title: Genetic Polymorphisms in the Apoptosis-Associated Gene CASP3 and the Risk of Lung Cancer in Chinese Population.
abstract: Caspase-3 (CASP3) plays a central role in executing cell apoptosis and thus in carcinogenesis. We previously investigated the relationship between functional polymorphisms in CAPS3 829 A>C and 20541 C>T and risk of esophageal squamous cell carcinoma. However little is known about the role of CASP3 variants in susceptibility to lung cancer. To figure out the contribution of CASP3 polymorphisms to lung cancer risk, genotypes of 1000 lung cancer patients and 1000 controls were conducted by RFLP-PCR (restriction fragment length polymorphism PCR). The transcriptional activity of CASP3 829 A>C was examined by dual luciferase reporter assay. Logistic regression was applied to calculate Odds ratios (OR) and 95% confidence intervals (95%CI). Compared with CASP3 829 AA genotype, AC and CC genotype had significantly increased risk of lung cancer with OR (95% CI) of 1.33 (1.09-1.63) and 1.55 (1.19-2.01), respectively. To further explore the possible impact of 829 A>C SNP on CASP3 transcriptional activity, we detected the dual luciferase activity of PGL3-promoter vectors containing 829A or 829C alleles in lung cancer cell lines and found that report gene expressions driven by 829A containing CASP3 promoter were 1.64-fold, 1.94-fold greater than those driven by CASP3 829C containing counterparts in A549 and NCI-H1975 cells (P<0.001). When stratified by sex, the significantly increased risk associated with CASP3 829 AC or CC genotype was obviousl in males with OR (95% CI) of 1.42 (1.11-1.81) and 1.51 (1.11-2.05), but not in females. When stratified by age, we found that CASP3 829 AC or CC genotype contributed to the risk of lung cancer in youngers with OR (95% CI) of 2.73 (1.71-4.34) and 4.02 (2.20-7.32), but not in elder group. We also found that 829AC or 829CC genotype increased adenocarcinoma risk compared with the AA genotype with OR (95%CI) of 1.33 (1.04-1.70) and 1.51(1.09-2.07). CASP3 polymorphism and smoking interaction was demonstrated related with higher risk of lung cancer. We achieved that the CASP3 829AC or 829CC genotypes was associated with increased risk of lung cancer in both non-smoker and smoker group, with OR (95%CI) of 1.48 (1.08-2.02) and OR (95%CI) of 1.64 (1.09-2.48) among non-smokers and OR (95%CI) of 2.68 (1.89-3.81) and OR (95%CI) of 3.23 (2.21-4.92) among smokers, respectively. Among carriers with 20541CT genotype, the ORs (95%CI) of risk with lung cancer for smoking <16, 16-28, or > 28 pack-years were 1.16(0.65-2.07), 1.66(0.98-2.82) and 5.01(3.31-7.58) compared with the 20541CC carriers. And among carriers with 20541CT genotype, the ORs (95%CI) were 0.86(0.33-2.20), 2.12(0.83-5.41) and 5.71(2.68-12.16). These results highlight apoptosis-related CASP3 as an important gene in human carcinogenesis and further support the CASP3 polymorphisms confer to the lung cancer susceptibility.
authors.affiliation: Department of Molecular Genetics, College of Life Science, North China University of Science and Technology, Tangshan, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Molecular Genetics, College of Life Science, North China University of Science and Technology, Tangshan, China.|Department of Epidemiology, School of Public Health, North China University of Science and Technology, Tangshan, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Molecular Genetics, College of Life Science, North China University of Science and Technology, Tangshan, China.
authors.forename: Hongge
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Epidemiology and Biostatistics, and State Key Laboratory of Environment Health (Incubation), MOE (Ministry of Education) Key Laboratory of Environment & Health, Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Lixuan
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Molecular Genetics, College of Life Science, North China University of Science and Technology, Tangshan, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Chemotherapy and Radiotherapy, Tangshan Gongren Hospital, Tangshan, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Molecular Genetics, College of Life Science, North China University of Science and Technology, Tangshan, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000072283:A549 Cells; D000368:Aged; D053148:Caspase 3 / Q000096:biosynthesis / Q000235:genetics*; D002681:China; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; C505407:CASP3 protein, human; D053148:Caspase 3