Abstract 2535: Screening PTEN-loss associated lncRNAs in prostate cancer

Abstract

Abstract Phosphatase and tensin homologue (PTEN) is a tumor suppressor gene that is frequently inactivated by deletion in prostate cancer (PCa). Occurring in around 20% of primary PCa tumors, and up to 50% in castration resistant tumors, it is the most frequent genomic aberration in PCa. Loss of PTEN activates the phosphoinositide 3-kinase-RAC-alpha serine/threonine-protein kinase (PI3K-AKT) pathway, which is associated with poor clinical outcomes. Despite the consequences of PTEN loss being well studied, most of what is known is restricted to protein-coding genes, with relatively little information about the role of non-coding genes. Using our recently created resource - the FC-R2 expression atlas, which encompasses expression levels for thousands of lncRNAs recently unveiled by the FANTOM consortium - we analyzed differential gene expression of PTEN-null vs PTEN-intact tumors with the goal of characterizing the molecular landscape of PTEN loss. First, we generated a consensus signature using two large PCa cohorts with experimentally validated PTEN status by Immunohistochemistry (IHC), applying a meta-analysis approach. This signature encompassed mainly protein coding genes due it being microarray based. In order to expand this signature beyond the coding genes, we relied on FC-R2-based TCGA-PRAD data. Since PTEN status was not available by IHC, we opted to call the status based on CNV. Then, we proceed to generate a PTEN-null signature using a generalized linear model approach. Both signatures were compared for concordance using correspondence-at-the-top plots and hypergeometric confidence intervals. Gene set enrichment analysis was performed in both signatures using a collection of obtained from the MSigDB database in order to characterize pathways involved in this event. Our results showed that the signature based on IHC validated samples agreed significantly with the CNV-based signature from TCGA for the genes in common. In the differential gene expression analysis on the TCGA cohort we observed 203 significant coding genes and 171 significant non-coding genes (FDR ≤ 0.01, LogFC ≥ 1). Notably, we identified several lncRNAs that have not been associated with PCa or PTEN loss, these include many classes of non-coding RNAs characterized by the FANTOM consortium such as: enhancers and promoters genes. Gene set enrichment analysis revealed that PTEN-null tumors are associated with epithelial-mesenchymal transition suggesting a possible role for these lncRNAs. In conclusion, by leveraging our resources, we were able to obtain comprehensive landscape of the PTEN loss in PCa for both the coding and non-coding counterpart. Furthermore, the association of many lncRNAs with PTEN loss was observed, many recently annotated by the FANTOM consortium, which can help us understand how genes are regulated in this event. In this work we show that despite being widely studied, there are still many components of PTEN loss in the form of lncRNAs highlighting potential markers for PTEN loss and clinical outcomes. Citation Format: Eddie Luidy Imada, Diego Fernando Sanchez, Wikum Dinalankara, Tamara Lotan, Luigi Marchionni. Screening PTEN-loss associated lncRNAs in prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2535.