ERG rearrangement is specific to prostate cancer and does not occur in any other common tumor

Abstract

Background Identification of specific somatic gene alterations is crucial for the insight into the development, progression, and clinical behavior of individual cancer types. The recently discovered recurrent ERG rearrangement in prostate cancer (PCa) might represent a PCa specific alteration that has not been systematically assessed in tumors other than PCa. Aim of this study was to assess, whether the ERG rearrangement and the distinct deletion site between TMPRSS2 and ERG, both predominantly resulting in a TMPRSS2-ERG fusion, occurs in tumors other than PCa. Design We assessed 54 different tumor types (2942 samples in total) for their ERG rearrangement status by FISH. To calibrate, we analyzed 285 PCa samples for the ERG rearrangement frequency. Additionally, we interrogated a high-resolution SNP data set across 3131 cancer specimens (26 tumor types) for copy number alterations. Results None of the 54 different tumor types assessed by FISH harbored an ERG rearrangement, whereas the PCa samples revealed an ERG rearrangement in 31.2%–49.5%, depending on the cohort. Furthermore, within the 26 tumor types assessed for copy number alterations by SNP, the distinct deletion site between TMPRSS2 and ERG (21q22.2-3) was detectable exclusively in PCa. Conclusion Although Ewing's sarcoma and AML have known rearrangements rarely involving ERG, we hypothesize that the ERG rearrangement as well as the distinct deletion site on 21q22.2-3 between TMPRSS2 and ERG, are PCa specific genomic alterations. These observations provide further insight into the oncogenesis of PCa and might be critical for the development of ERG rearrangement assessment as a clinical tool.

ERG protein expression and genomic rearrangement status in primary and metastatic prostate cancer—a comparative study of two monoclonal antibodies

“…13 Among these, the most commonly observed and highly PCa-specific event is the promoting linkage of the androgen-regulated gene TMPRSS2 to the oncogenic transcription factor ERG. 18 Other, but rarely observed 5 0 fusions partners of ERG, are SLC45A3 and NDRG1. 2,3 In the vast majority of PCa, ERG rearrangements result in a clonal overexpression of chimeric fusion transcripts encoding truncated variants of the ERG protein.…”

“…TMA construction was performed as described earlier. 12,18 Briefly, formalinfixed paraffin-embedded PCa tissue blocks were sectioned at 3 mm thick sections, mounted on slides and stained with haematoxylin and eosin. Prior to TMA construction, representative cancer areas were marked by a pathologist (S P).…”

“…Furthermore, despite its high prevalence and clonal nature, 13 --17 the ERG rearrangement is highly specific to PCa. 18 Thus, a diagnostic as well as companion diagnostic utilization of the ERG rearrangement in PCa is imminent, whereas a prognostic and predictive relevance is still controversial.…”

Potential for targeted therapy in prostate cancers with ERG abnormalities

“…[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.…”

“…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. 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.…”