Association Between CASP8 and CASP10 Polymorphisms and Toxicity Outcomes With Platinum-Based Chemotherapy in Chinese Patients With Non-Small Cell Lung Cancer
Association Between CASP8 and CASP10 Polymorphisms and Toxicity Outcomes With Platinum-Based Chemotherapy in Chinese Patients With Non-Small Cell Lung Cancer
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DOI：
10.1634/theoncologist.2011-0419
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发表时间：
2012-12-01
期刊：
影响因子：
5.8
通讯作者：
Jin, Li
中科院分区：
文献类型：
--
作者：
Qian, Ji;Qu, Hui-Qi;Jin, Li
Caspase-8和Caspase-10在肿瘤发生和化疗疗效中都发挥着重要作用。在这项研究中，我们旨在全面评估caspase-8(CASP8)和caspase-10(CASP10)基因的单核苷酸多态性(SNPs)与一线铂类化疗对晚期非小细胞肺癌(NSCLC)患者毒性结果的关系。我们对663例接受铂类化疗的晚期非小细胞肺癌患者CASP8和CASP10的13个Tag SNPs进行了基因分型。在由279名患者组成的发现组中确定了SNPs与化疗毒性结果之间的关联，然后在由384名患者组成的独立组中进行了验证。在发现和验证集合中，CASP8 rs12990906的变异纯合子和CASP8的rs3769827和CASP10的rs11674246和rs3731714的杂合子总体上严重毒性的风险显著较低。然而，只有与rs12990906变异的关联在血液学毒性风险验证集中被重复。在分层分析中，我们发现其他一些SNP，包括rs3769821、rs3769825、rs7608692和rs12613347，在一些亚组中与严重的毒性风险显著相关，例如在非吸烟患者、腺癌患者和接受顺铂联合治疗的患者中。单倍型分析也发现了一致的结果。我们的结果提供了新的证据，表明CASP8和CASP10的多态可能调节接受铂类化疗的晚期非小细胞肺癌患者的毒性结局。如果得到证实，这些发现将促进基于基因的铂类化疗方案的选择。肿瘤学家2012；17：1551-1561
Caspase-8 and caspase-10 play crucial roles in both cancer development and chemotherapy efficacy. In this study, we aimed to comprehensively assess single nucleotide polymorphisms (SNPs) of the caspase-8 (CASP8) and caspase-10 (CASP10) genes in relation to toxicity outcomes with first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). We genotyped 13 tag SNPs of CASP8 and CASP10 in 663 patients with advanced NSCLC treated with platinum-based chemotherapy regimens. Associations between SNPs and chemotherapy toxicity outcomes were identified in a discovery set of 279 patients and then validated in an independent set of 384 patients. In both the discovery and validation sets, variant homozygotes of CASP8 rs12990906 and heterozygotes of CASP8 rs3769827 and CASP10 rs11674246 and rs3731714 had a significantly lower risk for severe toxicity overall. However, only the association with the rs12990906 variant was replicated in the validation set for hematological toxicity risk. In a stratified analysis, we found that some other SNPs, including rs3769821, rs3769825, rs7608692, and rs12613347, were significantly associated with severe toxicity risk in some subgroups, such as in nonsmoking patients, patients with adenocarcinoma, and patients treated with cisplatin combinations. Consistent results were also found in haplotype analyses. Our results provide novel evidence that polymorphisms in CASP8 and CASP10 may modulate toxicity outcomes in patients with advanced NSCLC treated with platinum-based chemotherapy. If validated, the findings will facilitate the genotype-based selection of platinum-based chemotherapy regimens. The Oncologist 2012;17:1551-1561