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Genetic Variants in Cell Cycle Control Pathway Confer Susceptibility to Lung Cancer

Authors' Affiliations: Departments of ¹ Epidemiology and ² Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Xifeng Wu, Department of Epidemiology, Unit 1340, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-2485; Fax: 713-792-4657; E-mail: xwu{at}mdanderson.org.

Purpose: To test the hypothesis that common sequence variants of cell cycle control genes may affect lung cancer predisposition.

Experimental Design: 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.