奥沙利铂在消化道肿瘤患者中药物相关基因单核苷酸多态性及化疗不良反应相关性研究

目的：分析我国消化道肿瘤患者奥沙利铂药物相关基因单核苷酸多态性的分布特点，探讨ABCB1、GSTP1、XRCC1基因多态性与奥沙利铂化疗毒性之间的关系，旨在为临床应用提供参考。方法：收集2015年5月至2017年5月在某院使用奥沙利铂化疗，并排除同时行放疗、使用奥沙利铂肝动脉灌注及随访失败患者共112例，采用荧光原位杂交检测法测定铂类药物相关基因位点，采用SPSS 19.0统计软件对的基因型分布进行χ²检验，判断等位基因频率分布是否符合Hardy-Weinberg平衡，收集患者相关信息及化疗不良反应，使用χ²检验和Fisher精确检验分析基因多态性与不良反应发生的相关性。结果：共收集112例消化道肿瘤行奥沙利铂静脉化疗患者的4个铂类药物相关基因位点，包括ABCB1T2677G（rs2032582）、ABCB1T3435C（rs1045642）、GSTP1 A313G（rs1695）、XRCC1 T1196C（rs25487），基因型分布均符合Hardy-Weinberg平衡。奥沙利铂静脉化疗共涉及3种化疗方案，经统计分析不同基因型患者使用奥沙利铂化疗后血液毒性及胃肠道反应差异均无显著性意义（P>0.05），GSTP1（313A>G）AA、AG、GG基因型患者使用奥沙利铂化疗后神经毒性的发生率有显著性差异（P<0.05）。结论：本研究纳入的消化道肿瘤患者的奥沙利铂药物相关基因位点单核苷酸多态性的分布基本与药物基因组学数据库中的中国汉族人群的基因频率基本相符，基因多态性与奥沙利铂化疗毒性反应的相关性研究结果不尽相同，亟需进行多中心联合研究以及对机制的深入研究以期更好地预测铂类药物化疗的毒性反应，辅助精准药物治疗，从而实现患者化疗药物的个体化选择。

Singlenucleotide polymorphism of oxaliplatin related genes in digestive tract tumors and the correlation of oxaliplatin chemotherapy adverse reactions

OBJECTIVE To analyze the distribution characteristics of single nucleotide polymorphisms(SNPs) of oxaliplatin in patients with digestive tract cancer in China, and to explore the relationship between ABCB1, GSTP1 and XRCC1 gene polymorphisms and oxaliplatin chemotherapy toxicity.METHODS A total of 112 patients with digestive tract tumors who were tested for platinum-related genes in our hospital from May 2015 to May 2017 were enrolled. Fluorescence in situ hybridization assay was used to detect platinum-related drug loci. SPSS19 was used to performed a χ² test on the genotype distribution to determine whether the allelic frequency distribution was consistent with the Hardy-Weinberg equilibrium; The information about the oxaliplatin intravenous chemotherapy and the adverse reactions of chemotherapy were collected in our hospital. The χ² test and Fisher's exact test were used to analyze the association between gene polymorphism and adverse reactions. RESULTS Four platinum-related loci, including ABCB1T2677G (rs 2032582), ABCB1T3435C (rs 1045642), GSTP1 A313G (rs 1695), and XRCC1 T1196C (rs 25487), were collected from 112 patients with gastrointestinal cancer undergoing oxaliplatin intravenous chemotherapy. The distribution was consistent with the Hardy-Weinberg equilibrium. Oxaliplatin intravenous chemotherapy involved three chemotherapy regimens. Statistical analysis showed that there was no significant difference in hematological toxicity and gastrointestinal reactions between patients with different genotypes treated with oxaliplatin (P>0.05). GSTP1(313A>G) patients with AA, AG and GG genotypes had statistically significant difference in the incidence of neurotoxicity after oxaliplatin chemotherapy (P<0.05). CONCLUSION The distribution of SNPs in platinum-related drug loci in patients with digestive tract tumors in this study is basically consistent with the gene frequency of Chinese Han population in the Pharmacogenetics and Pharmacogenomics Knowledge Base. The results of the correlation study on the toxicity of oxaliplatin chemotherapy varied. Multi-center joint study and in-depth study on mechanism are urgently needed to better predict the toxicity of platinum-based chemotherapy and guide precise drug therapy, so as to realize the individualized selection of chemotherapy drugs for patients.