Molecular Composition of Genomic TMPRSS2-ERG Rearrangements in Prostate Cancer

Abstract

There is increasing interest in the use of cell-free circulating tumor DNA (ctDNA) as a serum marker for therapy assessment in prostate cancer patients. Prostate cancer is characterized by relatively low numbers of mutations, and, in contrast to many other common epithelial cancers, commercially available single nucleotide mutation assays for quantification of ctDNA are insufficient for therapy assessment in this disease. However, prostate cancer shares some similarity with translocation-affected mesenchymal tumors (e.g., leukemia and Ewing sarcoma), which are common in pediatric oncology, where chromosomal translocations are used as biomarkers for quantification of the tumor burden. Approximately 50% of prostate cancers carry a chromosomal translocation resulting in generation of the TMPRSS2-ERG fusion gene, which is unique to the tumor cells of each individual patient because of variability in the fusion breakpoint sites. In the present study, we examined the structural preconditions for TMPRSS2-ERG fusion sites in comparison with mesenchymal tumors in pediatric patients to determine whether the sequence composition is suitable for the establishment of tumor-specific quantification assays in prostate cancer patients. Genomic repeat elements represent potential obstacles to establishment of quantification assays, and we found similar proportions of repeat elements at fusion sites in prostate cancer to those reported for mesenchymal tumors, where genomic fusion sequences are established as biomarkers. Our data support the development of the TMPRSS2-ERG fusion gene as a noninvasive tumor marker for therapy assessment, risk stratification, and relapse detection to improve personalized therapy strategies for patients with prostate cancer.

Genomic Breakpoint Characterization and Transcriptome Analysis of Metastatic, Recurrent Desmoplastic Small Round Cell Tumor

“…DSRCT breakpoints were further notable for the complete absence of filler bases at their breakpoint junction. Filler bases have been identified in approximately 15–20% of breakpoints in other fusion-based tumors and are a byproduct of NHEJ [ 33 , 35 ]. Together, these findings suggest DSRCT genomic breakpoints may form predominantly through MMEJ rather than NHEJ [ 36 , 37 ].…”

Blood-Derived Biomarkers of Diagnosis, Prognosis and Therapy Response in Prostate Cancer Patients

“…Quantification of cell-free circulating tumour nucleotides in blood samples is another promising new molecular strategy for non-invasive tumour monitoring in prostate cancer [ 79 ]. CfDNA may be more suitable than CTCs to estimate therapy efficiency in patients with early-stage disease [ 80 ].…”

“…50% of patients results from the fusion of the androgen-regulated gene, transmembrane protease serine 2 gene ( TMPRSS2 , chr21q22.2), with E-twenty-six (ETS)-related gene ( ERG , chr21q22.3). This rearrangement is detectable in CTCs or as cfDNA and might be considered as a highly tumour-specific, non-invasive molecular biomarker for therapy assessment, risk stratification and relapse detection [ 79 , 87 , 88 ]. Furthermore, prostate cancer carrying this rearrangement can regulate the recruitment and infiltration of regulatory T cells (Tregs) in the tumour [ 89 ].…”

Dysregulation of Type II Transmembrane Serine Proteases and Ligand-Dependent Activation of MET in Urological Cancers

“…The proteolytic cleavage and activation of hemagglutinin protein are also essential for the viral infectivity of influenza A virus (strains of H1N1, H3N2, and H7N9) [73,74]. Recent studies revealed that a gene fusion of TMPRSS2 to erythroblast transformation-specific (ETS) transcription factors is commonly observed in prostate cancer tissues [75,76]. Among these, fusion of TMPRSS2 and ERG is the most common (approximately 50%) chromosomal rearrangement [75,76].…”

“…Recent studies revealed that a gene fusion of TMPRSS2 to erythroblast transformation-specific (ETS) transcription factors is commonly observed in prostate cancer tissues [75,76]. Among these, fusion of TMPRSS2 and ERG is the most common (approximately 50%) chromosomal rearrangement [75,76]. However, no apparent proteolytic activity in this fusion protein has been reported (the protein mainly acts as a transcription factor).…”