Rs895819 in MIR27A improves the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine‐associated toxicity

Abstract

The objective of this study was to determine whether genotyping of MIR27A polymorphisms rs895819A>G and rs11671784C>T can be used to improve the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine-associated toxicity (FP-toxicity). Patients treated previously in a prospective study with fluoropyrimidine-based chemotherapy were genotyped for rs895819 and rs11671784, and DPYD c.2846A>T, c.1679T>G, c.1129-5923C>G and c.1601G>A. The predictive value of MIR27A variants for early-onset grade 3 FP-toxicity, alone or in combination with DPYD variants, was tested in multivariable logistic regression models. Random-effects meta-analysis was performed, including previously published data. A total of 1,592 patients were included. Allele frequencies of rs895819 and rs11671784 were 0.331 and 0.020, respectively. In DPYD wild-type patients, MIR27A variants did not affect risk of FP-toxicity (OR 1.3 for 1 variant MIR27A allele vs. none, 95% CI: 0.87-1.82, p 5 0.228). In contrast, in patients carrying DPYD variants, the presence of 1 rs895819 variant allele was associated with increased risk of FP-toxicity (OR 4.9, 95% CI: 1.24-19.7, p 5 0.023). Rs11671784 was not associated with FP-toxicity (OR 2.9, 95% CI: 0.47218.0, p 5 0.253). Patients carrying a DPYD variant and rs895819 were at increased risk of FP-toxicity compared to patients wild type for rs895819 and DPYD (OR 2.4, 95% CI: 1.27-4.37, p 5 0.007), while patients with a DPYD variant but without a MIR27A variant were not (OR 0.3 95% CI: 0.0621.17, p 5 0.081). In meta-analysis, rs895819 remained significantly associated with FP-toxicity in DPYD variant allele carriers, OR 5.4 (95% CI: 1.83-15.7, p 5 0.002). This study demonstrates the clinical validity of combined MIR27A/DPYD screening to identify patients at risk of severe FP-toxicity.Fluoropyrimidines are among the most frequently prescribed anticancer drugs for gastrointestinal, breast and head and neck cancers. Of the patients treated, 10-30% experiences severe, potentially lethal, fluoropyrimidine-associated toxicity. [1][2][3][4] The most well-established cause of intolerance to fluoropyrimidines is deficiency of the main 5-fluorouracil (5-FU) metabolic enzyme, dihydropyrimidine dehydrogenase (DPD).5-8 DPD deficiency can be the result of polymorphisms in DPYD-the gene encoding DPD-and DPYD variants have therefore received wide-spread attention as predictors of fluoropyrimidine-associated toxicity. 3,[9][10][11][12]

Quantitative Contribution of rs75017182 to Dihydropyrimidine Dehydrogenase mRNA Splicing and Enzyme Activity

“…Previously, we showed that expression of the microRNA miR‐27a negatively correlated with DPD function and that the relatively common miR‐27a polymorphism rs895819 was significantly associated with reduced DPD expression and enzyme activity . Subsequent studies showed that rs895819 significantly interacted with rs55886062, rs67376798, and rs75017182 to potentiate toxicity risk in carriers . In addition to microRNA‐mediated regulation, DPYD expression was also recently shown to be epigenetically regulated with potential contributions to 5‐FU toxicity and response .…”

The SNPs in pre-miRNA are related to the response of capecitabine-based therapy in advanced colon cancer patients

“…More and more studies have provided evidences to demonstrate that the SNPs in the miRNA genes, through impacting the interaction of miRNA with target genes and/or affecting the expression level of mature miRNA, result in dysregulation of target gene and consequent individual drug response and toxicity [ 9 ]. Several studies have shown that the miRNA-related SNPs are related to the efficacy and/or occurrence of adverse events of capecitabine-based chemotherapy for CRC patients [ 10 , 11 ]. For instance, Sclafani et al .…”

“…have shown that polymorphisms in the miR-27a genomic region (MIR27A) can be used to improve the predictive value of DPYD variants to identify the risk of severe fluoropyrimidine associated toxicity in cancer patients. The patients carrying a DPYD + /MIR27A + genotype are at much higher risk of early severe fluoropyrimidine associated toxicity than those with a DPYD + /MIR27A − genotype [ 11 ]. Another common polymorphism (rs895819A > G) in MIR27A was found to be associated with a early-onset toxicity in fluoropyrimidine-based chemotherapy in the patients carrying DPYD risk variants [ 12 ].…”

Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity

“…Importantly, however, DPYD genotyping inherently has suboptimal sensitivity and positive predictive value (PPV), as a result of the fact that activity of DPD is regulated not only at the level of DPYD , but also to a relevant extent at the transcriptional level (e.g., by transcription factors SP1 and SP3) and the post-transcriptional level (e.g., by microRNA 27-a and 27-b; van Kuilenburg, 2004; Zhang et al , 2006; Offer et al , 2014; Amstutz et al , 2015; Meulendijks et al , 2016). Genetic variants in TYMS , the gene encoding 5-FU’s target thymidylate synthase (TS), have also been associated with risk of fluoropyrimidine-associated toxicity (Rosmarin et al , 2014), but in contrast to DPYD variants there is currently insufficient evidence for clinical validity of TYMS variants.…”