TMPRSS2-ERG Status Is Not Prognostic Following Prostate Cancer Radiotherapy: Implications for Fusion Status and DSB Repair

“BACKGROUND: Pre-clinical data suggest that TMPRSS2-ERG gene fusions, present in about 50% of prostate cancers (PCa), may be a surrogate for DNA repair status and therefore a biomarker for DNA damaging agents. To test this hypothesis, we examined whether TMPRSS2-ERG status was associated with biochemical failure after clinical induction of DNA damage following image-guided radiotherapy (IGRT). METHODS: Pre-treatment biopsies from two cohorts of intermediate-risk PCa patients (T1/T2, GS < 8, PSA < 20ng/mL) (> 7 years follow-up) were analyzed: (1) 126 patients with DNA samples assayed by array Comparative Genomic Hybridization for TMPRSS2-ERG fusion (CGH-cohort); and (2), 118 patients whose biopsies were scored within a tissue microarray (TMA) immunostained for ERG overexpression (surrogate for TMPRSS2-ERG fusion) (IHC-cohort). Patients were treated with IGRT with a median dose of 76 Gy. The potential role of TMPRSS2-ERG status as a prognostic factor for biochemical relapse-free rate (bRFR; nadir + 2 ng/mL) was evaluated in the context of clinical prognostic factors in multivariate analyses using Cox proportional hazards models. RESULTS: TMPRSS2-ERG fusion by aCGH was identified in 27 patients (21%) in the CGH-cohort and ERG overexpression was found in 59 patients (50%) in the IHC-cohort. In both cohorts TMPRSS2-ERG status was not associated with bRFR on univariate or multivariate analyses. CONCLUSIONS: In two similarly-treated IGRT cohorts, TMPRSS2-ERG status was not prognostic for bRFR, in disagreement with the hypothesis that these PCa have DNA repair defects that render them clinically more radiosensitive. TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response.”

Phase II Trial Targeting Genetic Anomaly in Castration-Resistant Metastatic Prostate Cancer Underway

“A new clinical trial is testing whether targeting treatments to a genetic anomaly can lead to better treatments for castration-resistant metastatic prostate cancer. The trial, led by investigators at the University of Michigan Comprehensive Cancer Center, is being conducted at 11 sites throughout the country.”

Urinary TMPRSS2:ERG and PCA3 in an active surveillance cohort: results from a baseline analysis in the Canary Prostate Active Surveillance Study

“Active surveillance is used to manage low risk prostate cancer. Both PCA3 and TMRPSS2-ERG are promising biomarkers that may be associated with aggressive disease. This study examines the correlation of these biomarkers with higher cancer volume and grade determined at the time of biopsy in an active surveillance cohort…”

Tumor associated copy number changes in the circulation of patients with prostate cancer identified through whole-genome sequencing

Patients with prostate cancer may present with metastatic or recurrent disease despite initial curative treatment. The propensity of metastatic prostate cancer to spread to the bone has limited repeated sampling of tumor deposits. Hence, considerably less is understood about this lethal metastatic disease, as it is not commonly studied. Here we explored whole-genome sequencing of plasma DNA to scan the tumor genomes of these patients noninvasively…”

PARP Inhibition Sensitizes to Low Dose-Rate Radiation TMPRSS2-ERG Fusion Gene-Expressing and PTEN-Deficient Prostate Cancer Cells

Exposure to genotoxic agents, such as irradiation produces DNA damage, the toxicity of which is augmented when the DNA repair is impaired. Poly (ADP-ribose) polymerase (PARP) inhibitors were found to be “synthetic lethal” in cells deficient in BRCA1 and BRCA2 that impair homologous recombination. However, since many tumors, including prostate cancer (PCa) rarely have on such mutations, there is considerable interest in finding alternative determinants of PARP inhibitor sensitivity…”

Monoallelic expression of TMPRSS2/ERG in prostate cancer stem cells

“While chromosomal translocations have a fundamental role in the development of several human leukaemias, their role in solid tumour development has been somewhat more controversial. Recently, it was shown that up to 80% of prostate tumours harbour at least one such gene fusion, and that the most common fusion event, between the prostate-specific TMPRSS2 gene and the ERG oncogene, is a critical, and probably early factor in prostate cancer development. Here we demonstrate the presence and expression of this significant chromosomal rearrangement in prostate cancer stem cells…”

Truncated ERG proteins affect the aggressiveness of prostate cancer

“Prostate cancer is a significant health problem around the world. It ranks second in newly diagnosed cancers and sixth in leading causes of cancer death among men. More than half of prostate cancer cases have E twenty-six (ETS) gene fusions, which are potential diagnostic markers for prostate cancer. TMPRSS2: ERG gene fusions are the most common types of gene fusions in prostate cancer. However, the association between TMPRSS2: ERG gene fusions and the aggressiveness of prostate cancer remains elusive. Recent studies showed conflicted results. We hypothesize that some N-terminal truncated ERG proteins encoded by TMPRSS2: ERG fusion genes account for the conflict…”

ERG induces androgen receptor-mediated regulation of SOX9 in prostate cancer

“Fusion of the androgen receptor-regulated (AR-regulated) TMPRSS2 gene with ERG in prostate cancer (PCa) causes androgen-stimulated overexpression of ERG, an ETS transcription factor, but critical downstream effectors of ERG-mediating PCa development remain to be established. Expression of the SOX9 transcription factor correlated with TMPRSS2:ERG fusion in 3 independent PCa cohorts, and ERG-dependent expression of SOX9 was confirmed by RNAi in the fusion-positive VCaP cell line.”