Genetic Variation in miR-27a Is Associated with Fluoropyrimidine-Associated Toxicity in Patients with Dihydropyrimidine Dehydrogenase Variants after Genotype-Guided Dose Reduction.

Dihydropyrimidine dehydrogenase () is the rate-limiting enzyme involved in the metabolism of fluoropyrimidine-based chemotherapy. However, single-nucleotide variants (SNVs) in only partially explain fluoropyrimidine-induced toxicity. The expression of has previously been shown to be regulated by microRNA-27a (miR-27a) and a common miR-27a SNV (rs895819) has been associated with an increased risk of toxicity in patients harboring a variant who received standard fluoropyrimidine dosing. We investigated if the miR-27a rs895819 SNV was associated with toxicity in wildtype patients and carriers of variants who received a reduced dose. The regulation of using miR-27a was investigated in HepG2 cells utilizing a miR-27a mimic. miR-27a overexpression decreased mRNA expression compared to control cells ( < 0.0001). In a cohort of patients that received pre-emptive genotyping, 45 patients had a variant and 180 were wildtype. Patients heterozygous for rs895819 had an increased risk of toxicity, which was seen in both patients who were wildtype for variants (OR (95%CI) = 1.99 (1.00-3.99)) and variant carriers (OR (95%CI) = 8.10 (1.16-86.21)). Therefore, miR-27a rs895819 may be a clinically relevant predictor of fluoropyrimidine-associated toxicities. Furthermore, toxicity was more profound in variant carriers, even after genotype-guided dose reduction. This suggests that patients may benefit from miR-27a genotyping to guide fluoropyrimidine dosing.