Abstract 2961: Characterization of methylation profiles reveals distinct epigenomic patterns in SCLC and NSCLC

Abstract

Abstract Background: Small cell lung cancer (SCLC) is a highly lethal malignancy characterized by rapid growth, early metastasis and poor prognosis. SCLC shows distinct molecular and clinical features when compared to other lung cancer subtypes. Previous analyses by us and others have identified genomic and proteomic differences between SCLC and Non-Small Cell Lung Cancer (NSCLC). Epigenetic alterations are some of the earliest events that could also lead to oncogenic changes and thus play an essential role in tumor initiation and progression. However, epigenetic differences between SCLC and NSCLC contributing to the alterations in gene and protein expression patterns, distinct biological features and therapeutic response have not been well characterized. Here, we investigate the differences in the methylation patterns of SCLC and NSCLC to provide novel insights into epigenetic associated gene alterations to identify potential therapeutic targets in SCLC. Material and Methods: A genome-wide DNA methylation profiling of SCLC and NSCLC cell lines was used for this investigation. We correlated DNA methylation status with gene expression and protein expression levels in 31 SCLC and 73 NSCLC lines to identify the relationship of epigenetic with genomic and proteomic features distinguishing SCLC from NSCLC. Results: SCLC and NSCLC lines exhibited different methylation profiles and we identified 484 genes that had a significant inverse correlation between methylation status and mRNA expression levels (Rho ≤ -0.5 and FDR = 0.01), (“genes regulated by methylation,” GRM) that distinguished SCLC from NSCLC. Ingenuity pathway analysis of the 484 genes identified significant associations with neuregulin signaling, immune trafficking, integrin signaling, glioma invasiveness canonical pathways. Proteomic profiling by Reverse Phase Protein Array (RPPA) validated the different expression of some of the 484 genes identifying nine that were hypermethylated and downregulated at protein levels in SCLC compared to NSCLC lines (PTEN, CyclinD1, Caveolin, Notch3, TAZ, HSP27, STAT6 and both total and phosphorylated levels of receptor tyrosine kinases such Her2 and, MET). Conclusions: Genome wide methylation, mRNA expression, and detailed proteomic analyses have identified specific epigenic differences between SCLC and NSCLC that impact on important signaling pathways including widespread loss of PTEN function and receptor tyrosine kinase (RTK) expression in SCLCs which need to be considered in developing new rationale therapies for SCLC. Citation Format: Seema Mukherjee, Bonnie S. Glisson, John D. Minna, Robert J. Cardnell, Luc Girard, Adi Gazdar, Lixia Diao, Jing Wang, Lauren A. Byers. Characterization of methylation profiles reveals distinct epigenomic patterns in SCLC and NSCLC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2961. doi:10.1158/1538-7445.AM2015-2961