Abstract 5551: Systematic analysis of novel noncoding genes associated with poor prognostic pathways in lung adenocarcinoma

Abstract

Abstract Non-coding genes are shown to play important roles in cancer progression with potential for serving as theranostic biomarkers. However, there is still a lack of studies to predict the biological roles of novel non-coding genes in tumorigenic pathways and associations with patient survival. Lung adenocarcinoma (LUAD) is the predominant histological subtype of lung cancer, which is the leading cause of cancer death. Nowadays, target therapies have improved LUAD patients’ survival about 6-12 months, but limited improvement of long-term survival, suggesting that discovering new therapeutic targets are important. Therefore, here we applied weighted correlation network analysis (WGCNA) to cluster highly correlated genes of transcriptomic data to accurately investigate the functions of non-coding genes with poor prognosis in lung adenocarcinoma (LUAD). We discovered a total of 627 differential expressed coding and non-coding genes (DEGs) from 6 transcriptomic datasets derived from LUAD patients with survival information. By using WGCNA, we discovered 6 non-coding candidates (PTTG3P, MIR497HG, HSP078, TBX5-AS1, LOC100506990, and C14orf64) and their core networks of DEGs, which were highly associated with patient survival and clustered in modules functioning in cell cycle and migration. We noticed that a previously known processed pseudogene, PTTG3P (Pituitary Tumor-transforming Gene 3), is highly correlated with poor survival and associated with mitosis of the cell cycle. Up-regulated PTTG3P expression in LUAD was in silico validated of RNA-seq data from TCGA compared to normal lung tissues (fold-change= 2, p-value< 0.0001) and associated with poor 5-year survival rates (HR= 1.83, p-value= 0.012). We further confirmed PTTG3P is highly expressed and associated with poor survival outcome of LUAD patients in Taiwan (HR= 1.75, p-value= 0.037) with RNA-ISH experiments. To examine the coding potential of pseudogene PTTG3P, we found that PTTG3P might encode a consensus 21 kDa novel polypeptide from a single exon by using various prediction programs of coding potential. Ectopic expression of PTTG3P in lung cancer cells indicated that PTTG3P protein can be detected resulted in shortening the process of metaphase to anaphase in cell cycle progression and promotion of cell proliferation. Knockdown experiments of PTTG3P further reversed aforementioned experiments. Together, we established a powerful and systematic strategy for functional classification of non-coding genes in association with poor prognosis of LUAD patients. We revealed that commonly annotated and processed pseudogenes defined as non-coding genes for lacking of introns and promoter regions could still be translated into functional polypeptides. We found processed pseudogene PTTG3P can be translated to a protein, which might play an important role in predicted function of mitosis and impact on poor survival in LUAD patients. Citation Format: Jou-Ho Shih, Yuh-Shan Jou. Systematic analysis of novel noncoding genes associated with poor prognostic pathways in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5551. doi:10.1158/1538-7445.AM2017-5551