Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data
Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data
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DOI：
10.1016/s1470-2045(15)00286-7
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发表时间：
2015-12-01
期刊：
影响因子：
51.1
通讯作者：
Schellens, Jan H. M.
中科院分区：
文献类型：
--
作者：
Meulendijks, Didier;Henricks, Linda M.;Schellens, Jan H. M.
二氢嘧啶脱氢酶（DPD）缺乏是导致氟嘧啶类药物不耐受的最常见原因，它可能是编码DPD（DPYD）基因的有害多态性所致，包括DPYD*2A和c.2846A>T。其他三种DPYD变异体c.1679T>G、c.1236G>A/HapB 3和c.1601G>A与DPD缺乏症相关，但这些变异体的临床有效性尚无确切证据。本系统综述和荟萃分析的主要目的是评估c.1679T>G、c.1236G>A/HapB 3和c.1601G>A作为严重氟嘧啶相关毒性预测因子的临床有效性。方法我们对2014年12月17日之前发表的文献进行了系统综述，以确定队列研究，研究DPYD c.1679T>G、c.1236G> A/HapB 3和c.1601G>A之间的相关性。c.1236G>A/HapB 3，和c.1601G>A和严重的（等级）氟尿嘧啶相关毒性，在用氟尿嘧啶（氟尿嘧啶、卡培他滨或替加氟-尿嘧啶作为单一药剂，与其它抗癌药物组合，或与放射疗法）治疗的患者中。在多变量分析中检索并分析个体患者数据，以获得校正的相对风险（RR）。使用随机效应荟萃分析汇总效应估计值。显著性阈值设定为p值小于0.0167（Bonferroni校正）。DPYD c.1679T>G与氟嘧啶相关毒性显著相关（校正RR 4. 40，95% CI 2.08-9.30，pA/HapB3（1. 59，1。29-1.97，pA和氟嘧啶相关毒性不显著（校正RR 1.52，95%CI 0.05）。86-2. 70，p=0。15）。对单个类型毒性的分析显示，c.1679T>G和c.1236G>A/HapB 3与胃肠道毒性一致相关（调整后RR 5.72，95%CI 1.40-23.33，p=0. 015; 2。04，1.49-2.78，pT也与严重的氟嘧啶相关毒性显著相关（校正RR 2。85，95% CI 1。75-4. 62，pA/HapB 3是临床上与氟尿嘧啶相关毒性的预测因子。除了已确定的变异体DPYD*2A和c.2846A>T之外，建议对这些变异体进行前期筛查，以提高接受氟尿嘧啶治疗的癌症患者的安全性。
Background The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including DPYD*2A and c.2846A>T. Three other variants DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity.Methods We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0.0167 (Bonferroni correction).Findings 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4. 40, 95% CI 2.08-9.30, pA/HapB3 (1. 59, 1. 29-1.97, pA and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1.52, 95% CI 0. 86-2. 70, p=0. 15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5.72, 95% CI 1.40-23.33, p=0. 015; and 2. 04, 1.49-2.78, pT were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2. 85, 95% CI 1. 75-4. 62, pA/HapB3 are clinically relevant predictors of fluoropyrimidineassociated toxicity. Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines.