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.
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.
Duke Cancer Institute, Duke University Medical Center, 905 Lasalle Street, Durham, NC 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.|Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 21116, China.
Meilin
M
Wang
Duke Cancer Institute, Duke University Medical Center, 905 Lasalle Street, Durham, NC 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Hongliang
H
Liu
Duke Cancer Institute, Duke University Medical Center, 905 Lasalle Street, Durham, NC 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Zhensheng
Z
Liu
Duke Cancer Institute, Duke University Medical Center, 905 Lasalle Street, Durham, NC 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Xiaohua
X
Yi
Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen , 37073 Göttingen , Germany.
Heike
H
Bickeboller
Lunenfeld-Tanenbaum Research Institute of Mount Sinai hospital , Toronto, Ontario , Canada.
Rayjean J
RJ
Hung
Genetic Epidemiology Group, International Agency for Research on Cancer , 69372 Lyon , France.
Paul
P
Brennan
Division of Cancer Epidemiology and Genetics, National Cancer Institute , Bethesda, MD 20892 , USA.
Maria Teresa
MT
Landi
Division of Cancer Epidemiology and Genetics, National Cancer Institute , Bethesda, MD 20892 , USA.
Neil
N
Caporaso
Department of Environmental Health and.|Department of Epidemiology, Harvard University School of Public Health, Boston, MA 02115, USA and.
David C
DC
Christiani
Community and Family Medicine, Geisel School of Medicine, Dartmouth College , Hanover, NH 03756 , USA.
Jennifer Anne
JA
Doherty
Community and Family Medicine, Geisel School of Medicine, Dartmouth College , Hanover, NH 03756 , USA.
Christopher I
CI
Amos
Duke Cancer Institute, Duke University Medical Center, 905 Lasalle Street, Durham, NC 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
Qingyi
Q
Wei
D018797:Cell Cycle Proteins / Q000235:genetics; D004260:DNA Repair; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D051758:Transcription Factor TFIIH / Q000235:genetics*
D018797:Cell Cycle Proteins; C118481:MSH5 protein, human; D051758:Transcription Factor TFIIH