University Institute of Clinical Chemistry, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Cancer Center, Rochester, Minnesota.
Clin Cancer Res. 2015 May 1;21(9):2038-44. doi: 10.1158/1078-0432.CCR-14-2817. Epub 2015 Feb 5.
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.
最近的研究表明，miR-27a 可直接调控二氢嘧啶脱氢酶（DPD），后者是氟嘧啶代谢中的关键酶。miR-27a 基因座（MIR27A）中的一个常见多态性（rs895819A>G）与健康志愿者中 DPD 活性降低有关，但这种影响的临床相关性尚不清楚。在此，我们评估了 MIR27A 种系变异与氟嘧啶早期毒性之间的关系。
对 514 例接受氟嘧啶类化疗的癌症患者进行 MIR27A 测序。在已知 DPD 基因（DPYD）风险变异和其他与毒性相关的附加协变量的背景下，评估 MIR27A 多态性与氟嘧啶早期毒性（第 1-2 周期）之间的关联。
rs895819A>G 与氟嘧啶早期毒性的关联强烈依赖于 DPYD 风险变异携带者的状态（P 交互作用=0.0025）。在携带 DPYD 风险变异的患者中，rs895819G 与毒性风险显著增加相关[比值比（OR），7.6；95%置信区间（CI），1.7-34.7；P=0.0085]。总体而言，携带 rs895819G 和 DPYD 风险变异的 17 例患者中，有 71%（12 例）发生严重毒性。在没有 DPYD 风险变异的患者中，rs895819G 与毒性风险适度降低相关（OR，0.62；95%CI，0.43-0.9；P=0.012）。
这些结果表明，miR-27a 和 rs895819A>G 可能与 DPYD 风险变异携带者的进一步毒性风险分层具有临床相关性。我们的数据表明，在 DPD 活性降低的氟嘧啶毒性患者中，miR-27a 对 DPD 的直接抑制作用主要相关。然而，在没有 DPYD 风险变异的患者中，miR-27a 对其他靶标的调控可能超过其对 DPD 的影响。
