Common TDP1 Polymorphisms in Relation to Survival among Small Cell Lung Cancer Patients: A Multicenter Study from the International Lung Cancer Consortium.
Common TDP1 Polymorphisms in Relation to Survival among Small Cell Lung Cancer Patients: A Multicenter Study from the International Lung Cancer Consortium.
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DOI：
10.1158/1078-0432.ccr-17-1401
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发表时间：
2017-12-15
期刊：
影响因子：
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通讯作者：
Chen C
中科院分区：
文献类型：
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作者：
Lohavanichbutr P;Sakoda LC;Amos CI;Arnold SM;Christiani DC;Davies MPA;Field JK;Haura EB;Hung RJ;Kohno T;Landi MT;Liu G;Liu Y;Marcus MW;O'Kane GM;Schabath MB;Shiraishi K;Slone SA;Tardón A;Yang P;Yoshida K;Zhang R;Zong X;Goodman GE;Weiss NS;Chen C
DNA拓扑异构酶抑制剂通常用于治疗小细胞肺癌（SCLC）。酪氨酸-DNA磷酸二酯酶（TDP1）可修复这类药物引起的DNA损伤，因此可能影响治疗结果。在这项研究中，我们研究了常见的TDP1单核苷酸多态性（snp）是否与SCLC患者的总生存率相关。国际肺癌协会（ILCCO）对来自10项研究的890例患者的两个TDP1 snp （rs942190和rs2401863）进行分析。Kaplan-Meier法和Cox回归分析用于评估基因型与诊断后36个月总死亡率的相关性，校正年龄、性别、种族和肿瘤分期。rs942190小等位基因（GG）纯合子患者的生存率低于携带AA等位基因的患者，风险比（HR）为1.36(95%可信区间（CI）： 1.08 ~ 1.72， p值=0.01)，而携带AG基因型患者的风险比（HR=1.04, 95% CI:0.84 ~ 1.29， p值=0.72）与生存率无相关性。对于rs2401863，小等位基因纯合子（CC）的患者往往比携带AA等位基因的患者生存率更高（HR=0.79, 95% CI: 0.61-1.02， p值=0.07）。基因型组织表达（GTEx）项目、DNA元件百科全书（ENCODE）和ePOSSUM web应用程序的结果支持rs942190的潜在功能。我们发现rs942190 GG基因型与SCLC患者相对较差的生存率相关。需要进一步的研究来证实这一结果，并确定该基因型是否可以作为DNA拓扑异构酶抑制剂治疗效果的预测标志物。
DNA topoisomerase inhibitors are commonly used for treating small cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common TDP1 single nucleotide polymorphisms (SNPs) are associated with overall survival among SCLC patients. Two TDP1 SNPs (rs942190 and rs2401863) were analyzed in 890 patients from 10 studies in the International Lung Cancer Consortium (ILCCO). The Kaplan-Meier method and Cox regression analyses were used to evaluate genotype associations with overall mortality at 36 months post-diagnosis, adjusting for age, sex, race, and tumor stage. Patients homozygous for the minor allele (GG) of rs942190 had poorer survival compared to those carrying AA alleles, with a hazard ratio (HR) of 1.36 (95% confidence interval (CI): 1.08–1.72, p-value=0.01), but no association with survival was observed for patients carrying the AG genotype (HR=1.04, 95% CI:0.84–1.29, p-value=0.72). For rs2401863, patients homozygous for the minor allele (CC) tended to have better survival than patients carrying AA alleles (HR=0.79, 95% CI: 0.61–1.02, p-value=0.07). Results from the Genotype Tissue Expression (GTEx) Project, the Encyclopedia of DNA Elements (ENCODE), and the ePOSSUM web application support the potential function of rs942190. We found the rs942190 GG genotype to be associated with relatively poor survival among SCLC patients. Further investigation is needed to confirm the result and to determine whether this genotype may be a predictive marker for treatment efficacy of DNA topoisomerase inhibitors.