PATHOLOGY

TMPRSS2-ERG gene fusions in “minimal” prostatic adenocarcinoma
Albadine R, Latour M, Haffner M, Toubaji A, Lotan T, Epstein JI, Netto GJ
Dep. of Pathology, Johns Hopkins, Baltimore, USA
Mod Pathol. 2009; 22 (suppl. 1): 155A

• Background: Minimal or “insignificant” prostatic adenocarcinoma (MinPCa) is defined as tumors with insufficient virulence to threaten survival. Given recent suggestion of TMPRSS2-ERG gene fusion association with aggressive PCa phenotype, we aimed to evaluate incidence of TMPRSS2-ERG fusion in MinPCa in comparison with grade matched “non-minimal” size PCa.
• Design: All 33 prostatectomies classified as containing MinPCa (2002-2003) were retrieved. Diagnois of MinPCa (Gleason Score 6 PCa with total tumor volume < 0.5 CC, single section) was confirmed by a urologic pathologist. Tissue microarray (TMA) was constructed from the 33 cases where each tumor and paired benign tissue was represented by up to triplicate, 1mm, spots. TMA sections of 59 additional archival PCa were used as controls (26 pT2 non-minimal in size, 31 pT3a and 2 pT3b). FISH analysis was performed using break-apart probes for 5’ and 3’ regions of ERG. Each spot was scored for presence of TMPRSS2-ERG fusion through deletion or translocation as well as for polyploidy (= 3 copies) at the ERG locus. At least 50 cells were scored per tumor.
• Results: MinPCa: TMPRSS2-ERG fusion was identified in 46% (16/35) of MinPCa. In 87% (14/16) of positive tumors, fusion was due to deletion. The remaining 13% (2/16) of fusions were based on the demonstration of a split in the two juxtaposed probe signals. Ch21 polyploidy ± fusion and duplication of ERG deletion were not observed in any MinPCa case. Control group: TMPRSS2-ERG fusion was identified in 59% (35/59) of tumors. In 77% (27/35) of positive tumors, fusion was due to deletion. Ch21 polyploidy with ± fusion was present in 13/59 (22%) while polyploidy with duplicate ERG deletion was found in 6/59 (10%) of control tumors. On statistical analysis, there was no significant difference in TMPRSS2-ERG fusion incidence between the MinPCa and control groups (p = 0.2). Statistically significant higher rates of ch 21 polyploidy ± fusion was present in control group (p = 0.0002). A trend approaching statistical significance for higher incidence of ch21 polyploidy with duplicate deletion was also present in the control group (p = 0.052).
• Conclusions: TMPRSS-ERG fusion rate of 46% is present in MinPCa. The latter is not significantly different from rate of fusion in control group of non-minimal pT2 and pT3 PCa. A higher rate of Ch21 polyploidy is detected in the control group compared to MinPCa. Our finding of a comparable rate of TMPRSS2-ERG fusion in MinPCa and non-minimal PCa argues against its value as a marker of aggressive PCa phenotype.
  
  
• Editorial Comment
  With higher number of prostate cancer detected in stage T1c due to screening, a higher number of small adenocarcinomas have been detected on needle biopsies. Many of these small adenocarcinomas may have criteria for minimal or “insignificant” cancer: tumor in no more than 2 cores, absence of Gleason grade 4 or 5, tumor not occupying more than 50% of the core, and favorable PSA density (1). It is important to note that these criteria relate to tumor volume and not biological behavior. It would be of utmost importance to know whether a minimal or “insignificant cancer” would behave as a latent (dormant or indolent) cancer or evolve to a clinical cancer.
  A notable discovery related to the molecular aspect of prostate carcinoma was the identification by Tomlins et al. (2) of a recurrent chromosomal arrangement encountered in the majority of prostate carcinomas that they studied. Possible rearrangements are of two general types. In the first, the promoter and/or enhancer elements of one gene are aberrantly juxtaposed to a proto-oncogene, thus causing altered expression of an oncogenic protein. In the second, the rearrangement fuses two genes, resulting in the production of a fusion protein that may have a new or altered activity. Tomlins et al. (2) identified recurrent gene fusions of the region of TMPRSS2 to ERG or ETV1 in prostate cancer tissues. TMPRSS2 (21q22.2) is a prostate-specific gene that is present in normal and neoplastic prostate tissue and is strongly induced by androgen in androgen-sensitive prostate cell lines. ERG (21q22.3) and ETV1 (7p21.2) are genes that encode ETS family transcription factors. TMPRSS2:ERG fusion is more frequent and occurs due to a deletion of a region on chromosome 21. TMPRSS2:ETS fusion prostate cancers comprise 40-50% of the PSA screened hospital based prostate carcinoma examined to date, making it the most common genetic rearrangement in human cancer. Emerging data suggested that TMPRSS2:ERG prostate cancer is associated with higher tumor stage and prostate specific death. Therefore, this fusion may be a marker for aggressive prostate cancer.
  The study by Albadine et al. found that TMPRSS-ERG fusion rate of 46% is present in minimal or “insignificant” prostate cancer. This finding is not significantly different from rate of fusion in control group of non-minimal confined cancer (pT2) or with extraprostatic extension cancer (pT3). The comparable rate of TMPRSS2-ERG fusion in minimal prostate cancer and non-minimal prostate cancer argues against its value as a marker of aggressive prostate cancer phenotype.

References
1. Bastian PJ, Mangold LA, Epstein JI, Partin AW: Characteristics of insignificant clinical T1c prostate tumors. A contemporary analysis. Cancer. 2004; 101: 2001-5.
2. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, et al.: Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005; 310: 644-8.

Dr. Athanase Billis
Full-Professor of Pathology
State University of Campinas, Unicamp
Campinas, São Paulo, Brazil
E-mail: athanase@fcm.unicamp.br