title: Genetic variants of genes in the Notch signaling pathway predict overall survival of non-small cell lung cancer patients in the PLCO study.
abstract: The Notch signaling pathway has been shown to have biological significance and therapeutic application in non-small cell lung cancer (NSCLC). We hypothesize that genetic variants of genes in the Notch signaling pathway are associated with overall survival (OS) of NSCLC patients. To test this hypothesis, we performed multivariate Cox proportional hazards regression analysis to evaluate associations of 19,571 single nucleotide polymorphisms (SNPs) in 132 Notch pathway genes with OS of 1,185 NSCLC patients available from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We found that five potentially functional tagSNPs in four genes (i.e., ADAM12 rs10794069 A > G, DTX1 rs1732793 G > A, TLE1 rs199731120 C > CA, TLE1 rs35970494 T > TC and E2F3 rs3806116 G > T) were associated with a poor OS, with a variant-allele attributed hazards ratio (HR) of 1.27 [95% confidence interval (95% CI) = 1.13-1.42, P = 3.62E-05], 1.30 (1.14-1.49, 8.16E-05), 1.40 (1.16-1.68, 3.47E-04), 1.27 (1.11-1.44, 3.38E-04), and 1.21 (1.09-1.33, 2.56E-04), respectively. Combined analysis of these five risk genotypes revealed that the genetic score 0-5 was associated with the adjusted HR in a dose-response manner (Ptrend = 3.44E-13); individuals with 2-5 risk genotypes had an adjusted HR of 1.56 (1.34-1.82, 1.46E-08), compared with those with 0-1 risk genotypes. Larger studies are needed to validate our findings.
authors.affiliation: Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.|Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Yanru
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.|Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Thoracic Surgery I, Peking University Cancer Hospital and Institute, Beijing 100142, China.
authors.forename: Xiaozheng
authors.initials: X
authors.lastname: Kang
authors.affiliation: Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D040641:Quantitative Trait Loci; D051880:Receptors, Notch / Q000235:genetics*; D012042:Registries; D012044:Regression Analysis; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D051880:Receptors, Notch
keywords: GWAS; Notch pathway; lung cancer; overall survival (OS); single nucleotide polymorphism (SNP)