Genetic variants in cell cycle control pathway confer susceptibility to lung cancer.
OBJECTIVE
To test the hypothesis that common sequence variants of cell cycle control genes may affect lung cancer predisposition.


METHODS
We explored lung cancer risk associations of 11 polymorphisms in seven cell cycle genes in a large case-control study including 1,518 Caucasian lung cancer patients and 1,518 controls.


RESULTS
When individuals with variant-containing genotypes were compared with homozygous wild-type carriers, a significantly increased lung cancer risk was identified for polymorphisms in p53 intron 6 [rs1625895; odds ratio (OR), 1.29; 95% confidence interval (95% CI), 1.08-1.55] and in p27 5' untranslated region (UTR; rs34330; OR, 1.27; 95% CI, 1.01-1.60). Compared with homozygous wild-types, the homozygous variant genotypes of STK15 F31I and CCND1 G870A were associated with a significantly altered lung cancer risk with ORs of 0.58 (95% CI, 0.37-0.90) and 1.26 (95% CI, 1.03-1.53), respectively. To assess the cumulative effects of all the investigated polymorphisms on lung carcinogenesis, we conducted a combined analysis and found that compared with low-risk individuals with few adverse alleles, individuals with more adverse alleles had an increased risk in a significant dose-dependent manner (P(trend) = 0.041). This pattern was more evident in ever smokers (P(trend) = 0.037), heavy smokers (P(trend) = 0.020), and older subjects (P(trend) = 0.011). Higher-order gene-gene interactions were evaluated using the classification and regression tree analysis, which indicated that STK15 F31I and p53 intron 6 polymorphisms might be associated with lung carcinogenesis in never/light-smokers and heavy smokers, respectively.


CONCLUSIONS
Our results suggest that cell cycle gene polymorphisms and smoking may function collectively to modulate the risk of lung cancer.
Wang
Wei
W
Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Spitz
Margaret R
MR
Yang
Hushan
H
Lu
Charles
C
Stewart
David J
DJ
Wu
Xifeng
X
D000328:Adult; D016022:Case-Control Studies; D002453:Cell Cycle / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006720:Homozygote; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012907:Smoking; D044465:White People