Department of Epidemiology, School of Public Health, University of California, Los Angeles, 71-225 CHS, Box 951772, 650 Charles E Young Drive, South, Los Angeles, CA 90095-1772, USA.
Carcinogenesis. 2010 Jul;31(7):1264-71. doi: 10.1093/carcin/bgq096. Epub 2010 May 17.
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 (OR(adj)) = 1.6, 95% confidence interval (CI): 1.2, 2.4], larynx (OR(adj) = 0.56, 95% CI: 0.32, 0.97) and liver (OR(adj) = 1.7, 95% CI: 1.0, 2.9). Additionally, positive associations were found for rs709816 with bladder cancer (OR(adj) = 4.2, 95% CI: 1.4, 12) and rs1063054 with lung cancer (OR(adj) = 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 (OR(adj) = 1.7, 95% CI: 1.1, 2.9) and UADT (OR(adj) = 2.0, 95% CI: 1.1, 3.7), specifically, oropharynx (OR(adj) = 2.1, 95% CI: 1.0, 4.2) and larynx (OR(adj) = 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.
烟草烟雾中的成分会导致 DNA 双链断裂（DSB），从而引发肿瘤。NBS1 基因产物是 DSB 检测和修复的重要组成部分，因此遗传变异可能会影响癌症的发展。我们在三项病例对照研究中研究了 NBS1 多态性和单倍型与新发生的与吸烟相关癌症之间的关联：洛杉矶：611 例肺癌和 601 例上呼吸道（UADT）癌症病例和 1040 例对照；纪念斯隆-凯特琳癌症中心：227 例膀胱癌病例和 211 例对照；中国泰兴：218 例食管癌、206 例胃癌、204 例肝癌病例和 415 例对照。rs1061302 与肺癌[校正比值比（OR（adj））= 1.6，95%置信区间（CI）：1.2，2.4]、喉癌（OR（adj）= 0.56，95%CI：0.32，0.97）和肝癌（OR（adj）= 1.7，95%CI：1.0，2.9）相关。此外，rs709816 与膀胱癌[调整比值比（OR（adj））= 4.2，95%置信区间（CI）：1.4，12]和 rs1063054 与肺癌[调整比值比（OR（adj））= 1.6，95%置信区间（CI）：1.0，2.3]呈阳性相关。肺癌和胃癌中与吸烟有关的癌症的一些关联因吸烟状况而异。CAC 单倍型与与吸烟有关的癌症呈正相关：肺癌（OR（adj）= 1.7，95%CI：1.1，2.9）和 UADT（OR（adj）= 2.0，95%CI：1.1，3.7），特别是口咽癌（OR（adj）= 2.1，95%CI：1.0，4.2）和喉癌（OR（adj）= 4.8，95%CI：1.7，14）。计算贝叶斯假发现概率以评估 I 型错误。似乎 NBS1 多态性和单倍型可能与吸烟相关的癌症有关，这些关联可能因吸烟状况而异。我们的研究结果还表明，位于 MRE-RAD50-NBS1 复合物结合区域或 microRNA 靶向途径的单核苷酸多态性可能会影响肿瘤的发展。这些假设应在功能研究中进一步检验。
