Genomic Profiling Defines Subtypes of Prostate Cancer with the Potential for Therapeutic Stratification

Abstract

The remarkable variation in prostate cancer clinical behavior represents an opportunity to identify and understand molecular features that can be used to stratify patients into clinical subgroups for more precise outcome prediction and treatment selection. Significant progress has been made in recent years in establishing the composition of genomic and epigenetic alterations in localized and advanced prostate cancers using array-based technologies and next generation sequencing approaches. The results of these efforts shed new light on our understanding of this disease and point to subclasses of prostate cancer that exhibit distinct vulnerabilities to therapeutics. The goal of this review is to categorize the genomic data and, where available, corresponding expression, functional, or related therapeutic information, from recent large-scale and in-depth studies that demonstrate a new appreciation for the molecular complexity of this disease. We focus on how these results inform our growing understanding of the mechanisms that promote genetic instability, as well as routes by which specific genes and biological pathways may serve as biomarkers or potential targets for new therapies. We summarize data that indicate the presence of genetic subgroups of prostate cancers and demonstrate the high level of intra- and intertumoral heterogeneity, as well as updated information on disseminated and circulating tumor cells. The integrated analysis of all types of genetic alterations that culminate in altering critical biological pathways may serve as the impetus for developing new therapeutics, repurposing agents used currently for treating other malignancies, and stratifying early and advanced prostate cancers for appropriate interventions.

Genomic Predictors of Outcome in Prostate Cancer

“…Due to the breadth of the topic and recent high-quality reviews, we have specifically focused on genomic tests that are already available or approaching the point of clinical use [4][5][6][7][8][9][10].…”

Methylation profiling identified novel differentially methylated markers includingOPCMLandFLRT2in prostate cancer

“…3 Hypermethylation of promoter CpG islands (CGIs) can silence tumor suppressor genes early during tumorigenesis, while significant global hypomethylation arises later in PCa progression. [4][5][6] It is likely that different patterns of DNA methylation may distinguish aggressive vs. indolent PCa and predict responses to specific treatments. Earlier studies have shown that promoter hypermethylation of specific genes are associated with PCa progression.…”

The context of prostate cancer genomics in personalized medicine

“…The results suggest that tumor-associated genomic aberrations may be utilized for cancer screening, diagnosis, risk prognosis, therapy prediction and outcome assessment (30)(31)(32). Blood PSA tests are frequently used to screen and detect early-stage cancer (33).…”

“…Individual patients have a distinct pattern of genetic alterations; therefore, treatment should be guided by the profile of diagnostic biomarkers (14,22,32). The AR signaling axis is a major target for numerous hormone therapies, throughout the stages of cancer (59)(60)(61).…”