD</i> 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 <i>DPYD</i> risk variants. <i>Clin Cancer Res; 21(9); 2038–44. ©2015 AACR</i>.</p></div>
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