The prostate cancer genome: Perspectives and potential

Abstract

Objectives

Prostate cancer has a variable clinical course, and molecular characterization has revealed striking mutational heterogeneity that may underlie the unpredictable clinical behavior of the disease. Advances in technology have resulted in a rapid expansion of our understanding of the genomic events responsible for the development and progression of prostate cancer. In this review, we discuss the genomic alterations underlying prostate cancer, and potential to utilize this knowledge for diagnostic and prognostic benefit.

Methods and Materials

We reviewed the relevant literature, with a focus on recent studies on somatic alterations in prostate cancer.

Results

Pathways known to affect tumorigenesis across a wide spectrum of tissues are dysregulated, such as the PI3K pathway, cell cycle control, and chromatin regulation. Lesions more specific to prostate cancer include alterations in androgen signaling, gene fusions of ETS transcription factors, and mutations in SPOP. Accumulating data suggests that prostate cancer can be subdivided based on a molecular profile of these genetic alterations.

Conclusions

These findings raise the possibility that prostate cancer could transition from a poorly understood, heterogeneous disease with a variable clinical course to a collection of homogenous subtypes, identifiable by molecular criteria, associated with distinct risk profiles, and perhaps amenable to specific management strategies or targeted therapies.

Introduction

Prostate cancer is a clinically heterogeneous disease. Over 230,000 cases of prostate cancer are estimated to be diagnosed in the United States in 2013 [1]. Many will have aggressive disease with progression, metastasis, and death from prostate cancer, which is the second most common cause of cancer death in the United States. However, others will have indolent disease that will not threaten their health during their natural lifetime. Recent years have brought a rapid expansion of data regarding the molecular basis of prostate cancer, with a remarkable genetic heterogeneity that may underlie the clinically variable behavior of the disease [2], [3], [4], [5], [6], [7]. This review focuses on the genomic changes in prostate cancer and relevance to clinical practice.

The complete genomes of about 75 prostate cancers have been reported, along with hundreds of prostate cancer exomes [2], [3], [6], [7], [8], [9]. These studies, along with myriad gene expression and copy number profiles, provide a relatively comprehensive picture of the alterations in prostate cancer at the genomic and gene expression levels. The prostate cancer genome displays relatively few focal chromosomal gains or losses (most commonly focal loss at PTEN) and overall low mutation rate (~1 per MB) compared with other cancers. In localized cancers, point mutations are most common in SPOP, which encodes the substrate-recognition component of a ubiquitin ligase, TP53 and PTEN, albeit with relatively low frequency (only about 5%–10% for each gene) [2], [5], [7], [10]. Following treatment with therapies targeting the androgen axis, metastatic lesions show amplifications and mutations of the AR gene. Approximately half of PSA-screened prostate cancers harbor recurrent gene fusions involving ETS transcription factors, typically fusing the 5′ untranslated region of an androgen-regulated gene (most commonly TMPRSS2) to nearly the entire coding sequence of an ETS transcription factor family member (most commonly ERG). Finally, whole-genome studies have revealed that relatively large numbers of chromosomal rearrangements, particularly in early onset cases, many involving known cancer-associated genes in distinctive complex patterns of rearrangement, which has been termed “chromoplexy” [6], [8], [9].

The spectrum of specific genomic lesions in prostate cancer is diverse, with considerable molecular heterogeneity between tumors. However, alterations in specific signaling pathways are recurrent. These include both pathways known to affect tumorigenesis across a wide variety of cancer types and as well as those more specific to prostate cancer. In addition, though impressive progress has been made in cataloging genomic alterations in prostate cancer, the prognostic significance of the majority of these changes remains unclear. Prostate cancer has intrinsic challenges to establishing these relationships—long natural history, necessity for long follow-up on large, well-annotated cohorts, issues of sampling and tumor multifocality, and complications defining and understanding initiating lesions versus those associated with progression and mortality.

The heterogeneity of prostate cancer complicates risk stratification and selection of management strategies. However, molecular classification holds the promise of identifying specific subclasses of prostate cancer associated with distinct patterns of genomic abnormalities. Genomic and transcriptomic analyses reveal that prostate tumors can be subclassified based on gene expression and SCNA signatures, with some success in predicting aggressive features of disease or impact on prognosis [5], [11], [12], [13]. Systematic sequencing studies continue to add data allowing the definition of molecular subclasses based on mutations and copy number aberrations (Fig. 1). These discoveries raise the possibility that prostate cancer might soon transition from a poorly understood, clinically heterogeneous disease to a collection of homogenous subtypes identifiable by molecular criteria, associated with specific genetic abnormalities, with distinct effects on patient prognosis, amenable to specific management strategies, and perhaps vulnerable to specific targeted therapies.