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Polymorphisms in MIR27A Associated with Early-Onset Toxicity in Fluoropyrimidine-Based Chemotherapy
Journal article   Open access   Peer reviewed

Polymorphisms in MIR27A Associated with Early-Onset Toxicity in Fluoropyrimidine-Based Chemotherapy

Ursula Amstutz, Steven M Offer, Johanna Sistonen, Markus Joerger, Robert B Diasio and Carlo R Largiadèr
Clinical cancer research, Vol.21(9), pp.2038-2044
05/01/2015
DOI: 10.1158/1078-0432.CCR-14-2817
PMID: 25655103
url
https://doi.org/10.1158/1078-0432.CCR-14-2817View
Published (Version of record) Open Access

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.
 Adolescent Adult Aged Aged, 80 and over Antineoplastic Agents - adverse effects Dihydrouracil Dehydrogenase (NADP) - genetics Female Fluorouracil - adverse effects Humans Male MicroRNAs - genetics Middle Aged Neoplasms - drug therapy Neoplasms - genetics Polymorphism, Single Nucleotide Reverse Transcriptase Polymerase Chain Reaction Young Adult

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