Association ofCASP3polymorphism with hematologic toxicity in patients with advanced non‐small‐cell lung carcinoma treated with platinum‐based chemotherapy

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Abstract
Apoptosis is a distinct mode of cell death that is responsible for the deletion of cells in tumors and in normal tissues. We pursued a pathway‐based approach to investigate the association of potentially functional genetic polymorphisms of the corresponding genes with the outcomes of platinum‐based chemotherapy in advanced non‐small‐cell lung cancer (NSCLC). AMALDI‐TOFmass spectrometer was used for genotyping 10 polymorphisms of eight apoptosis‐related genes, includingBCL2rs1801018, rs1564483, rs2279115,BAXrs4645878, caspase (CASP3) rs6948,CASP8rs3834129,CASP10rs13006529, rs3900115, tumor necrosis factor α (TNFα) rs1800629, and macrophage migration inhibitory factor (MIF) rs755622. The associations between these single nucleotide polymorphisms and the outcomes of 445 advancedNSCLCpatients treated with platinum‐based chemotherapy were evaluated. TheCASP3rs6948 polymorphism was most significantly associated with hematologic toxicity in a dose‐dependent manner. The incidence of severe hematologic toxicity was significantly lower in C allele carriers (P = 0.005; odds ratio = 0.524; 95% confidence interval = 0.333–0.824) and still significant after aBonferroni correction. The function of this single nucleotide polymorphism in gene expression was also investigated. QuantitativePCRshowed that individuals with theCallele had lower levels ofCASP3transcripts in peripheral blood lymphocytes. Luciferase reporter assays showed that the minorCallele significantly decreased the reporter gene expression level. In addition, theTNFαrs1800629 mutant allele significantly elevated gastrointestinal toxicity (P = 0.020; odds ratio = 3.020; 95% confidence interval = 1.188–7.676), when compared to the wild‐type homozygote. No other association was found. In conclusion, for the first time, our study suggests thatCASP3rs6948 might influenceCASP3expression and be associated with severe hematologic toxicity risk. (Cancer Sci, doi: 10.1111/j.1349‐7006.2012.02323.x, 2012)

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