Associations between NBS1 polymorphisms, haplotypes and smoking-related cancers

• Published in: Carcinogenesis (New York) Vol. 31; no. 7; pp. 1264 - 1271
• Main Authors: Park, Sungshim L., Bastani, Delara, Goldstein, Binh Y., Chang, Shen-Chih, Cozen, Wendy, Cai, Lin, Cordon-Cardo, Carlos, Ding, Baoguo, Greenland, Sander, He, Na, Hussain, Shehnaz K., Jiang, Qingwu, Lee, Yuan-Chin A., Liu, Simin, Lu, Ming-Lan, Mack, Thomas M., Mao, Jenny T., Morgenstern, Hal, Mu, Li-Na, Oh, Sam S., Pantuck, Allan, Papp, Jeanette C., Rao, Jianyu, Reuter, Victor E., Tashkin, Donald P., Wang, Hua, You, Nai-Chieh Y., Yu, Shun-Zhang, Zhao, Jin-Kou, Zhang, Zuo-Feng
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.07.2010
• Subjects: Adolescent; Adult; Aged; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Case-Control Studies; Cell Cycle Proteins - genetics; Female; Haplotypes; Humans; Linkage Disequilibrium; Lung Neoplasms - etiology; Lung Neoplasms - genetics; Male; Medical sciences; Middle Aged; Molecular Epidemiology; Neoplasms - etiology; Neoplasms - genetics; Nuclear Proteins - genetics; Polymorphism, Single Nucleotide; Smoking - adverse effects; Tobacco, tobacco smoking; Toxicology; Tumors; Association; Genetic variability; Tobacco smoking; Genotype; Malignant tumor; Haplotype; Cancer; Polymorphism
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgq096

Constituents of tobacco smoke can cause DNA double-strand breaks (DSBs), leading to tumorigenesis. The NBS1 gene product is a vital component in DSB detection and repair, thus genetic variations may influence cancer development. We examined the associations between NBS1 polymorphisms and haplotypes and newly incident smoking-related cancers in three case–control studies (Los Angeles: 611 lung and 601 upper aero-digestive tract (UADT) cancer cases and 1040 controls; Memorial Sloan-Kettering Cancer Center: 227 bladder cancer cases and 211 controls and Taixing, China: 218 esophagus, 206 stomach, 204 liver cancer cases and 415 controls). rs1061302 was associated with cancers of the lung [adjusted odds ratio (ORadj) = 1.6, 95% confidence interval (CI): 1.2, 2.4], larynx (ORadj = 0.56, 95% CI: 0.32, 0.97) and liver (ORadj = 1.7, 95% CI: 1.0, 2.9). Additionally, positive associations were found for rs709816 with bladder cancer (ORadj = 4.2, 95% CI: 1.4, 12) and rs1063054 with lung cancer (ORadj = 1.6, 95% CI: 1.0, 2.3). Some associations in lung and stomach cancers varied with smoking status. CAC haplotype was positively associated with smoking-related cancers: lung (ORadj = 1.7, 95% CI: 1.1, 2.9) and UADT (ORadj = 2.0, 95% CI: 1.1, 3.7), specifically, oropharynx (ORadj = 2.1, 95% CI: 1.0, 4.2) and larynx (ORadj = 4.8, 95% CI: 1.7, 14). Bayesian false-discovery probabilities were calculated to assess Type I error. It appears that NBS1 polymorphisms and haplotypes may be associated with smoking-related cancers and that these associations may differ by smoking status. Our findings also suggest that single-nucleotide polymorphisms located in the binding region of the MRE-RAD50-NBS1 complex or microRNA targeted pathways may influence tumor development. These hypotheses should be further examined in functional studies.