Journal Article

Lung cancer and DNA repair genes: multilevel association analysis from the International Lung Cancer Consortium

Rémi Kazma, Marie-Claude Babron, Valérie Gaborieau, Emmanuelle Génin, Paul Brennan, Rayjean J. Hung, John R. McLaughlin, Hans E. Krokan, Maiken B. Elvestad, Frank Skorpen, Endre Anderssen, Tõnu Vooder, Kristjan Välk, Andres Metspalu, John K. Field, Mark Lathrop, Alain Sarasin and Simone Benhamou

in Carcinogenesis

Volume 33, issue 5, pages 1059-1064
Published in print May 2012 | ISSN: 0143-3334
Published online March 2012 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgs116
Lung cancer and DNA repair genes: multilevel association analysis from the International Lung Cancer Consortium

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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 × 103). 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.

Journal Article.  4616 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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