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.

MicroRNA-647 promotes the therapeutic effectiveness of argon–helium cryoablation and inhibits cell proliferation through targeting TRAF2 via the NF-κB signaling pathway in non-small cell lung cancer

“…The TNF/TRAF2/ASK1/p38 kinase pathway may contain useful biomarkers to identify lung cancer patients at high risk. 23 TRAF2 regulates mTORC2 signaling via interaction with OTUD7B. 24 It is also able to modulate two kinase cascades that lead to the activation of JNK and NF-κB to regulate cell biological processes.…”

Constructing a global transcriptional regulatory landscape for early non-small cell lung cancer to identify hub genes and key pathways

“…Multiple functional modules were involved in the cytokine-cytokine receptor interaction signaling pathway, IL-17 signaling pathway, TNF signaling pathway, PPAR signaling pathway and PI3K/AKt signaling pathway, which may serve as potential pathways in the promotion of early NSCLC. The IL-7 signaling pathway promotes the pathogenesis of NSCLC [ 10 ], and activation of the TNF signaling pathway via inflammatory response may result in a poor prognosis of NSCLC [ 11 ]. It has also been verified that the PI3K/AKt signaling pathways are involved in the regulation of apoptosis in NSCLC cells, suggesting that the PI3K/AKt signaling pathway is associated with NSCLC [ 12 ].…”

CP-25, a Novel Anti-inflammatory and Immunomodulatory Drug, Inhibits the Functions of Activated Human B Cells through Regulating BAFF and TNF-alpha Signaling and Comparative Efficacy with Biological Agents

“…TNF-alpha is a potent inflammatory mediator and apoptosis inducer ( Hildebrandt et al, 2015 ). TNF-alpha has an impact on B cell subsets and the subset of memory B cells was enlarged by TNF-alpha ( Wang et al, 2013 ; Glaesener et al, 2014 ).…”