title: Genetic variation in the TNF/TRAF2/ASK1/p38 kinase signaling pathway as markers for postoperative pulmonary complications in lung cancer patients.
abstract: Post-operative pulmonary complications are the most common morbidity associated with lung resection in non-small cell lung cancer (NSCLC) patients. The TNF/TRAF2/ASK1/p38 kinase pathway is activated by stress stimuli and inflammatory signals. We hypothesized that genetic polymorphisms within this pathway may contribute to risk of complications. In this case-only study, we genotyped 173 germline genetic variants in a discovery population of 264 NSCLC patients who underwent a lobectomy followed by genotyping of the top variants in a replication population of 264 patients. Complications data was obtained from a prospective database at MD Anderson. MAP2K4:rs12452497 was significantly associated with a decreased risk in both phases, resulting in a 40% reduction in the pooled population (95% CI:0.43-0.83, P = 0.0018). In total, seven variants were significant for risk in the pooled analysis. Gene-based analysis supported the involvement of TRAF2, MAP2K4, and MAP3K5 as mediating complications risk and a highly significant trend was identified between the number of risk genotypes and complications risk (P = 1.63 × 10(-8)). An inverse relationship was observed between association with clinical outcomes and complications for two variants. These results implicate the TNF/TRAF2/ASK1/p38 kinase pathway in modulating risk of pulmonary complications following lobectomy and may be useful biomarkers to identify patients at high risk.
authors.affiliation: Departments of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Michelle A T
authors.initials: MA
authors.lastname: Hildebrandt
authors.affiliation: Departments of Thoracic &Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX; and Division of Thoracic Surgery.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Roth
authors.affiliation: Departments of Thoracic &Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX; and Division of Thoracic Surgery.
authors.forename: Ara A
authors.initials: AA
authors.lastname: Vaporciyan
authors.affiliation: Departments of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Xia
authors.initials: X
authors.lastname: Pu
authors.affiliation: Departments of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Departments of Thoracic &Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX; and Division of Thoracic Surgery.
authors.forename: Arlene M
authors.initials: AM
authors.lastname: Correa
authors.affiliation: 1] Departments of Thoracic &Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX; and Division of Thoracic Surgery [2] City of Hope National Cancer Center, Durate, CA.
authors.forename: Jae Y
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Departments of Thoracic &Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX; and Division of Thoracic Surgery.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Swisher
authors.affiliation: Departments of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human