Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance
Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance
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DOI：
10.1158/1535-7163.mct-06-0327
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发表时间：
2006-11-01
影响因子：
5.7
通讯作者：
Gamelin, Erick
中科院分区：
文献类型：
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作者：
Morel, Alain;Boisdron-Celle, Michele;Gamelin, Erick
目的：尽管二氢嘧啶脱氢酶基因(DPYD)的单核苷酸多态性(SNP)会影响酶活性和5-氟尿嘧啶(5-FU)毒性的严重程度，但目前尚无治疗前检测方法。我们调查了22个DPYD基因SNP，它们各自的发生率，它们与3-4级毒副作用的联系，以及它们的实际处理：在487名患者中寻找9个，在171名患者中调查13个。患者和方法：在以5-FU为基础的治疗前，用焦磷酸测序方法检测WBC中的SNPs。进行密切的临床和生物学随访。结果：187例患者中发现5种不同的SNPs(IVS14+1G>；A、2846A>；T、1679T>；G、85T>；C、-1590T>；C)。300名患者没有SNP。44例患者在第一周期或第二周期中出现3-4级毒副作用。60%携带IVS14+1G&gT；A或2846A&gT；T SNP的患者和唯一携带1679T&gT；G SNP的患者出现早期3~4级毒性反应，而-1590T&gT；C、85T&gT；C SNP或无SNP患者的这一比例分别为0%、5.5%和15%。对于3到4级毒性的病例，要么必须迅速停止治疗，要么可以安全地继续进行个别剂量调整。检测这三个SNP作为毒性预测因子的敏感性、特异性、阳性预测值和阴性预测值分别为0.31、0.98、0.62和0.94。结论：对3个DPYD单核苷酸多态进行预检测，可避免严重的毒副作用。这种方法适合于临床实践，应与药理学方法进行比较或结合。在二氢嘧啶脱氢酶缺乏的情况下，5-FU的应用通常可以安全地继续进行个体化剂量调整。
Purpose: Although single nucleotide polymorphisms (SNP) of the dihydropyrimidine dehydrogenase gene (DPYD) have been reported, which affect enzyme activity and the severity of 5-fluorouracil (5-FU) toxicity, no pretherapeutic detection has thus far been developed. We investigated 22 DPYD gene SNPs, their respective incidence, their link with grade 3 to 4 toxic side effects, and their management in practice: 9 were looked for in 487 patients, whereas 13 others were investigated in 171 patients. Patients and Methods: SNPs were detected before 5-FU-based treatment in WBC using a Pyrosequencing method. Close clinical and biological follow-up was done. Results: Five different SNPs were found in 187 patients (IVS14 + 1G > A, 2846A > T, 1679T > G, 85T > C, -1590T > C). Three hundred patients had no SNP. Forty-four patients had grade 3 to 4 toxic side effects in either the first or second cycle. Sixty percent of patients with either IVS14 + 1G > A or 2846A > T SNPs and the only patient with 1679T > G SNP experienced early grade 3 to 4 toxicity, compared with 0%, 5.5%, and 15% of those with either -1590T > C, 85T > C SNP, or no SNP, respectively. In cases with grade 3 to 4 toxicity, treatment either had to be quickly stopped, or could be safely continued with an individual dose adjustment. Sensitivity, specificity, and positive and negative predictive values of the detection of these three major SNPs as toxicity predictive factors were 0.31, 0.98, and 0.62 and 0.94, respectively. Conclusion: Pretreatment detection of three DPYD SNPs could help to avoid severe toxic side effects. This approach is suitable for clinical practice and should be compared or combined with pharmacologic approaches. In the case of dihydropyrimidine dehydrogenase deficiency, 5-FU administration often can be safely continued with an individual dose adjustment.