DPYD*6 plays an important role in fluoropyrimidine toxicity in addition to DPYD*2A and c.2846A>T: a comprehensive analysis in 1254 patients
DPYD*6 plays an important role in fluoropyrimidine toxicity in addition to DPYD*2A and c.2846A>T: a comprehensive analysis in 1254 patients
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除DPYD*2A和c.2846A>T外，DPYD*6在氟嘧啶毒性中也发挥重要作用：1254例患者的综合分析
DOI：
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
R. Danesi
中科院分区：
文献类型：
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作者：
M. Del Re;S. Cinieri;A. Michelucci;S. Salvadori;F. Loupakis;M. Schirripa;C. Cremolini;S. Crucitta;C. Barbara;A. Di Leo;T. Latiano;F. Pietrantonio;S. Di Donato;P. Simi;A. Passardi;F. D. De Braud;G. Altavilla;C. Zamagni;R. Bordonaro;A. Butera;E. Maiello;C. Pinto;A. Falcone;V. Mazzotti;R. Morganti;R. Danesi
二氢嘧啶脱氢酶（DPYD）是一种高度多态性的基因，典型的缺陷变体（即c.1236G> a /HapB3, c.1679T>G, c.1905+1G> a和c.2846A>T）的特征是酶活性受损，并且在使用氟嘧啶治疗的患者中存在严重药物不良反应（adr）的风险。通过先发制人的DPYD筛查识别不良代谢物可能会降低adr的发生率，但许多经典变异的野生型基因型患者仍可能出现adr。因此，寻找与不良反应相关的其他DPYD多态性可能会提高氟嘧啶治疗的安全性。本研究纳入1254例接受含氟嘧啶方案治疗的患者，并分为队列1和队列2（对照组）。队列1包括982例胃肠道G≥2和/或血液学G≥3不良反应的患者，队列2包括272例不需要减量、延迟或停止治疗的患者。筛选两组DPYD变异基因C . 496a >G、C . 1236g >A/HapB3、C . 1601g >A （DPYD*4）、C . 1627a >G （DPYD*5）、C . 1679t >G （DPYD*13）、C . 1896t >C、C .1905 + 1G>A （DPYD*2A）、C . 2194g >A （DPYD*6）和C . 2846a >T，评估其与毒性的相关性。两个队列的遗传分析是通过从3ml全血中提取DNA的Real-Time PCR进行的。DPYD C . 496a >G、C . 1601g >A、C . 1627a >G、C . 1896t >C和C . 2194g >A变异均存在于队列1和2中，而C .1905+1G>A和C . 2846a >T仅存在于队列1中。未发现DPYD c.1679T>G和c.1236G>A/HapB3。单因素分析发现，c.1905+1G>A、c.2194G>A和c.2846A>T等位基因与胃肠道和血液学adr显著相关（p < 0.05）， c.496A>G变异与中性粒细胞减少症呈正相关（p = 0.06）。总之，除了已知的c.1905+1G>A和c.2846A>T变异外，c.2194G>A还与临床相关的不良反应相关，应进行预防性评估，以降低氟嘧啶相关不良反应的风险。
Dihydropyrimidine dehydrogenase (DPYD) is a highly polymorphic gene and classic deficient variants (i.e., c.1236G>A/HapB3, c.1679T>G, c.1905+1G>A and c.2846A>T) are characterized by impaired enzyme activity and risk of severe adverse drug reactions (ADRs) in patients treated with fluoropyrimidines. The identification of poor metabolizers by pre-emptive DPYD screening may reduce the rate of ADRs but many patients with wild-type genotype for classic variants may still display ADRs. Therefore, the search for additional DPYD polymorphisms associated with ADRs may improve the safety of treatment with fluoropyrimidines. This study included 1254 patients treated with fluoropyrimidine-containing regimens and divided into cohort 1, which included 982 subjects suffering from gastrointestinal G≥2 and/or hematological G≥3 ADRs, and cohort 2 (control group), which comprised 272 subjects not requiring dose reduction, delay or discontinuation of treatment. Both groups were screened for DPYD variants c.496A>G, c.1236G>A/HapB3, c.1601G>A (DPYD*4), c.1627A>G (DPYD*5), c.1679T>G (DPYD*13), c.1896T>C, c.1905 + 1G>A (DPYD*2A), c.2194G>A (DPYD*6), and c.2846A>T to assess their association with toxicity. Genetic analysis in the two cohorts were done by Real-Time PCR of DNA extracted from 3 ml of whole blood. DPYD c.496A>G, c.1601G>A, c.1627A>G, c.1896T>C, and c.2194G>A variants were found in both cohort 1 and 2, while c.1905+1G>A and c.2846A>T were present only in cohort 1. DPYD c.1679T>G and c.1236G>A/HapB3 were not found. Univariate analysis allowed the selection of c.1905+1G>A, c.2194G>A and c.2846A>T alleles as significantly associated with gastrointestinal and hematological ADRs (p < 0.05), while the c.496A>G variant showed a positive trend of association with neutropenia (p = 0.06). In conclusion, c.2194G>A is associated with clinically-relevant ADRs in addition to the already known c.1905+1G>A and c.2846A>T variants and should be evaluated pre-emptively to reduce the risk of fluoropyrimidine-associated ADRs.
影响因子：
11.2
作者：
Offer SM;Fossum CC;Wegner NJ;Stuflesser AJ;Butterfield GL;Diasio RB
通讯作者：
Diasio RB