Recurrent gene fusions in prostate cancer

Abstract

The discovery of recurrent gene fusions in a majority of prostate cancers has important clinical and biological implications in the study of common epithelial tumors. Gene fusion and chromosomal rearrangements were previously thought to be the primary oncogenic mechanism of hematological malignancies and sarcomas. The prostate cancer gene fusions that have been identified thus far are characterized by 5' genomic regulatory elements, most commonly controlled by androgen, fused to members of the ETS family of transcription factors, leading to the over-expression of oncogenic transcription factors. ETS gene fusions likely define a distinct class of prostate cancer which may have a bearing on diagnosis, prognosis and rational therapeutic targeting.

Overexpression of C-MYC oncogene in prostate cancer predicts biochemical recurrence

“…Extensive efforts have been focused on further elucidation of the biological basis of CaP onset/progression that may lead to the development of new diagnostic and prognostic markers, and identification of potential therapeutic targets. [4][5][6] Alterations in the expression of chromosome 8 genes (losses at 8q21-22 and amplifications at 8q24) have been identified in CaP. 7 Amplification at the 8q24 locus, which includes the C-MYC proto-oncogene, has been suggested as potential prognostic factor for CaP.…”

Potential for targeted therapy in prostate cancers with ERG abnormalities

“…1,2,7 Subsequent studies have found these gene fusions to appear early in prostate cancer development, 6 present in a subset of cases of prostatic intra-epithelial neoplasia and putative precursor lesions. 2,8,9 Likewise, ERG fusions are present throughout the spectrum of the various microscopic manifestations of prostate cancer, 6,10,11 supporting their role as a key step in the pathogenesis of prostate cancer in general. However, other genetic alterations appear to be contributory components of tumor development, such as loss of PTEN and activation of the PI3-kinase pathway, particularly in the setting of progression from an intraepithelial neoplasm to invasive adenocarcinoma.…”

“…[1][2][3][4][5][6] Most commonly, fusion of the transcriptional regulator gene ERG (ETSrelated gene) with TMPRSS2 is seen, present in half or more of prostate cancers, although other partner genes, such as ETV1, ETV4 and ETV5, may be involved in translocations. 1,2,7 Subsequent studies have found these gene fusions to appear early in prostate cancer development, 6 present in a subset of cases of prostatic intra-epithelial neoplasia and putative precursor lesions.…”

“…However, other genetic alterations appear to be contributory components of tumor development, such as loss of PTEN and activation of the PI3-kinase pathway, particularly in the setting of progression from an intraepithelial neoplasm to invasive adenocarcinoma. 2,4,12 Although abnormalities of ETS genes are sometimes found in tumors of other organs, ERG-TMPRSS2 fusion is not seen in common neoplasms of other sites, both epithelial and non-epithelial. 3 As such, these abnormalities have begun to demonstrate tremendous potential for broad applications in diagnosis, prognostication and treatment of prostate cancer.…”

“…3 As such, these abnormalities have begun to demonstrate tremendous potential for broad applications in diagnosis, prognostication and treatment of prostate cancer. 2,5 With regard to therapy, however, gene rearrangements involving transcription factors have unfortunately been largely considered poor targets for pharmacologic therapy, due to their lack of enzymatic activity, location within the nucleus and complex interaction with other proteins required for function. 13,14 Nonetheless, in a recent study by Brenner et al, 7 the authors identified a potential avenue of utility for poly(ADPribose) polymerase 1 (PARP1) inhibition in treatment and prognostication for patients with ETS-abnormal prostate cancer, opening the door for a wide spectrum of potential applications.…”