Polymorphisms in the CASPASE genes and survival in patients with early-stage non-small-cell lung cancer.

PURPOSE This study was conducted to determine the impact of potentially functional polymorphisms in the CASPASE (CASP) genes on the survival of early-stage non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS Four hundred eleven consecutive patients with surgically resected NSCLC were enrolled. Nine potentially functional polymorphisms in the CASP3, CASP7, CASP8, CASP9, and CASP10 genes were investigated. The genotype and haplotype associations with overall survival (OS) and disease-free survival (DFS) were analyzed. RESULTS Patients with the rs2227310 GG genotype had a significantly decreased OS and DFS compared with patients with the CC + CG genotype (adjusted hazard ratio [aHR] for OS, 1.67; 95% CI, 1.19 to 2.35; P = .003; aHR for DFS, 1.62; 95% CI, 1.19 to 2.22; P = .002). The rs4645981C>T genotype also had a significant effect on OS and DFS (under a recessive model; aHR for OS, 2.00; 95% CI, 1.04 to 3.85; P = .04; aHR for DFS, 2.76; 95% CI, 1.58 to 4.80; P = .0003). When the rs2227310 and rs4645981 genotypes were combined, patients with one or two bad genotypes had worse OS and DFS compared with those who had zero bad genotypes (aHR for OS, 1.75; 95% CI, 1.25 to 2.45; P = .001; aHR for DFS, 1.66; 95% CI, 1.23 to 2.26; P = .001). CONCLUSION The CASP7 rs2227310 and CASP9 rs4645981 polymorphisms may affect survival in early-stage NSCLC. The analysis of these polymorphisms can help identify patients at high risk for a poor disease outcome.

[1]  S. Toyooka,et al.  Adjuvant chemotherapy for completely resected non-small-cell lung cancer. , 2009, Acta medica Okayama.

[2]  Dong Sun Kim,et al.  Polymorphisms in the Caspase7 gene and the risk of lung cancer. , 2009, Lung cancer.

[3]  S. Kam,et al.  Polymorphisms in the FAS and FASL Genes and Survival of Early Stage Non–small Cell Lung Cancer , 2009, Clinical Cancer Research.

[4]  Hui Zhao,et al.  Genetic variants and haplotypes of the caspase‐8 and caspase‐10 genes contribute to susceptibility to cutaneous melanoma , 2008, Human mutation.

[5]  S. Kam,et al.  Identification of polymorphisms in the Caspase‐3 gene and their association with lung cancer risk , 2008, Molecular carcinogenesis.

[6]  Changqing Zeng,et al.  Reply to ”A promoter polymorphism in the CASP8 gene is not associated with cancer risk” , 2008, Nature Genetics.

[7]  M. González-Gay,et al.  Caspase 7 influences susceptibility to rheumatoid arthritis. , 2007, Rheumatology.

[8]  P. Donnelly,et al.  Replicating genotype–phenotype associations , 2007, Nature.

[9]  Changqing Zeng,et al.  A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers , 2007, Nature Genetics.

[10]  Zhifu Sun,et al.  Gene Expression Profiling on Lung Cancer Outcome Prediction: Present Clinical Value and Future Premise , 2006, Cancer Epidemiology Biomarkers & Prevention.

[11]  Dong Sun Kim,et al.  Polymorphisms in the caspase-8 gene and the risk of lung cancer. , 2006, Cancer genetics and cytogenetics.

[12]  J. Park,et al.  Caspase 9 promoter polymorphisms and risk of primary lung cancer. , 2006, Human molecular genetics.

[13]  P. Bugert,et al.  Association of the CASP10 V410I variant with reduced familial breast cancer risk and interaction with the CASP8 D302H variant. , 2006, Carcinogenesis.

[14]  Sunil Singhal,et al.  Prognostic Implications of Cell Cycle, Apoptosis, and Angiogenesis Biomarkers in Non–Small Cell Lung Cancer: A Review , 2005, Clinical Cancer Research.

[15]  J. Ferlay,et al.  Global Cancer Statistics, 2002 , 2005, CA: a cancer journal for clinicians.

[16]  B. Ponder,et al.  Association of a common variant of the CASP8 gene with reduced risk of breast cancer. , 2004, Journal of the National Cancer Institute.

[17]  G. Salvesen,et al.  The protein structures that shape caspase activity, specificity, activation and inhibition. , 2004, The Biochemical journal.

[18]  Timothy R. Rebbeck,et al.  Assessing the function of genetic variants in candidate gene association studies , 2004, Nature Reviews Genetics.

[19]  Bengt Bergman,et al.  Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. , 2004, The New England journal of medicine.

[20]  J. Minna,et al.  Molecular genetics of lung cancer. , 2003, Seminars in oncology.

[21]  Alexei Degterev,et al.  A decade of caspases , 2003, Oncogene.

[22]  A. Gazdar,et al.  Apoptosis and lung cancer: A review , 2003, Journal of cellular biochemistry.

[23]  W. Travis,et al.  The new World Health Organization classification of lung tumours , 2001, European Respiratory Journal.

[24]  E. Lander,et al.  Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Y. Soini,et al.  Expression of caspases‐3, ‐6 and ‐8 and their relation to apoptosis in non‐small cell lung carcinoma , 2001, International journal of cancer.

[26]  G. Evan,et al.  Proliferation, cell cycle and apoptosis in cancer , 2001, Nature.

[27]  P. Donnelly,et al.  A new statistical method for haplotype reconstruction from population data. , 2001, American journal of human genetics.

[28]  Warren C. Lathe,et al.  Prediction of deleterious human alleles. , 2001, Human molecular genetics.

[29]  S. Lowe,et al.  Apoptosis in cancer. , 2000, Carcinogenesis.

[30]  Martin Raff,et al.  Cell suicide for beginners , 1998, Nature.

[31]  Y. Soini,et al.  Histopathological evaluation of apoptosis in cancer. , 1998, The American journal of pathology.

[32]  N. Thornberry,et al.  Caspases: killer proteases. , 1997, Trends in biochemical sciences.

[33]  C. Mountain,et al.  Revisions in the International System for Staging Lung Cancer. , 1997, Chest.

[34]  E. Alnemri,et al.  Mch3, a novel human apoptotic cysteine protease highly related to CPP32. , 1995, Cancer research.

[35]  C. Thompson,et al.  Apoptosis in the pathogenesis and treatment of disease , 1995, Science.

[36]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[37]  M. Lutter,et al.  Biochemical pathways of caspase activation during apoptosis. , 1999, Annual review of cell and developmental biology.