IDENTIFICATION OF A LONG NON-CODING RNA SIGNATURE ASSOCIATED WITH TUMOR PROGRESSION TO CASTRATION-RESISTANT PROSTATE CANCER

LEDESMA-BAZÁN, SABRINA; VAZQUEZ, ELBA; GUERON, GERALDINE; COTIGNOLA, JAVIER

Congreso; 28th Annual Prostate Cancer Foundation Scientific Retreat; 2021

Prostate Cancer Foundation

Background: The majority of the human genome is transcribed into non-coding RNAs which perform a myriad of tasks in the cells. Their dysregulation is associated with the development and progression of several pathological processes, including cancer. Patients who develop prostate cancer have a wide spectrum of clinical outcomes that range from an indolent tumor to a metastatic castration-resistant prostate cancer (CRPC). Even though several molecular mechanisms leading to the development and progression of prostate cancer have been described, the biology of these tumors remains elusive. Therefore, the main goal in this study was to identify long non-coding RNA (lncRNAs) associated with the progression of prostate tumors to CRPC.Methods: We browed the public repositories Gene Expression Omnibus (NCBI/GEO) and European Bioinformatics Institute (EMBL/EBI), and downloaded raw RNAseq data from primary prostate adenocarcinomas (pre- and post-androgen deprivation therapy (ADT); n=40 and n=11 (paired to 11 pre-ADT), respectively) and CRPC (n=8). The dataset used were: GSE31528, GSE48403, GSE51005, GSE54460 and PRJEB25542. We performed differential gene expression of 17,009 lncRNAs with R/Bioconductor using two statistical models: DESeq2 and edgeR. We selected for further analysis the lncRNAs that were identified as dysregulated by both algorithms.Results: We identified 12 lncRNAs that responded to ADT and were further dysregulated in CRPC; three of them were previously reported as players in prostate cancer development and progression (PCA3, PCAT18 and PCGEM1), validating the pipeline used in this study. Interestingly, all of them showed the same expression pattern: 1) post-ADT tumors had significantly lower expression compared with pre-ADT tissues (11/40 were paired samples); and 2) CRPCs showed significant higher levels compared with post-ADT tumors, and the expression was similar, or even higher, to primary pre-ADT tumors. Unsupervised clustering analysis revealed that the expression profile of these 12 lncRNAs could cluster post-ADT and CRPC samples apart. Primary tumors pre-ADT were more heterogeneous and clustered together with post-ADT or CRPC tumors. This suggests that primary prostate tumors which might potentially progress to CRPC might be detected at the time of diagnosis according to their lncRNA expression profile. Conclusions: In summary, herein we describe a gene expression profile comprised of 12 lncRNAs that respond to hormonal therapy and that are dysregulated in CRPC. The study of this expression signature might help to characterize primary tumors with low/high risk of progression to CRPC. In addition, these lncRNAs might become druggable targets to halt or delay prostate cancer progression. These results constitute a foundation to the development of novel research to identify diagnostic, prognostic and/or therapeutic-response biomarkers in prostate cancer patients.