A Six-Nucleotide Insertion-Deletion Polymorphism in the CASP8 Promoter Associated with Risk and Progression of Bladder Cancer

Purpose: Caspase-8 (CASP8) is a key regulator of apoptosis or programmed cell death, an essential defense mechanism against hyperproliferation and malignancy. We hypothesized that the variants in the CASP8 gene are associated with risk of bladder cancer. Experimental Design: In a hospital-based case-control study of 365 case patients with newly diagnosed bladder transitional cell carcinoma and 368 cancer-free controls frequency-matched by age and sex, we genotyped the functional -652 6N ins/del polymorphism (rs3834129) in the promoter of CASP8 and assessed its associations with risk of bladder cancer and interaction with tobacco smoking. Results: A significant decreased risk of bladder cancer was found for the CASP8 -652 6N ins/del (adjusted odds ratio, 0.72; 95% confidence interval, 0.53-0.99) and del/del (odds ratio, 0.37; 95% confidence interval, 0.18-0.77) genotypes. Furthermore, a significant additive interaction between CASP8 polymorphism and tobacco smoking on bladder cancer risk was observed. Conclusions: These results suggested that the CASP8 -652 6N ins/del polymorphism is involved in etiology of bladder cancer and thus may be a marker for genetic susceptibility to bladder cancer in Chinese populations. Larger studies are warranted to validate our findings.

[1]  A. Lophatananon,et al.  CASP8 D302H and meningioma risk: an analysis of five case-control series. , 2009, Cancer letters.

[2]  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.

[3]  A. Cox,et al.  The CASP8 -652 6N del promoter polymorphism and breast cancer risk: a multicenter study , 2008, Breast Cancer Research and Treatment.

[4]  Q. Wei,et al.  A Novel Functional Polymorphism C1797G in the MDM2 Promoter Is Associated with Risk of Bladder Cancer in a Chinese Population , 2008, Clinical Cancer Research.

[5]  C. Mahotka,et al.  Caspase-8 and its inhibitors in RCCs in vivo: the prominent role of ARC , 2008, Apoptosis.

[6]  A. Lophatananon,et al.  The Common D302H Variant of CASP8 Is Associated with Risk of Glioma , 2008, Cancer Epidemiology Biomarkers & Prevention.

[7]  P. Broderick,et al.  CASP8 variants D302H and −652 6N ins/del do not influence the risk of colorectal cancer in the United Kingdom population , 2008, British Journal of Cancer.

[8]  B. Henderson,et al.  A promoter polymorphism in the CASP8 gene is not associated with cancer risk , 2008, Nature Genetics.

[9]  J. Opferman,et al.  Apoptosis in the development of the immune system , 2008, Cell Death and Differentiation.

[10]  N. Socci,et al.  A Polymorphism in HDM2 (SNP309) Associates with Early Onset in Superficial Tumors, TP53 Mutations, and Poor Outcome in Invasive Bladder Cancer , 2007, Clinical Cancer Research.

[11]  N. Malats,et al.  Epidemiology of urinary bladder cancer: from tumor development to patient’s death , 2007, World Journal of Urology.

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

[13]  Jaana M. Hartikainen,et al.  A common coding variant in CASP8 is associated with breast cancer risk , 2007, Nature Genetics.

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

[15]  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.

[16]  Xue-Ru Wu.  Urothelial tumorigenesis: a tale of divergent pathways , 2005, Nature Reviews Cancer.

[17]  P. Bugert,et al.  Re: Association of a common variant of the CASP8 gene with reduced risk of breast cancer. , 2005, Journal of the National Cancer Institute.

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

[19]  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.

[20]  N. Rigotti,et al.  The fallacy of “light” cigarettes , 2004, BMJ : British Medical Journal.

[21]  Wafik S El-Deiry,et al.  TRAIL and apoptosis induction by TNF-family death receptors , 2003, Oncogene.

[22]  P. Brennan,et al.  Gene-environment interaction and aetiology of cancer: what does it mean and how can we measure it? , 2002, Carcinogenesis.

[23]  M. Hengartner.  The biochemistry of apoptosis , 2000, Nature.

[24]  G. Steineck,et al.  Epidemiology and Etiology of Premalignant and Malignant Urothelial Changes , 2000, Scandinavian journal of urology and nephrology. Supplementum.

[25]  Lawrence D. True,et al.  The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder , 1998 .

[26]  J. Blenis,et al.  Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade , 1998, Current Biology.

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

[28]  S. Hecht,et al.  Tobacco smoke carcinogens and breast cancer , 2002, Environmental and molecular mutagenesis.

[29]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[30]  F. Mostofi,et al.  The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. , 1998, The American journal of surgical pathology.