title: Association between CASP8 and CASP10 polymorphisms and toxicity outcomes with platinum-based chemotherapy in Chinese patients with non-small cell lung cancer.
abstract: 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.
authors: State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Science, Fudan University, Handan Road, Shanghai 200433, China.
authors: Ji
authors: J
authors: Qian
authors: Hui-Qi
authors: HQ
authors: Qu
authors: Lixin
authors: L
authors: Yang
authors: Ming
authors: M
authors: Yin
authors: Qiming
authors: Q
authors: Wang
authors: Shaohua
authors: S
authors: Gu
authors: Qihan
authors: Q
authors: Wu
authors: Xueying
authors: X
authors: Zhao
authors: Wenting
authors: W
authors: Wu
authors: Junjie
authors: J
authors: Wu
authors: Xiaoming
authors: X
authors: Tan
authors: Wenqing
authors: W
authors: Chen
authors: Haijian
authors: H
authors: Wang
authors: Jiucun
authors: J
authors: Wang
authors: Weiwei
authors: W
authors: Fan
authors: Hongyan
authors: H
authors: Chen
authors: Baohui
authors: B
authors: Han
authors: Daru
authors: D
authors: Lu
authors: Qingyi
authors: Q
authors: Wei
authors: Li
authors: L
authors: Jin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D044466:Asian People / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D053455:Caspase 10 / Q000235:genetics*; D053181:Caspase 8 / Q000235:genetics*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010984:Platinum / Q000008:administration & dosage / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide
chemical_list: D010984:Platinum; C505530:CASP8 protein, human; D053455:Caspase 10; D053181:Caspase 8; C506438:CASP10 protein, human; D002945:Cisplatin