Associations between NBS1 polymorphisms, haplotypes and smoking-related cancers.
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.
Park
Sungshim L
SL
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.
Bastani
Delara
D
Goldstein
Binh Y
BY
Chang
Shen-Chih
SC
Cozen
Wendy
W
Cai
Lin
L
Cordon-Cardo
Carlos
C
Ding
Baoguo
B
Greenland
Sander
S
He
Na
N
Hussain
Shehnaz K
SK
Jiang
Qingwu
Q
Lee
Yuan-Chin A
YC
Liu
Simin
S
Lu
Ming-Lan
ML
Mack
Thomas M
TM
Mao
Jenny T
JT
Morgenstern
Hal
H
Mu
Li-Na
LN
Oh
Sam S
SS
Pantuck
Allan
A
Papp
Jeanette C
JC
Rao
Jianyu
J
Reuter
Victor E
VE
Tashkin
Donald P
DP
Wang
Hua
H
You
Nai-Chieh Y
NC
Yu
Shun-Zhang
SZ
Zhao
Jin-Kou
JK
Zhang
Zuo-Feng
ZF
D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000209:etiology / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000009:adverse effects*
D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins