Protein in Prostate Biopsy May Signal Higher Risk of Cancer

“A new study shows that men who have a specific marker present in their prostate biopsy may benefit from close follow-up and additional biopsies. When present, the marker—a protein found in the biopsied tissue—increases the chance that cancer will develop in the prostate. This could identify patients that need to be carefully monitored from those that do not, a decision that is currently difficult to make for clinicians. The study is published in the Journal of Clinical Oncology.

Evaluation of ERG Responsive Proteome in Prostate Cancer

“Background: Gene fusion between TMPRSS2 promoter and the ERG proto-oncogene is a major genomic alteration found in over half of prostate cancers (CaP), which leads to aberrant androgen dependent ERG expression. Despite extensive analysis for the biological functions of ERG in CaP, there is no systematic evaluation of the ERG responsive proteome (ERP). ERP has the potential to define new biomarkers and therapeutic targets for prostate tumors stratified by ERG expression. METHODS: Global proteome analysis was performed by using ERG (+) and ERG (-) CaP cells isolated by ERG immunohistochemistry defined laser capture microdissection and by using TMPRSS2-ERG positive VCaP cells treated with ERG and control siRNA…Conclusions: This study delineates the global proteome for prostate tumors stratified by ERG expression status. The ERP data confirm the functions of ERG in inhibiting cell differentiation and activating cell growth, and identify potentially novel biomarkers and therapeutic targets.”

ETS Factors Reprogram the Androgen Receptor Cistrome and Prime Prostate Tumorigenesis in Response to PTEN Loss

“Studies of ETS-mediated prostate oncogenesis have been hampered by a lack of suitable experimental systems. Here we describe a new conditional mouse model that shows robust, homogenous ERG expression throughout the prostate. When combined with homozygous Ptenloss, the mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG markedly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included the restoration of AR transcriptional output and upregulation of genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETS variant 1 (ETV1) positively regulated the AR cistrome and transcriptional output in ETV1-translocated, PTEN-deficient human prostate cancer cells. In two large clinical cohorts, expression of ERG and ETV1 correlated with higher AR transcriptional output in PTEN-deficient prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.”

Recurrent Deletion of 3p13 Targets Multiple Tumor Suppressor Genes and Defines a Distinct Subgroup of Aggressive ERG Fusion Positive Prostate Cancers

“Deletion of 3p13 has been reported from about 20% of prostate cancers. The clinical significance of this alteration and the tumor suppressor gene(s) driving the deletion remain to be identified. We have mapped the 3p13 deletion locus using SNP array analysis and performed fluorescence in situ hybridization (FISH) analysis to search for associations between 3p13 deletion, prostate cancer phenotype and patient prognosis in a tissue microarray containing more than 3,200 prostate cancers. SNP array analysis of 72 prostate cancers revealed a small deletion at 3p13 in 14 (19%) of the tumors, including the putative tumor suppressors FOXP1, RYBP, and SHQ1.”

Altered DNA Methylation Landscapes of Polycomb-Repressed Loci Are Associated with Prostate Cancer Progression and ERG Oncogene Expression in Prostate Cancer

“To assess differentially methylated “landscapes” according to prostate cancer Gleason score (GS) and ERG oncogene expression status, and to determine the extent of polycomb group (PcG) target gene involvement, we sought to assess the genome-wide DNA methylation profile of prostate cancer according to Gleason score and ERG expression.”

New Gene-Targeting Drug is Being Studied in a Phase 2 Clinical Trial

A phase II clinical trial is being held to investigate the effect of an experimental drug, ABT-888, on castration-resistant prostate cancer (CRPC) in patients who have a genetic mutation known as a TMPRSS2:ERG gene fusion. In lab studies, ABT-888 used in combination with the prostate cancer drug abiraterone (Zytiga), helped shrink prostate cancer tumors and was especially effective for shrinking tumors that had the genetic mutation. The clinical trial is being led by investigators at the University of Michigan Comprehensive Cancer Center and conducted at multiple sites throughout the country. For more information about this trial, “A Randomized Gene Fusion-Stratified Phase II Trial of Abiraterone with or without ABT-888 for Patients with Metastatic Castration-Resistant Prostate Cancer,” call the U-M Cancer Answerline at 800-865-1125.

Altered DNA methylation landscapes of polycomb-repressed loci are associated with Gleason score and ERG oncogene expression in prostate cancer

To assess differentially methylated ‘landscapes’ according to prostate cancer (PCa) Gleason score (GS) and ERG oncogene expression status, and to determine the extent of polycomb group (PcG) target gene involvement, we sought to assess the genome-wide DNA methylation profile of PCa according to GS and ERG expression…”

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…”