Abstract 3479: Identification and characterization of clinically relevant long non coding RNA PLUCAT1 in lung adenocarcinoma
Authors: Sudhanshu Shukla, Lanbo Xiao, Brendan Veeneman, Yuping Zhang, Yashar Niknafs, Sethuramsundaram Pitchiya, Arul Chinnaiyan
Journal: Cancer Research (2017)

Abstract Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. Disease subtypes include lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) and LUAD accounts for nearly 50% of lung malignancies. Late diagnosis and limited chemotherapy options are the primary reason for poor prognosis and even among patients diagnosed early with Stage 1 disease, recurrence occurs in 35-50% of cases. Lack of discriminatory biomarkers has hampered clinical and therapeutic management, as current practice tends to group all patients together. Several attempts to develop gene signatures from microarray datasets to stratify risk among lung adenocarcinoma patients have not yielded clinical utility due to poor cross validation and lack of robustness. The development of RNA-Seq methodologies now enables accurate quantification of transcriptional abundance that is reproducible and reliable. Capitalizing on this technology and large datasets such as the cancer genome atlas (TCGA) as well as individual efforts, thousands of cancer samples are available for analysis to facilitate deeper understanding of the disease. One major discovery resulting from large RNA-Seq datasets are functional long noncoding RNAs (lncRNAs; exceeding 200 nucleotides in length) that can be expressed in tissue-, linage- and cancer-specific expression patterns. In our previous study we identified a highly significant prognostic marker set using 255 TCGA LUAD patients. In the training cohort, 96 genes had prognostic association with p&amp;lt;0.001, including 5 long noncoding RNAs (lncRNAs). Stepwise regression generated a four-gene signature, including one lncRNA. Signature high risk cases had worse overall survival (OS) in the TCGA validation cohort (HR=3.07, 95%CI=2.00-14.62). The four-gene signature was then validated in two independent patient cohorts. The signature consisted of three protein coding gene and a lncRNA (PLUCAT1). Knockdown studies showed that the lncRNA promoted lung cell growth in vitro. Also, inhibition of PLUCAT1 using both siRNA and ASOs induced cellular senescence in lung cells. Further, RNA pull down followed by mass-spec identified QKI as a binding partner of PLUCAT1. QKI is a tumor suppressor gene shown to change splicing pattern in many cancer types. We now show that PLUCAT1-QKI interaction has functional consequences and changes splicing pattern of significant number of genes as assessed by RNA sequencing. Taken together, we have identified PLUCAT1, a member of 4 gene prognostic signature, as a robust prognostic marker for lung adenocarcinoma prognosis. We also, show that PLUCAT1 binds with tumor suppressor QKI and inhibits QKI activity. Citation Format: Sudhanshu Shukla, Lanbo Xiao, Brendan Veeneman, Yuping Zhang, Yashar Niknafs, Sethuramsundaram Pitchiya, Arul Chinnaiyan. Identification and characterization of clinically relevant long non coding RNA PLUCAT1 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 3479. doi:10.1158/1538-7445.AM2017-3479