title: Lung cancer and DNA repair genes: multilevel association analysis from the International Lung Cancer Consortium.
abstract: Lung cancer (LC) is the leading cause of cancer-related death worldwide and tobacco smoking is the major associated risk factor. DNA repair is an important process, maintaining genome integrity and polymorphisms in DNA repair genes may contribute to susceptibility to LC. To explore the role of DNA repair genes in LC, we conducted a multilevel association study with 1655 single nucleotide polymorphisms (SNPs) in 211 DNA repair genes using 6911 individuals pooled from four genome-wide case-control studies. Single SNP association corroborates previous reports of association with rs3131379, located on the gene MSH5 (P = 3.57 × 10-5) and returns a similar risk estimate. The effect of this SNP is modulated by histological subtype. On the log-additive scale, the odds ratio per allele is 1.04 (0.84-1.30) for adenocarcinomas, 1.52 (1.28-1.80) for squamous cell carcinomas and 1.31 (1.09-1.57) for other histologies (heterogeneity test: P = 9.1 × 10(-)(3)). Gene-based association analysis identifies three repair genes associated with LC (P < 0.01): UBE2N, structural maintenance of chromosomes 1L2 and POLB. Two additional genes (RAD52 and POLN) are borderline significant. Pathway-based association analysis identifies five repair pathways associated with LC (P < 0.01): chromatin structure, DNA polymerases, homologous recombination, genes involved in human diseases with sensitivity to DNA-damaging agents and Rad6 pathway and ubiquitination. This first international pooled analysis of a large dataset unravels the role of specific DNA repair pathways in LC and highlights the importance of accounting for gene and pathway effects when studying LC.
authors.affiliation: Université Paris-Sud, Villejuif, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Kazma
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Babron
authors.forename: Valérie
authors.initials: V
authors.lastname: Gaborieau
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Génin
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Rayjean J
authors.initials: RJ
authors.lastname: Hung
authors.forename: John R
authors.initials: JR
authors.lastname: McLaughlin
authors.forename: Hans E
authors.initials: HE
authors.lastname: Krokan
authors.forename: Maiken B
authors.initials: MB
authors.lastname: Elvestad
authors.forename: Frank
authors.initials: F
authors.lastname: Skorpen
authors.forename: Endre
authors.initials: E
authors.lastname: Anderssen
authors.forename: Tõnu
authors.initials: T
authors.lastname: Vooder
authors.forename: Kristjan
authors.initials: K
authors.lastname: Välk
authors.forename: Andres
authors.initials: A
authors.lastname: Metspalu
authors.forename: John K
authors.initials: JK
authors.lastname: Field
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Alain
authors.initials: A
authors.lastname: Sarasin
authors.forename: Simone
authors.initials: S
authors.lastname: Benhamou
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D015398:Signal Transduction; D012907:Smoking / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C118481:MSH5 protein, human