Abstract 3554: Gene and miRNA expression networks specific to never smoker lung adenocarcinoma

Abstract

Abstract While smoking is well recognized as a major risk factor for lung cancer, there is a growing incidence of lung cancer in never smokers which is in turn the fifth leading cause of cancer-related death worldwide. Never smokers (NS) who develop lung cancer exhibit disparate profiles of somatic mutations and clinical responses to targeted therapy relative to lung cancer arising in current or former “ever” smokers (ES), suggesting that ES and NS lung cancer arise through distinct molecular processes. We therefore sought to characterize mRNA and miRNA expression differences specific to NS adenocarcinoma (AdC) to gain insights into the molecular differences underlying NS and ES AdC carcinogenesis. Total RNA was isolated from matched pairs of lung AdC tumor and adjacent histologically normal tissue obtained from 22 subjects (8 NS, 14 ES). Large and small RNA libraries were sequenced on the Illumina HiSeq 2000. Tumor-specific gene and miRNA expression differences between NS and ES were identified using linear mixed-effects ANOVA. MiRConnx was used to construct miRNA-mRNA networks. We identified 120 mRNA and 15 miRNA whose expression was modified uniquely in NS lung AdC. In the predicted miRNA-mRNA regulatory network, additional analysis pinpointed modulation of the development and cellular metabolism canonical pathway within genes connected to several of the differentially expressed miRNA (GATHER, p<0.001). Several of the differentially expressed mRNA and miRNA were validated by qRT-PCR in samples from an independent cohort. In summary, the construction of a miRNA-mRNA regulatory network has enabled us to identify molecular alterations that may be specific to NS lung AdC. Ultimately, these findings may serve to broaden the landscape of personalized therapeutic and treatment options by identifying targetable molecular interactions and therapeutic drug candidates for lung AdC in never smokers. Citation Format: Rebecca Kusko, Carly Garrison, Teresa Wang, Josh Campbell, Joseph Perez-Rogers, Lingqi Luo, Jennifer Beane, Gang Liu, Humam Kadara, Steven Belinsky, Marc E. Lenburg, Avrum Spira. Gene and miRNA expression networks specific to never smoker lung adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3554. doi:10.1158/1538-7445.AM2014-3554