Related Experiment Video
Updated: May 22, 2026
Endobronchial Ultrasound-guided Intratumoral Injection of Cisplatin for the Treatment of Isolated Mediastinal Recurrence of Lung Cancer
Published on: February 12, 2017
Association of CASP3 polymorphism with hematologic toxicity in patients with advanced non-small-cell lung carcinoma
Shaohua Gu1, Qihan Wu, Xueying Zhao
1State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes for Biomedical Sciences, Fudan University, Shanghai, China.
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). A MALDI-TOF mass spectrometer was used for genotyping 10 polymorphisms of eight apoptosis-related genes, including BCL2 rs1801018, rs1564483, rs2279115, BAX rs4645878, caspase (CASP3) rs6948, CASP8 rs3834129, CASP10 rs13006529, 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 advanced NSCLC patients treated with platinum-based chemotherapy were evaluated. The CASP3 rs6948 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 a Bonferroni correction. The function of this single nucleotide polymorphism in gene expression was also investigated. Quantitative PCR showed that individuals with the C allele had lower levels of CASP3 transcripts in peripheral blood lymphocytes. Luciferase reporter assays showed that the minor C allele significantly decreased the reporter gene expression level. In addition, the TNFα rs1800629 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 that CASP3 rs6948 might influence CASP3 expression and be associated with severe hematologic toxicity risk.
Insights
Genetic variations in apoptosis-related genes impact chemotherapy outcomes. The CASP3 rs6948 polymorphism is linked to reduced severe hematologic toxicity in non-small-cell lung cancer patients receiving platinum-based treatment.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Apoptosis is crucial for cell death in tumors and normal tissues.
- Platinum-based chemotherapy is a standard treatment for advanced non-small-cell lung cancer (NSCLC).
- Genetic variations may influence treatment response and toxicity.
Purpose of the Study:
- To investigate the association between genetic polymorphisms in apoptosis-related genes and outcomes of platinum-based chemotherapy in advanced NSCLC patients.
- To identify specific genetic markers predicting chemotherapy toxicity and efficacy.
Main Methods:
- Genotyping of 10 polymorphisms in eight apoptosis-related genes (BCL2, BAX, CASP3, CASP8, CASP10, TNFα, MIF) using MALDI-TOF mass spectrometry.
- Evaluating associations between single nucleotide polymorphisms (SNPs) and clinical outcomes in 445 advanced NSCLC patients.
- Functional studies including quantitative PCR and luciferase reporter assays to assess SNP impact on gene expression.
Main Results:
- The CASP3 rs6948 polymorphism was significantly associated with reduced severe hematologic toxicity in a dose-dependent manner (P = 0.005).
- C allele carriers of CASP3 rs6948 exhibited lower incidence of severe hematologic toxicity and reduced CASP3 gene expression.
- The TNFα rs1800629 mutant allele was associated with increased gastrointestinal toxicity (P = 0.020).
Conclusions:
- The CASP3 rs6948 polymorphism may influence CASP3 expression and serve as a predictive marker for severe hematologic toxicity risk in NSCLC patients.
- TNFα rs1800629 may be a risk factor for gastrointestinal toxicity in this patient group.
- These findings highlight the potential of pharmacogenetics in personalizing NSCLC treatment.
Related Concept Videos
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...