Abstract LB-267: Transcriptomic and epigenomic analysis of metastatic castration-resistant prostate cancer and a pan-cancer analysis of its genetic signatures

Abstract

Abstract Prostate cancer (PCa) is the 2nd leading cause of non-cutaneous cancer related deaths in the United States. The 5-year survival rate for local or regional disease is high. However, many patient’s disease will progress to the aggressive metastatic castration-resistant form of prostate cancer (mCRPC) - the estimated mortality rates of mCRPC is 19.5% for 2020 (www.cancer.org). Treatment with docetaxel or cabazitaxel alone or in combination with bevacizumab, thalidomide and prednisone increases survival rate slightly, but lead to drug resistance. The use of immunotherapy has further increased overall survival by 4-5 months. Therefore, a greater understanding of the underlying molecular mechanisms responsible for disease progression is needed.To understand and identify appropriate targets for therapy, we performed mRNA and miRNA expression studies and identified potential candidate cancer pathway genes and miRNA-mRNA pairs as biomarkers for aggressive Prostate cancer (mCRPC). Gene expression signatures were identified using differential expression (DE) analysis softwares. Spearman’s rank-based correlation and TargetScan were used to assess the association between mRNA and miRNA expression. We identified disparate mRNA and miRNA expression signatures for aggressive vs non-aggressive prostate cancers. The gene signatures were validated using the human prostate cancer patient cohort from The Cancer Genome Atlas (TCGA) database. The top ten genes that were significantly (p<0.0001) associated with patient survival in PCa patients, stratified by Gleason scores, were PLAU, TGFB1, SERPINE1, MET, TIPM1, ITGA3, SERPINB5, PLAUR, CDKN1A and IGF1. Ingenuity Pathway Analysis (IPA) identified the activation of angiogenesis pathway as key factor for cancer aggressiveness. Epigenetic analysis showed distinct alterations in aggressive vs non-aggressive PCa. We also identified miRNA-mRNA pairs (including PLAU- mir181) which may influence differential gene expression in advanced-stage cancers. Furthermore, we performed a pan-cancer analysis of these top PCa survival-associated genes in other solid tumor types using patient expression profiles from the TCGA database. Our results identified significant (p<0.05) associations of the expression of the following genes with cancer survival: PLAU (testicular, skin, lung, pancreatic and brain); TGBF1 (bladder, cervical and testicular); SERPINE1 (bladder and cervical); TIPM1 (bladder); ITGA3 (endometrial and cervical); SERPINB5 (endometrial); PLAUR (cervical); CDKN1A (bladder); and IGF1 (ovarian). In conclusion, we used genomic, transcriptomic and epigenomic approaches to identify and validate genetic signatures that may be used to further understand the molecular basis of aggressive cancers (specifically mCRPC) and develop personalized treatments with the goal of improving overall survival. Citation Format: Taraswi Mitra Ghosh, Amit Kumar Mitra, Joshua Davis, Brian Cummings, Clayton Yates, Robert Arnold. Transcriptomic and epigenomic analysis of metastatic castration-resistant prostate cancer and a pan-cancer analysis of its genetic signatures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-267.