title: 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: IARC, 150 cours Albert Thomas, F-69372 Lyon Cedex 08, France. hung@iarc.fr
authors: Rayjean J
authors: RJ
authors: Hung
authors: Meili
authors: M
authors: Baragatti
authors: Duncan
authors: D
authors: Thomas
authors: James
authors: J
authors: McKay
authors: Neonila
authors: N
authors: Szeszenia-Dabrowska
authors: David
authors: D
authors: Zaridze
authors: Jolanta
authors: J
authors: Lissowska
authors: Peter
authors: P
authors: Rudnai
authors: Eleonora
authors: E
authors: Fabianova
authors: Dana
authors: D
authors: Mates
authors: Lenka
authors: L
authors: Foretova
authors: Vladimir
authors: V
authors: Janout
authors: Vladimir
authors: V
authors: Bencko
authors: Amelie
authors: A
authors: Chabrier
authors: Norman
authors: N
authors: Moullan
authors: Federico
authors: F
authors: Canzian
authors: Janet
authors: J
authors: Hall
authors: Paolo
authors: P
authors: Boffetta
authors: Paul
authors: P
authors: Brennan
mesh_terms: D000328:Adult; D000368:Aged; D001499:Bayes Theorem; D014408:Biomarkers, Tumor / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics*; D064447:Checkpoint Kinase 2; D045647:DNA Glycosylases / Q000235:genetics; D015254:DNA Modification Methylases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D045643:DNA Repair Enzymes