Inherited predisposition of lung cancer: a hierarchical modeling approach to DNA repair and cell cycle control pathways.

Abstract

The DNA repair systems maintain the integrity of the human genome and cell cycle checkpoints are a critical component of the cellular response to DNA damage. We hypothesized that genetic variants in DNA repair and cell cycle control pathways will influence the predisposition to lung cancer, and studied 27 variants in 17 DNA repair enzymes and 10 variants in eight cell cycle control genes in 1,604 lung cancer patients and 2,053 controls. To improve the estimation of risks for specific variants, we applied a Bayesian approach in which we allowed the prior knowledge regarding the evolutionary biology and physicochemical properties of the variant to be incorporated into the hierarchical model. Based on the estimation from the hierarchical modeling, subjects who carried OGG1 326C/326C homozygotes, MGMT 143V or 178R, and CHEK2 157I had an odds ratio of lung cancer equal to 1.45 [95% confidence interval (95% CI), 1.05-2.00], 1.18 (95% CI, 1.01-1.40), and 1.58 (95% CI, 1.14-2.17). The association of CHEK2 157I seems to be overestimated in the conventional analysis. Nevertheless, this association seems to be robust in the hierarchical modeling. None of the pathways seem to have a prominent effect. In general, our study supports the notion that sequence variation may explain at least some of the variation of inherited susceptibility. In particular, further investigation of OGG1, MGMT, and CHEK2 focusing on the genetic regions where the present markers are located or the haplotype blocks tightly linked with these markers might be warranted.

• Authors: Rayjean J Hung, Meili Baragatti, Duncan Thomas, James McKay, Neonila Szeszenia-Dabrowska, David Zaridze, Jolanta Lissowska, Peter Rudnai, Eleonora Fabianova, Dana Mates, Lenka Foretova, Vladimir Janout, Vladimir Bencko, Amelie Chabrier, Norman Moullan, Federico Canzian, Janet Hall, Paolo Boffetta, Paul Brennan
• Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology (Cancer Epidemiol Biomarkers Prev) Vol. 16 Issue 12 Pg. 2736-44 (Dec 2007) ISSN: 1055-9965 [Print] United States
• PMID: 18086781 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Tumor Suppressor Proteins
• DNA Modification Methylases
• MGMT protein, human
• Checkpoint Kinase 2
• CHEK2 protein, human
• Protein Serine-Threonine Kinases
• DNA Glycosylases
• oxoguanine glycosylase 1, human
• DNA Repair Enzymes

Topics

• Adult
• Aged
• Bayes Theorem
• Biomarkers, Tumor (genetics)
• Cell Cycle (genetics)
• Checkpoint Kinase 2
• DNA Glycosylases (genetics)
• DNA Modification Methylases (genetics)
• DNA Repair (genetics)
• DNA Repair Enzymes (genetics)
• Female
• Genetic Predisposition to Disease
• Humans
• Lung Neoplasms (genetics)
• Male
• Middle Aged
• Polymerase Chain Reaction
• Polymorphism, Single Nucleotide
• Protein Serine-Threonine Kinases (genetics)
• Risk Factors
• Smoking (adverse effects)
• Tumor Suppressor Proteins (genetics)