Common gene rearrangements in prostate cancer

Abstract

Prostate cancer is a common heterogeneous disease, and most patients diagnosed in the post prostate-specific antigen (PSA) era present with clinically localized disease, the majority of which do well regardless of treatment regimen undertaken. Overall, those with advanced prostate cancer at time of diagnosis do poorly after androgen withdrawal therapy. Understanding the biologic underpinning of prostate cancer is necessary to best determine the risk of disease progression and would be advantageous for the development of novel therapeutic approaches to impede or prevent disease. This review focuses on the recently identified common ETS and non-ETS gene rearrangements in prostate cancer. Although multiple molecular alterations have been detected in prostate cancer, a detailed understanding of gene fusion prostate cancer should help explain the clinical and biologic diversity, providing a rationale for a molecular subclassification of the disease.

Fig 1.

Targeting prostate cancer by using the gene fusion “on/off” switches. Gene fusion prostate cancers present an opportunity to target specific promoters and ETS genes. Several approaches can be considered in targeting gene fusion prostate cancers. In this schematic, the TMPRSS2 5′ promoter acts as an on switch in the presence of androgens and, in some settings, estrogen. Therefore, targeting the androgen receptor (AR) site of TMPRSS2 with small molecules may effectively decrease the expression of the fusion transcript. Approaches to target the mRNA fusion transcript by using short interfering RNA (siRNA) might be an effective means of decreasing the specific oncogenic fusion transcript. Small molecules might also be generated against the specific 3′ ETS gene or putative collaborating lesions such as PTEN or MYC). DHT, dehydrotestosterone; Rx, drug therapy (eg, small molecules, siRNA).

Fig 2.

Two models of prostate cancer progression. The standard view has been that prostate cancer progresses through a series of molecular lesions. In the linear model, molecular events, including mutations, deletions, and amplifications, occur in sequence corresponding to progression of disease from the morphologically appearing benign prostate tissue, moving to high-grade prostatic intraepithelial neoplasia (PIN), then progressing to invasive prostate cancer, and finally to local and distant metastatic spread. However, in this review, we support the view that prostate cancer progresses through a wide range of lesions that lead to several possible pathways, some of which may not progress at all. In the molecular diversity model, alterations occur that might be classified as gatekeeper lesions. Once these events occur, additional events may lead to PIN that does not have the capacity to progress or PIN that may progress. Accumulation of molecular alterations associated with aggressive disease such as the overexpression of EZH2 or PTEN mutations may lead to invasive disease that progresses to metastatic disease, whereas other lesions such as 5q or 6q gain and overexpression of AZGP1 might be seen most often in indolent disease. Mutations and alterations associated with p53 and the androgen receptor (AR) are probably late events and may play a key role in the development of castration-resistant disease. SNP, single-nucleotide polymorphism.

Fig 3.

Molecular events associated with prostate cancer development and progression. Recent work has identified several genes and pathways associated with prostate cancer progression. Critical pathways depicted in this schematic of a prostate cancer cell include disruption of the WNT signaling, PI3K/AKT/PTEN and RAS/RAF/MAPF kinase pathways. Other pathways may be involved in the inactivation of GST-pi through methylation and histone methylation by polycomb genes such as EZH2. The activation of alterations of the androgen receptor (AR) is also believed to play a central role in disease progression from the androgen-dependent state to the castration-resistant state observed in advanced disease. The ETS fusion cancers often harbor an upstream, hormonally regulated promoter (eg, TMPRSS2 or SLC45A3). These promoters are known androgen response elements (AREs) and act as amplifiers of the ETS gene expression in the setting of androgens. Interestingly, recent work has also demonstrated the presence of estrogen binding sites on the TMPRSS2 promoter site (not depicted), suggesting a mechanism for continued expression of the ETS fusion transcript in the castration state of low androgens. DHT, dehydrotestosterone.

Fig 4.

Prostate cancer gene fusion classification. The ongoing effort to screen prostate cancer patients for gene fusions, in combination with the recent technology advances, has resulted in a comprehensive gene fusion landscape. This schematic highlights all published gene fusions categorized into ETS rearrangements, RAF kinase gene fusions, and SPINK1-positive, ETS rearrangement–negative prostate cancers. The percentages highlight the estimated frequency of each gene fusion on the basis of published screens.

Fig 5.

ERG rearranged prostate cancer and high-grade prostatic intraepithelial neoplasia (HGPIN) express high levels of truncated ERG protein. Representative examples of prostate cancers and HGPIN (A and C) showing similar ERG protein expression by immunohistochemistry (a rabbit anti-ERG monoclonal antibody, clone EPR 3864, Epitomics, Burlingame, CA). Hematoxylin and eosin stain demonstrates prostatic cancerous glands (A) and another case with HGPIN (C). ERG protein expression by immunohistochemistry demonstrates strong expression in both cancer (B) and HGPIN (D). In (C), the PIN label indicates discrete demarcation between HGPIN and histologically benign luminal epithelial cells labeled B (×40).

Fig 6.

The diagnostic predictive and prognostic implication of ETS fusion prostate cancer. The fusion of two genes to form a novel chimeric mRNA transcript represents a unique opportunity to develop a diagnostic test. Recent studies have demonstrated that the fusion transcript can be identified in the serum and urine from men with prostate cancer. The urine assay is being developed commercially with the goal of establishing a highly specific test. Prostate tissue derived from clinical biopsies, transurethral resection of the prostate samples, or radical prostatectomies can be used to detect the ETS rearrangement events by using fluorescent in situ hybridization (FISH) or reverse transcriptase polymerase chain reaction (PCR). The identification of ETSrearrangements may have prognostic implications in specific settings (eg, an active surveillance clinical trial) and may also be predictive of response to targeted therapies such as those targeting the androgen receptors. The significance of these clinical assays will largely depend on future studies that determine to what extent ETS rearrangement prostate cancers behave differently from nonrearranged prostate cancers. Bx, biopsy.