Abstract
BackgroundTMPRSS2:ERG fusions are frequent in prostate cancer, and occur predominantly in young patients. Several studies had proposed intratumoral heterogeneity of these fusions. This study was designed to determine frequency and extent of ERG fusion heterogeneity in early-onset prostate cancer (EO-PCA, <50 years) and in elderly patients.MethodsThe prostates from 63 EO-PCA and 62 elderly prostate cancer patients were thoroughly reviewed for presence of cancer foci. All 1592 tumor-containing sections were analyzed by immunohistochemistry for ERG expression.ResultsThe prostates included in this study contained one tumor focus in 44, two tumor foci in 21, three tumor foci in 32, four tumor foci in 15, and five or more tumor foci in 13 patients. Among 59 cancer foci with ≤3 mm, 19 (32.2 %) were homogeneously ERG positive, 39 66.1 %) were homogeneously ERG negative, and one case (1.7 %) showed a heterogeneous ERG status. The fraction of homogeneously ERG positive cancer foci remained largely constant (14–37 %) with increasing tumor focus diameter but the fraction of heterogeneous ERG findings continuously increased with tumor size and reached 39 % in cancer foci larger than 22 mm. On a patient level, ERG expression was markedly more frequent in EO-PCA than in elderly patients: 13 % of EO-PCA were homogeneously and 62 % were heterogeneously ERG positive. In elderly patients, 3 % of cancers were homogeneously and 57 % were heterogeneously ERG positive (p = 0.0721).ConclusionThese data show that about 20–30 % of prostate cancer foci have early ERG fusions. ERG fusions further occur in about 50 % of initially ERG negative cancer foci during cancer progression. The vast majority of cancers are heterogeneous for TMPRSS2:ERG fusions on a patient level, challenging the concept of classifying prostate cancer patients into “fusion type” and “non-fusion type” prostate cancer.
Highlights
Transmembrane Protease (TMPRSS2):Erythroblast Transformation-Specific Related Gene (ERG) fusions are frequent in prostate cancer, and occur predominantly in young patients
A patient was considered heterogeneous for ERG immunostaining if different tumor foci had different ERG results or if at least one tumor focus showed a mixture of ERG positive and ERG negative tumor cells
Among 74 patients with heterogeneous ERG findings, there were 25 patients (34 %) where heterogeneity was only seen between different tumor foci and 49 patients (66 %) where heterogeneity was within one or several tumor foci
Summary
TMPRSS2:ERG fusions are frequent in prostate cancer, and occur predominantly in young patients. The most important objectives of current prostate cancer research include the development of improved tools for early detection of the disease, with markers for reliably pre-therapeutic distinction between patients requiring aggressive treatment and those who do not, as well as improved systemic treatment options for patients with aggressive and metastatic disease. It is hoped, that the rapidly increasing knowledge of the molecular basis of prostate cancer will eventually lead to relevant clinical applications. Detecting ERG expression by immunohistochemistry and visualization of ERG rearrangements by fluorescence in situ hybridization (FISH) have proven as reliable methods for detecting TMPRSS2:ERG fusions [4, 5]
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