title: Genetic variations in cancer-related significantly mutated genes and lung cancer susceptibility.
abstract: BACKGROUND
  Cancer initiation and development are driven by key mutations in driver genes. Applying high-throughput sequencing technologies and bioinformatic analyses, The Cancer Genome Atlas (TCGA) project has identified panels of somatic mutations that contributed to the etiology of various cancers. However, there are few studies investigating the germline genetic variations in these significantly mutated genes (SMGs) and lung cancer susceptibility.
  
  
  METHODS
  We comprehensively evaluated 1655 tagged single nucleotide polymorphisms (SNPs) located in 127 SMGs identified by TCGA, and test their association with lung cancer risk in large-scale case-control study. Functional effect of the validated SNPs, gene mutation frequency and pathways were analyzed.
  
  
  RESULTS
  We found 11 SNPs in 8 genes showed consistent association (P < 0.1) and 8 SNPs significantly associated with lung cancer risk (P < 0.05) in both discovery and validation phases. The most significant association was rs10412613 in PPP2R1A, with the minor G allele associated with a decreased risk of lung cancer [odds ratio = 0.91, 95% confidence interval (CI): 0.87-0.96, P = 2.3 × 10-4]. Cumulative analysis of risk score built as a weight sum of the 11 SNPs showed consistently elevated risk with increasing risk score (P for trend = 9.5 × 10-9). In stratified analyses, the association of PPP2R1A:rs10412613 and lung cancer risk appeared stronger among population of younger age at diagnosis and never smokers. The expression quantitative trait loci analysis indicated that rs10412613, rs10804682, rs635469 and rs6742399 genotypes significantly correlated with the expression of PPP2R1A, ATR, SETBP1 and ERBB4, respectively. From TCGA data, expression of the identified genes was significantly different in lung tumors compared with normal tissues, and the genes' highest mutation frequency was found in lung cancers. Integrative pathway analysis indicated the identified genes were mainly involved in AKT/NF-κB regulatory pathway suggesting the underlying biological processes.
  
  
  CONCLUSIONS
  This study revealed novel genetic variants in SMGs associated with lung cancer risk, which might contribute to elucidating the biological network involved in lung cancer development.
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, USA.|Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, USA.|Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: R
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Chang
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Harmon Center for Therapeutic Oncology, University of Texas Southwestern Medical Center, Dallas.
authors.forename: J D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Department of Thoracic & Cardiovascular Surgery, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Roth
authors.affiliation: Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: B
authors.initials: B
authors.lastname: Han
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wu
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016009:Chi-Square Distribution; D005260:Female; D005787:Gene Frequency; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D015999:Multivariate Analysis; D009154:Mutation; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D040641:Quantitative Trait Loci; D015203:Reproducibility of Results; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor
keywords: TCGA; eQTL; lung cancer; pathway analysis; significantly mutated genes; tagSNP