Urologic Oncology: Seminars and Original Investigations
Review articleThe prostate cancer genome: Perspectives and potential
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.
Section snippets
ETS gene fusions
Fusions involving androgen-regulated genes and members of the ETS transcription factor family are the most common known molecular abnormality in prostate cancer, seen in a majority of cases [14], [15], [16], [17], [18], [19]. These most commonly manifest as fusion of the 5′ untranslated region of the TMPRSS2 gene and the coding areas of ERG. Over 10 androgen-regulated genes have been identified as 5′ fusion partners; other members of the ETS family that serve as 3′ partners include ETV1, ETV4,
SPOP mutations and CHD1 deletions
Mutations in SPOP represent the most common point mutations in primary prostate cancer, with recurrent mutations in SPOP in 6% to 15% of multiple independent cohorts [2], [6], [7], [37]. The SPOP gene encodes the substrate-recognition component of a Cullin3-based E3-ubiquitin ligase; missense mutations are found exclusively in the structurally defined substrate-binding cleft of SPOP, indicating that prostate cancer–derived mutations will alter substrate binding [2], [7]. One substrate of
Androgen signaling
Androgen signaling has been a focus in prostate cancer since the discovery that castration of men with advanced disease results in cancer regression. Genomic data confirming recurrent lesions in the androgen signaling axis reinforces its cardinal importance; however, lesions in the AR gene itself are largely, if not completely, restricted to CRPC [41], [42], [43]. The AR gene undergoes gene amplification, point mutations, and alteration in splicing leading to increased activity in prostate
PI3K pathway
The PI3K pathway is among the most commonly altered in human cancer, including in approximately 25% to 70% of prostate cancers, with metastatic tumors having significantly higher incidence. The PTEN tumor suppressor deactivates PI3K signaling; deletions at the PTEN locus occur in nearly 40% of primary prostate cancers, with inactivating mutations in another 5% to 10%; both are more common in advanced disease [2], [3], [4], [5], [9], [33], [52]. Functional studies across model systems repeatedly
p53
The tumor suppressor, p53 (TP53), is the most commonly mutated gene in human cancer. Recent data show deletions at the TP53 locus in about 25% to 40% of prostate cancer samples, with point mutations in 5% to 40% of cases [2], [3], [4], [5], [33], [37]. It is noteworthy that roughly 25% to 30% of clinically localized cancers harbor lesions in TP53, suggesting these alterations are not exclusively late events in the genomic history of the disease [2], and further analysis of whole-genome data
SPINK1
As studies have characterized the molecular nature of prostate cancer, additional potential subtypes have emerged. SPINK1 is a secreted protease overexpressed specifically in a subset of ETS-prostate cancers (about 10%), with SPINK1 overexpression associated with aggressive disease and increased risk of biochemical recurrence [32], [35], [64]. Furthermore, the oncogenic effects of SPINK1 may be mediated in part by its interaction with EGFR; inhibition of EGFR signaling with clinically
Ras/Raf/MAPK pathway
The MAPK pathway plays a critical role in a variety of human cancers; however, its role in prostate cancer is less well established. Signaling intermediates commonly activated in cancer, such as Ras and Raf, activate MAPK signaling and may enhance transcriptional activity of the androgen receptor [66]. Up-regulation of MAPK pathway components and upstream intermediates are common and enriched in prostate cancer metastases; however, mutations in these components are relatively rare [2], [3], [5]
Mutations in chromatin regulatory pathways
Chromatin remodeling has emerged as a major mechanism showing alterations across the spectrum of human cancers. Dysregulation of proteins involved in chromatin regulation can have far-reaching cellular effects, affecting genome-wide control of gene expression and playing key roles in DNA repair and genome maintenance. Mutations in a number of genes involved in histone modifications have been identified in prostate cancer, including KDM6A/UTX, MLL2, and MLL3 [2], [3], [5], [37]. Interestingly,
Temporal relationships among genomic events
Establishing the temporal sequence of genomic events in prostate cancer—which lesions occur early and act as cancer initiators vs. those that come later and are associated with disease progression—is critical for defining prostate cancer progression and aggressiveness at the molecular level. A reliable molecular “map” of progression could prove invaluable in a number of ways, such as for patients on active surveillance or for improved risk stratification for patients with intermediate-risk
Conclusion
Recent years have seen major strides in defining the genomic alterations in prostate cancer, elucidating molecular mechanisms underlying the disease, and applying this information to patient care. Advances in molecular subclassification of prostate cancers raise the possibility of a 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
Acknowledgments
S.A.T. is supported by a Career Development Award from the University of Michigan Prostate Cancer S.P.O.R.E. and has been supported by the Prostate Cancer Foundation. C.E.B. is supported by the Prostate Cancer Foundation and a Urology Care Foundation Research Scholar Award. S.A.T. is a coinventor on a patent issued to the University of Michigan on ETS fusions in prostate cancer. The diagnostic field of use has been licensed to Gen-Probe, Inc., who has sublicensed certain rights to Ventana
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