State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Science, Fudan University, Handan Road, Shanghai 200433, China.
Oncologist. 2012;17(12):1551-61. doi: 10.1634/theoncologist.2011-0419. Epub 2012 Jul 27.
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.
半胱氨酸天冬氨酸蛋白酶 8（CASP8）和半胱氨酸天冬氨酸蛋白酶 10（CASP10）在癌症的发生发展及化疗疗效中均发挥着重要作用。本研究旨在全面评估晚期非小细胞肺癌（NSCLC）患者一线铂类化疗相关毒性结局与 CASP8 和 CASP10 基因单核苷酸多态性（SNP）的相关性。我们对 663 例接受铂类化疗方案治疗的晚期 NSCLC 患者的 CASP8 和 CASP10 基因的 13 个标签 SNP 进行了基因分型。在包含 279 例患者的发现集和包含 384 例患者的验证集中，鉴定了 SNP 与化疗毒性结局之间的相关性。在发现集和验证集中，CASP8 rs12990906 变异纯合子和杂合子及 CASP10 rs11674246 和 rs3731714 杂合子均显著降低了整体严重毒性的风险。然而，仅 rs12990906 变异在验证集中与血液学毒性风险相关。在分层分析中，我们发现某些其他 SNP（包括 rs3769821、rs3769825、rs7608692 和 rs12613347）在某些亚组（如非吸烟患者、腺癌患者和接受顺铂联合治疗的患者）中与严重毒性风险显著相关。单体型分析也得出了一致的结果。本研究结果提供了新的证据，表明 CASP8 和 CASP10 中的多态性可能调节接受铂类化疗的晚期 NSCLC 患者的毒性结局。如果得到验证，这些发现将有助于基于基因型选择铂类化疗方案。
