Chromosome Mechanisms Giving Rise to the TMPRSS2-ERG Fusion Oncogene in Prostate Cancer and HGPIN Lesions

Teixeira, Manuel R.

doi:10.1097/pas.0b013e31815b6056

Cited by 18 publications

(13 citation statements)

References 5 publications

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“…Although there were limitations in our conclusions, many previous studies supported our results, indicating that chromosome rearrangement was found in more than half of PCa cells and new proteins encoded by fusion genes advanced the development of cancer (Perner et al, 2006;Saramaki and Visakorpi, 2007;Teixeira, 2008;Demichelis et al, 2009). A recent finding in cancer cells is that the 3-dimensional structure of DNA displays ultrahigh compression in the changed chromosome, which will manipulate thousands of downstream genes.…”

Section: Discussionsupporting

confidence: 80%

Analysis of fusion gene expression in prostate tumors by using single-end reads

Dd¹,

Jy²,

Wang³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Fusion gene expression, a kind of chromosome rearrangement mode, has been strongly linked to prostate cancer diagnosis and prognosis as well as to the Gleason score and the American Joint Committee on Cancer stage assessment. In combination with traditional methods for locating fusion genes and scoring their association with cancer cell growth, proliferation, and invasion through the basement membrane, the emerging high-throughput sequencing technologies offer a panorama of fusion genes in a genome and facilitate the discovery of new fusion modes. We describe here a method for using single-end reads to analyze fusion gene expression in prostate tumors. We obtained the fusion gene expression profiling of prostate tumors, clustered them into several biological pathways, highlighted three "rediscovered" fusion genes (TMPRSS2-ERG, KLK2, and KLK3) and proved the reliability of our method.

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Section: Discussionsupporting

confidence: 80%

Analysis of fusion gene expression in prostate tumors by using single-end reads

Dd¹,

Jy²,

Wang³

et al. 2013

Genet. Mol. Res.

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“…We and others have subsequently confirmed the presence of this chimeric gene in about 50% of PCa patients (Cerveira et al, 2006;Hermans et al, 2006;Perner et al, 2006;Soller et al, 2006;Yoshimoto et al, 2006). The mechanism behind this rearrangement is either an interstitial deletion in 21q22.2-3, where TMPRSS2 and ERG are located 3 Mbp apart or an insertion of the sequences between the two fusion partners into another chromosome, although a translocation mechanism is theoretically also possible (Teixeira, 2008). Other ETS family genes, namely ETV1, ETV4, and ETV5, have been found fused with TMPRSS2 or with other 5 0 partners (Prensner and Chinnaiyan, 2009), although at much lower frequencies.…”

Section: Introductionmentioning

confidence: 54%

Relative 8q gain predicts disease‐specific survival irrespective of the TMPRSS2‐ERG fusion status in diagnostic biopsies of prostate cancer

Barros-Silva

Ribeiro

Rodrigues

et al. 2011

Genes Chromosomes & Cancer

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Screening tools have greatly improved prostate cancer (PCa) detection, but the disease course is heterogeneous, and standard clinicopathological parameters do not fully discriminate aggressive from indolent tumors. To evaluate the prognostic value of the TMPRSS2-ERG fusion gene combined with chromosome arm 8q relative gain in diagnostic biopsies of PCa, we studied a consecutive series of 200 diagnostic needle biopsies from patients with 10-year disease-specific survival data. TMPRSS2-ERG fusion gene status and relative 8q gain were assessed by fluorescent in situ hybridization in whole formalin fixed paraffin-embedded biopsies. The TMPRSS2-ERG fusion gene was detected in 43.5% of PCa and was associated with lower Gleason score (P = 0.045), whereas relative 8q gain was present in 48% of PCa and was associated in high-Gleason score (P < 0.001). ERG rearrangement alone was not associated with clinical outcome, whereas relative 8q gain predicted worse disease-specific survival in PCa patients both with and without the TMPRSS2-ERG fusion gene (P < 0.001), independently of Gleason score, clinical stage, and treatment modality. We conclude that relative 8q gain in diagnostic needle biopsies is a poor prognostic factor independent of the TMPRSS2-ERG fusion gene status and of standard clinicopathological parameters.

