Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients.
Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with fluoropyrimidine-related toxicity in cancer patients.
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DOI：
10.1371/journal.pone.0004003
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Meindl A
中科院分区：
文献类型：
--
作者：
Gross E;Busse B;Riemenschneider M;Neubauer S;Seck K;Klein HG;Kiechle M;Lordick F;Meindl A
携带二氢嘧啶脱氢酶基因(DPYD)突变的癌症患者在使用5-氟尿嘧啶(5-FU)或卡培他滨等氟尿嘧啶药物化疗后，有很高的风险经历严重的药物不良反应。预先检测这种对嘧啶分解代谢的损害可以预防严重的、潜在的致命性副作用。由于已知的有害突变只解释了有限比例的药物不良事件，我们系统地寻找与增强药物毒性相关的其他DPYD变异。我们进行了覆盖整个编码区的全基因方法，并比较了氟嘧啶类化疗方案耐受性好(n = 89)和耐受性差(n = 39)的癌症患者之间的DPYD基因频率。应用Logistic回归分析和滑动窗口方法，我们确定了非同义多态C.496A>；G(p.Met166Val)与氟嘧啶相关的III和IV级毒性最强的关联。然后，我们用53名药物不良反应患者的独立样本证实了我们的初步结果。92例中毒病例的合并优势比为4.42[95%CI2.12-9.23]；p(趋势)和t；0.001；p(校正) = 为0.001；归因危险度为56.9%。比较肿瘤类型匹配的样本组，C.496A和GT；G与毒性的相关性在胃食道癌和乳腺癌患者中尤其存在，但在结直肠恶性肿瘤患者中未达到显著水平。我们的结果显示，令人信服的证据表明，至少在不同的肿瘤类型中，常见的DPYD基因多态性强烈地导致了氟嘧啶类药物不良反应的发生。这种变异的携带者可以从调整氟嘧啶药物的个体化剂量或替代疗法中受益。
Cancer patients carrying mutations in the dihydropyrimidine dehydrogenase gene (DPYD) have a high risk to experience severe drug-adverse effects following chemotherapy with fluoropyrimidine drugs such as 5-fluorouracil (5-FU) or capecitabine. The pretreatment detection of this impairment of pyrimidine catabolism could prevent serious, potentially lethal side effects. As known deleterious mutations explain only a limited proportion of the drug-adverse events, we systematically searched for additional DPYD variations associated with enhanced drug toxicity. We performed a whole gene approach covering the entire coding region and compared DPYD genotype frequencies between cancer patients with good (n = 89) and with poor (n = 39) tolerance of a fluoropyrimidine-based chemotherapy regimen. Applying logistic regression analysis and sliding window approaches we identified the strongest association with fluoropyrimidine-related grade III and IV toxicity for the non-synonymous polymorphism c.496A>G (p.Met166Val). We then confirmed our initial results using an independent sample of 53 individuals suffering from drug-adverse-effects. The combined odds ratio calculated for 92 toxicity cases was 4.42 [95% CI 2.12–9.23]; p (trend)<0.001; p (corrected) = 0.001; the attributable risk was 56.9%. Comparing tumor-type matched sets of samples, correlation of c.496A>G with toxicity was particularly present in patients with gastroesophageal and breast cancer, but did not reach significance in patients with colorectal malignancies. Our results show compelling evidence that, at least in distinct tumor types, a common DPYD polymorphism strongly contributes to the occurrence of fluoropyrimidine-related drug adverse effects. Carriers of this variant could benefit from individual dose adjustment of the fluoropyrimidine drug or alternate therapies.
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影响因子：
3.4
作者：
Magne, Nicolas;Etienne-Grimaldi, Marie-Christine;Milano, Gerard
通讯作者：
Milano, Gerard
影响因子：
3.1
作者：
Diasio, RB;Johnson, MR
通讯作者：
Johnson, MR
影响因子：
11.5
作者：
Largillier, Rmy;Etienne-Grimaldi, Marie-Christine;Milano, Gerard
通讯作者：
Milano, Gerard
DOI：
10.1097/00008571-200004000-00002
发表时间：
2000-04-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
Collie-Duguid, ESR;Etienne, MC;McLeod, HL
通讯作者：
McLeod, HL
影响因子：
5.7
作者：
Morel, Alain;Boisdron-Celle, Michele;Gamelin, Erick
通讯作者：
Gamelin, Erick