UROLOGICAL SURVEY   ( Download pdf )

 

PATHOLOGY

Morphological Features of TMPRSS2: ERG Fusion Prostate Cancer
JM Mosquera, S Perner, F Demichelis, MD Hoffer, KD Mertz, P Paris, J
Simko, C Collins, T Bismar, MA Rubin.
Brigham and Women’s Hospital, Boston, MA; Harvard Medical School, Boston, MA; University of Ulm, Ulm, Germany; SRA Division Bioinformatics Group, Povo, Trento, Italy; University of California, San Francisco, CA; McGill University, Montreal, QC, Canada; MIT and Harvard Medical School, Cambridge, MA; Dana Farber Harvard Comprehensive Cancer Center, Boston, MA, USA
Mod Pathol. 2007; 20 (suppl 2): 165A

  • Background: TMPRSS2:ETS fusion prostate cancers (PCA) comprise 40-50% of the PSA screened hospital based PCA examined to date making it the most common genetic rearrangement in human cancer. The most common variant involves TMPRSS2 and ERG. Emerging data from our group and others suggests that TMPRSS2:ERG PCA is associated with higher tumor stage and PCA specific death. The goal of this study was to determine if this common somatic alteration is associated with a morphologic phenotype.
  • Design: We assessed 253 PCA cases for TMPRSS2:ERG fusion status using FISH. Tumors were assessed for presence or absence of 8 morphologic features. The reviewers were blinded to the fusion status. Statistical analysis was performed to look for significant associations between morphologic features and TMPRSS2:ERG fusion status.
  • Results: Five morphologic features were associated with TMPRSS2:ERG PCA: blue-tinged mucin (85% of cases, n = 23/27), cribriform growth pattern (68%, n = 50/74), macronucleoli (78%, n = 39/50), intraductal tumor spread (88%, n = 38/43), and signet-ring cell-like features (82%, n = 9/11) all with p-values < 0.05. Only 24% (n = 30/125) of tumors without any of these features displayed the TMPRSS2:ERG fusion. In contrast, 55% (n = 38/69) of cases with one feature (RR = 3.88), 86% (n = 38/44) of cases with two features (RR = 20.06), and 93% (n = 14/15) of cases with three or more features (RR = 44.33) were fusion positive (p < 0.001).
  • Conclusions: This is the first study to our knowledge that demonstrates a significant link between a molecular alteration in PCA and distinct phenotypic features. The strength of these findings is similar to BRCA-1/2 breast cancers and HNPCC colon cancer. The biologic effect of TMPRSS2:ERG overexpression may drive pathways that favor these common morphologic features that pathologists observe on a daily basis. These features should also be helpful in diagnosing TMPRSS2:ERG fusion PCA which may have both prognostic and therapeutic implications. Validation studies are underway.

  • Editorial Comment
    A central aim in cancer research is to identify altered genes that play a causal role in cancer development. 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. In 2005, Tomlins SA et al. (1) identified recurrent gene fusions of the region of TMPRSS2 to ERG or ETV1 in prostate cancer tissues. These fusions may have important implications for understanding prostate cancer tumorigenesis and developing novel diagnostics and targeted therapeutics.
    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 suggest 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 aim of the study by Mosquera JM et al. was to find morphological features of TMPRSS2:ERG fusion prostate cancer that may indicate more aggressive tumors. The authors found that tumors with blue-tinged mucin, cribriform growth pattern, macronucleoli, intraductal spread and signet-ring cell-like features were frequently associated with the fusion. When 3 or more features were combined, 93% of the cases presented TMPRSS2:ERG fusion.

Reference

1. 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