Abstract B91: Genetic variations in the JAK-STAT pathway are associated with postoperative pulmonary complications after lobectomy in lung cancer patients

Abstract

Abstract Background: Lung cancer patients who received lobectomy are at high risk of developing postoperative pulmonary complications. Clinical factors have been investigated to predict high risk patients; however, additional predictors are needed to accurately and reliably evaluate risk. Evidence has shown a relationship between the JAK-STAT pathway with pulmonary inflammation and lung injuries. Methods: We conducted a two stage discovery-validation study to evaluate the associations between genetic variations in JAK-STAT signaling pathway and the risk of developing postoperative pulmonary complications following lobectomy. A total of 223 SNPs from 27 genes were genotyped and analyzed in 264 early stage non-small cell lung cancer (NSCLC) patients who received lobectomy. Twelve significant (P<0.05) SNPs were then validated in additional 264 NSCLC patients. Results: Four SNPs showed a consistent effect in both discovery and validation populations and had a pooled p value < 0.05. Among them, PIAS3:rs10910829 was significantly associated with increased risk of developing complications in both the discovery (OR=1.78, 95%CI=1.16-2.74, P=0.008) and validation (OR=1.52, 95%CI=1.03-2.25, P=0.036) populations. PIAS2:rs9304337 was associated with decreased risk in the discovery set (OR= 0.45, 95%CI=0.21-0.95, P=0.037) and reached borderline significance (OR=0.53, 95%CI=0.26-1.05, P=0.071) in the validation set. A dose-response effect of increasing risk of developing complications with increasing number of unfavorable genotypes each patient carried was identified in the discovery population. Those with the highest number of unfavorable genotypes had an 8.82-fold increase (95% CI= 2.58-30.18) in risk compared to those with the lowest number. This effect was replicated in the validation population (P<0.001). A significant improvement in discriminatory ability was observed with the addition of the four genetic loci identified in our study to the epidemiological/clinical-based receiver operating characteristic curve in predicting the risk of developing complications. The area under the curve (AUC) was increased 8% from 0.68 for the initial model to 0.76 with the genetic variables. Bootstrap resampling internally validated the significance of this AUC difference (ΔAUC=0.024-0.129) and this improvement was replicated in the validation dataset. Conclusions: We identified genetic variations in the JAK-STAT pathway associated with risk of developing postoperative pulmonary complications in NSCLC patients. These biomarkers could be translated into the clinic to assist in identifying surgical patients who are at higher risk of developing pulmonary complications. Citation Format: Xia Pu, Michelle A.T. Hildebrandt, Jae Y. Kim, Yuanqing Ye, Ara A. Vaporciyan, Arlene M. Correa, Stephen G. Swisher, Jack A. Roth, Xifeng Wu. Genetic variations in the JAK-STAT pathway are associated with postoperative pulmonary complications after lobectomy in lung cancer patients. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B91.