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Carcinogenesis Advance Access published online on August 1, 2008
Carcinogenesis, doi:10.1093/carcin/bgn178
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Pathway-based evaluation of 380 candidate genes and lung cancer susceptibility suggests the importance of the cell cycle pathway

H Dean Hosgood, III1,2,*, Idan Menashe1, Min Shen1, Meredith Yeager1, Jeff Yuenger1, Preetha Rajaraman1, Xingzhou He3, Nilanjan Chatterjee1, Neil Caporaso1, Yong Zhu2, Stephen Chanock1, Tongzhang Zheng2 and Qing Lan1

1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD
2 Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT
3 Chinese Center for Disease Control and Prevention, Beijing, China

* To whom proofs and correspondence should be addressed: H. Dean Hosgood, email (hosgoodd{at}mail.nih.gov), phone (301-594-4649), fax (301-402-1819), National Cancer Institute, Division of Cancer Epidemiology and Genetics, Occupational and Environmental Epidemiology Branch. 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, Maryland 20892-7240

Common genetic variation may play an important role in altering lung cancer risk. We conducted a pathway-based candidate gene evaluation to identify genetic variations that may be associated with lung cancer in a population-based case-control study in Xuan Wei, China (122 cases; 111 controls). A total of 1260 single nucleotide polymorphisms (SNPs) in 380 candidate genes for lung cancer were successfully genotyped and assigned to one of ten pathways based on gene ontology. Logistic regression was used to assess the marginal effect of each SNP on lung cancer susceptibility. The minP test was used to identify statistically significant association at the gene level. Important pathways were identified using a test of proportions and the rank truncated product methods. The cell cycle pathway was found as the most important pathway (p = 0.044) with four genes significantly associated with lung cancer (PLA2G6 minP = 0.001, CCNA2 minP = 0.006, GSK3β minP = 0.007, and EGF minP = 0.013), after adjusting for multiple comparisons. Interestingly, most cell cycle genes that were associated with lung cancer in this analysis were concentrated in the AKT signaling pathway, which is essential for regulation of cell cycle progression and cellular survival, and may be important in lung cancer etiology in Xuan Wei. These results should be viewed as exploratory until they are replicated in a larger study.

Key Words: lung cancer • cell cycle • apoptosis • EGF • CCNA2 • GSK3β

Received June 2, 2008; revised July 20, 2008; accepted July 25, 2008.


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