Combinations of Polymorphisms in Genes Involved in the 5-Fluorouracil Metabolism Pathway Are Associated with Gastrointestinal Toxicity in Chemotherapy-Treated Colorectal Cancer Patients
Combinations of Polymorphisms in Genes Involved in the 5-Fluorouracil Metabolism Pathway Are Associated with Gastrointestinal Toxicity in Chemotherapy-Treated Colorectal Cancer Patients
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DOI：
10.1158/1078-0432.ccr-11-0304
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发表时间：
2011-06-01
影响因子：
11.5
通讯作者：
Poulsen, Henrik E.
中科院分区：
文献类型：
--
作者：
Afzal, Shoaib;Gusella, Milena;Poulsen, Henrik E.
目的：本研究的目的是调查是否参与5-氟尿嘧啶（5-FU）的药代动力学和药效学的基因编码的蛋白质的多态性的特定组合与治疗引起的toxicity.Experimental设计的风险增加：我们分析了两个队列的161和340例患者，探索和验证队列，分别。所有患者均接受以5-FU为基础的辅助化疗。我们分析了13个功能多态性，并应用了四重分析策略，使用个体多态性，单倍型，表型酶活性或表达分类的基础上组合的功能多态性在特定的基因。结果：与亚甲基四氢叶酸还原酶（MTHFR）低活性相关的等位基因与毒性风险降低相关[OR（探索）0.39（95% CI：0.21-0.71，P = 0.003），OR（验证）0.63（95% CI：0.41-0.95，P = 0.03）]。MTHFR 1298 A>C和胸苷酸合成酶（TYMS）30-UTR（非翻译区）插入/缺失多态性的特定组合与两个队列中毒性增加显著相关[OR（探索）2.40（95% CI：1.33-4.29，P 0.003），OR（验证）1.81（95% CI：1.18-2.79，P = 0.007）]。特定的组合也与增加的累积发病率和早期发生的严重毒性在treatment.Conclusions：我们的研究结果表明，MTHFR活性和特定的MTHFR 1298 A>C和TYMS 30-UTR插入/缺失多态性的组合是可能的预测5-FU治疗相关的毒性。临床癌症研究; 17（11）; 3822-9。（C）2011年《非洲标准化评论》。
Purpose: The purpose of this study was to investigate whether specific combinations of polymorphisms in genes encoding proteins involved in 5-fluorouracil (5-FU) pharmacokinetics and pharmacodynamics are associated with increased risk of treatment-induced toxicity.Experimental Design: We analyzed two cohorts of 161 and 340 patients, the exploration and validation cohort, respectively. All patients were treated similarly with 5-FU-based adjuvant chemotherapy. We analyzed 13 functional polymorphisms and applied a four-fold analysis strategy using individual polymorphisms, haplotypes, and phenotypic enzyme activity or expression classifications based on combinations of functional polymorphisms in specific genes. Furthermore, multifactor dimensionality reduction analysis was used to identify a genetic interaction profile indicating an increased risk of toxicity.Results: Alleles associated with low activity of methylene tetrahydrofolate reductase (MTHFR) were associated with decreased risk of toxicity [OR(Exploration) 0.39 (95% CI: 0.21-0.71, P = 0.003), OR(Validation) 0.63 (95% CI: 0.41-0.95, P = 0.03)]. A specific combination of the MTHFR 1298A>C and thymidylate synthase (TYMS) 30-UTR (untranslated region) ins/del polymorphisms was significantly associated with increased toxicity in both cohorts [OR(Exploration) 2.40 (95% CI: 1.33-4.29, P 0.003), OR(Validation) 1.81 (95% CI: 1.18-2.79, P = 0.007)]. The specific combination was also associated with increased cumulative incidence and earlier occurrence of severe toxicity during treatment.Conclusions: Our results indicate that MTHFR activity and a specific combination of the MTHFR 1298A>C and TYMS 30-UTR ins/del polymorphisms are possible predictors of 5-FU treatment-related toxicity. Clin Cancer Res; 17(11); 3822-9. (C)2011 AACR.