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Genetic variant in DNA repair gene GTF2H4 is associated with lung cancer risk: a large-scale analysis of six published GWAS datasets in the TRICL consortium.

About this Publication
Title
Genetic variant in DNA repair gene GTF2H4 is associated with lung cancer risk: a large-scale analysis of six published GWAS datasets in the TRICL consortium.
Pubmed ID
27288692 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Carcinogenesis. 2016 Sep; Volume 37 (Issue 9): Pages 888-896
Authors
Wang M, Liu H, Liu Z, Yi X, Bickeboller H, Hung RJ, Brennan P, Landi MT, Caporaso N, Christiani DC, Doherty JA, TRICL Research Team, Amos CI, Wei Q
Affiliations
  • Duke Cancer Institute, Duke University Medical Center, 905 Lasalle Street, Durham, NC 27710, USA.
  • Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen , 37073 Göttingen , Germany.
  • Lunenfeld-Tanenbaum Research Institute of Mount Sinai hospital , Toronto, Ontario , Canada.
  • Genetic Epidemiology Group, International Agency for Research on Cancer , 69372 Lyon , France.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute , Bethesda, MD 20892 , USA.
  • Department of Environmental Health and.
  • Community and Family Medicine, Geisel School of Medicine, Dartmouth College , Hanover, NH 03756 , USA.
Abstract

DNA repair pathways maintain genomic integrity and stability, and dysfunction of DNA repair leads to cancer. We hypothesize that functional genetic variants in DNA repair genes are associated with risk of lung cancer. We performed a large-scale meta-analysis of 123,371 single nucleotide polymorphisms (SNPs) in 169 DNA repair genes obtained from six previously published genome-wide association studies (GWASs) of 12160 lung cancer cases and 16838 controls. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) using the logistic regression model and used the false discovery rate (FDR) method for correction of multiple testing. As a result, 14 SNPs had a significant odds ratio (OR) for lung cancer risk with P FDR < 0.05, of which rs3115672 in MSH5 (OR = 1.20, 95% CI = 1.14-1.27) and rs114596632 in GTF2H4 (OR = 1.19, 95% CI = 1.12-1.25) at 6q21.33 were the most statistically significant (P combined = 3.99×10(-11) and P combined = 5.40×10(-10), respectively). The MSH5 rs3115672, but not GTF2H4 rs114596632, was strongly correlated with MSH5 rs3131379 in that region (r (2) = 1.000 and r (2) = 0.539, respectively) as reported in a previous GWAS. Importantly, however, the GTF2H4 rs114596632 T, but not MSH5 rs3115672 T, allele was significantly associated with both decreased DNA repair capacity phenotype and decreased mRNA expression levels. These provided evidence that functional genetic variants of GTF2H4 confer susceptibility to lung cancer.

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