Study On The Association Between CASP Family Gene Mutation And Platinum - Containing Chemotherapy In Advanced Non - Small Cell Lung Cancer

The products of caspase genes (such as caspase3-12which can elevate endonuclease activity and induce apoptosis) are important regulators and executioners in apoptosis process and play a crucial role in the development and progression of cancer and the same on chemotherapy cytotoxicity of cancer. In this research, we explored whether caspase genes’ single nucleotide polymorphisms (SNPs) can modulate incidence of adverse events and survivals in advanced NSCLC patients treated with first-line platinum-based chemotherapy.40SNPs of6apoptosis-related caspase genes were genotyped in1004patients with advanced NSCLC treated with platinum-based chemotherapy regimens (including221treated with cisplain-navelbine,195with cisplatin-gemcitabine,190with carboplatin-Paclitaxel, and108with cisplatin-paclitaxel). Information about grade3or4overall toxicity, gastrointestinal toxicity (nausea/vomiting) and hematologic toxicity (leukocytopenia, agranulocytosis, anemia, thrombocytopenia) was available, as well as objective response and survival (OS and PFS). The association between the outcome and genotyping database by special date analysis software was assessed.There were several polymorphisms of Caspase genes significantly associated with risk of grade3or4toxicity and treated response, as well as OS/PFS on overall platinum-based treatment. The variant homozygotes of CASP12rs506601and heterozygotes of CASP7rs12416109polymorphisms exhibited strong influence on the occurrence of severe anemia (adjusted OR:5.72, P=0.001and adjusted OR:7.70, P=0.001) respectively. On the other hand, the variant homozygotes of CASP8rs12990906was associated with significantly decreased risk to severe overall toxicity (adjusted OR:0.54, P=0.004) undering a dominant model and allelic analysis (P=0.017, P=0.003respectively), gastrointestinal toxicity (adjusted OR:0.47, P=0.034) and hematological toxicity (adjusted OR:0.58, P=0.016). Heterozygotes of CASP7rs2227310and rs4353229as well as rsl2415607variant allele were strongly associated with a better OS of NSCLC (adjusted HR:0.73, P=0.003; HR:0.72, P=0.002; and HR:0.76, P=0.009, respectively). In stratification analysis by chemotherapy regiments, we also found several evident correlations between Caspase gene polymorphisms and toxicity:the GA and AA genotypes of rs12613347showed significantly protective effect to overall toxicity (adjusted OR:0.60, P=0.010) and gastrointestinal toxicity (adjusted OR:0.58, P=0.008) in patients treated with Cisplatin under a dominant model; and the variant heterozygotes of rs4645983had the adverse effect in patients treated with Carboplatin (P=0.001, P=0.003, respectively), we also found that some other SNPs, including CASP8rs3769821, rs3769825, rs7608692and CASP10rs12613347were significantly associated with severe toxicity risks in some subgroups such as in non-smoker patients, patients with Adenocarcinoma, On the other hand, treated with paclitaxel, individuals carrying variant allele of CASP7rs2227310, rs4353229and rs12415607had significantly improved OS (HR:0.60, P=0.008; HR:0.58, P=0.004; and HR:0.61, P=0.010; respectively). Consistent with the results in single SNP analysis, we found much evident correlations between haplotypes and severe overall toxicity in all the3blocks of CASP8and CASP10, especially for block1of CASP8(Ptrend=6.86×10-4), haplotypes A/A and G/G had a protect effect on severe overall toxicity compared with the most common haplotype A/G (OR=0.73, P=0.028; OR=0.71, P=2.74×10-4, respectively). Some significant associations were also found between the haplotypes of these3blocks with hematological toxicity, moreover, survivals of patients with one or two copies of the most common haplotypes A-G-A-A-G-A-G-C-G of CASP7blockl and A-A-G-G-A of CASP7block2were significantly longer than that of patients with zero copy (19.7versus16.2and19.4versus15.8months; and adjust P=0.001for both, respectively)We also analyzed mRNA expression by genotypes of CASP gene SNPs based on the transcript expression profiling data of270lymphoblastoid cell lines from HapMap samples (including90CEU samples,90CHB/JPT samples and90YRI samples). Functional assay revealed that CASP8rs3754935, rs3769827rs3769825, rs3769821; CASP7rs12415607, rs1127687, rs6585241and rs11196449were significantly correlated with the expression level of CASP genes in HapMap lymphoblastoid cell lines.Conclusions:Our study, for the first time, provides evidence that the genetic polymorphisms in the Caspase pathway genes such as CASP7and CASP8may have an impact on the toxicity, objective response and suvival outcomes of platinum-based chemotherapy in Chinese advanced NSCLC patients, and may play the predictive role as prognostic biomarkers for chemotherapy, if validated in larger and further studies.