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“…Such ERG gene fusions occur during the initiation of PCa progression, which can then lead to the transition from high-grade prostatic intraepithelial neoplasia lesions to invasive carcinoma (4, 5). The TMPRSS2-ERG rearrangement can occur either by interstitial deletion (2, 6, 7) or by chromosomal translocation (8) as both fusion protein partners are located on chromosome 21q just 3 Mb apart. Recent studies reported that androgen stimulation facilitates chromosomal proximity of the TMPRSS2 and ERG genomic loci in several cell lines (9, 10), which can then drive the formation of TMPRSS2-ERG rearrangements at low frequency (9, 11).…”

Section: Introductionmentioning

confidence: 99%

The TMPRSS2–ERG Gene Fusion Blocks XRCC4-Mediated Nonhomologous End-Joining Repair and Radiosensitizes Prostate Cancer Cells to PARP Inhibition

Chatterjee

Choudhary

Alswillah

et al. 2015

Molecular Cancer Therapeutics

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Exposure to genotoxic agents, such as ionizing radiation (IR) produces DNA damage leading to DNA double-strand breaks (DSBs); IR toxicity is augmented when the DNA repair is impaired. We reported that radiosensitization by a PARP inhibitor (PARPi) was highly prominent in prostate cancer (PCa) cells expressing the TMPRSS2-ERG gene fusion protein. Here, we show that TMPRSS2-ERG blocks non-homologous end-joining (NHEJ) DNA repair by inhibiting DNA-PKcs. VCaP cells, which harbor TMPRSS2-ERG and PC3 cells that stably express it displayed γH2AX and 53BP1 foci constitutively, indicating persistent DNA damage that was absent if TMPRSS2-ERG was depleted by siRNA in VCaP cells. The extent of DNA damage was enhanced and associated with TMPRSS2-ERG’s ability to inhibit DNA-PKcs function, as indicated by its own phosphorylation (Thr2609, Ser2056) and that of its substrate, Ser1778-53BP1. DNA-PKcs deficiency caused by TMPRSS2-ERG destabilized critical NHEJ components on chromatin. Thus, XRCC4 was not recruited to chromatin, with retention of other NHEJ core factors being reduced. DNA-PKcs autophosphorylation was restored to the level of parental cells when TMPRSS2-ERG was depleted by siRNA. Following IR, TMPRSS2-ERG-expressing PC3 cells had elevated Rad51 foci and homologous recombination (HR) activity, indicating that HR compensated for defective NHEJ in these cells, hence addressing why TMPRSS2-ERG alone did not lead to radiosensitization. However, the presence of TMPRSS2-ERG, by inhibiting NHEJ DNA repair, enhanced PARPi-mediated radiosensitization. IR in combination with PARPi resulted in enhanced DNA damage in TMPRSS2-ERG-expressing cells. Thus, by inhibiting NHEJ, TMPRSS2-ERG provides a synthetic lethal interaction with PARPi in PCa patients expressing TMPRSS2-ERG.

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Chromosome Mechanisms Giving Rise to the TMPRSS2-ERG Fusion Oncogene in Prostate Cancer and HGPIN Lesions

Cited by 18 publications

References 5 publications

Analysis of fusion gene expression in prostate tumors by using single-end reads

Analysis of fusion gene expression in prostate tumors by using single-end reads

Relative 8q gain predicts disease‐specific survival irrespective of the TMPRSS2‐ERG fusion status in diagnostic biopsies of prostate cancer

The TMPRSS2–ERG Gene Fusion Blocks XRCC4-Mediated Nonhomologous End-Joining Repair and Radiosensitizes Prostate Cancer Cells to PARP Inhibition

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