Genome-Based Classification and Therapy of Prostate Cancer

Abstract

In the past decade, multi-national and multi-center efforts were launched to sequence prostate cancer genomes, transcriptomes, and epigenomes with the aim of discovering the molecular underpinnings of tumorigenesis, cancer progression, and therapy resistance. Multiple biological markers and pathways have been discovered to be tumor drivers, and a molecular classification of prostate cancer is emerging. Here, we highlight crucial findings of these genome-sequencing projects in localized and advanced disease. We recapitulate the utility and limitations of current clinical practices to diagnosis, prognosis, and therapy, and we provide examples of insights generated by the molecular profiling of tumors. Novel treatment concepts based on these molecular alterations are currently being addressed in clinical trials and will lead to an enhanced implementation of precision medicine strategies.

Dysregulated Transcriptional Control in Prostate Cancer

“…The incidence of prostate cancer is the second highest in men and represents a leading cause of cancer mortality worldwide [1]. The recent progress made in whole-genome and transcriptome sequencing of primary, advanced, and metastasized tumor samples allowed major advances in the characterization of this heterogeneous disease [2,3,4,5,6]. Prostate cancer has a relatively low mutational burden of about one mutation per megabase [5,7], but multiple recurrent chromosomal losses and gains are frequent [2].…”

“…The recent progress made in whole-genome and transcriptome sequencing of primary, advanced, and metastasized tumor samples allowed major advances in the characterization of this heterogeneous disease [2,3,4,5,6]. Prostate cancer has a relatively low mutational burden of about one mutation per megabase [5,7], but multiple recurrent chromosomal losses and gains are frequent [2]. Gene fusions involving E26 transformation-specific ( ETS ) family members and coding mutations mainly affecting speckle-type POZ protein (SPOP), forkhead box protein A1 (FOXA1), and isocitrate dehydrogenase 1 (IDH1) are found in primary prostate cancer [2,3,4,5,8,9].…”

“…Prostate cancer has a relatively low mutational burden of about one mutation per megabase [5,7], but multiple recurrent chromosomal losses and gains are frequent [2]. Gene fusions involving E26 transformation-specific ( ETS ) family members and coding mutations mainly affecting speckle-type POZ protein (SPOP), forkhead box protein A1 (FOXA1), and isocitrate dehydrogenase 1 (IDH1) are found in primary prostate cancer [2,3,4,5,8,9]. Several alterations affecting the androgen receptor (AR) and androgen signaling emerge in castration-resistant prostate cancer (CRPC) as an adaptation to treatment [2,3,4,5,8,10].…”

MicroRNA Shuttle from Cell-To-Cell by Exosomes and Its Impact in Cancer

“…Thus, they do not differ between malignant and benign prostate tumors. The majority of PCa patients is diagnosed at the age above 65 and display localized (within the prostate) or regionally confined (spread into immediate surrounding tissue) tumors [146]. Curative therapies for PCa patients at early tumor stages are surgery and radiation, but approximately one-third of the patients develop a biochemically recurrent disease (rising PSA levels) which is treated with androgen deprivation therapy (ADT) [147].…”

Clinical Applications of Molecular Biomarkers in Prostate Cancer

“…At present, the optimal application and combination of the available treatments-active surveillance, surgery, radiotherapy, androgen-deprivation therapy (ADT), next-generation androgen receptor signalling inhibitors (ARSI), chemotherapy, immunotherapy, etc.-is not clear. Given the complexity of therapeutic decision-making in these patients, we need to determine which patients are most likely to benefit from a given treatment, establish the optimal sequence of treatments, and enrol appropriate and selected patients in clinical trials involving targeted therapies [10].…”