The TMPRSS2-ERG gene fusion is a gene rearrangement of the 5'untranslated region of the androgen-regulated TMPRSS2 gene with an ETS family member, either ERG or ETV1. It occurs in 50% of men with prostate cancer (CaP), usually early in the disease process. Detection of TMPRSS2-ERG gene fusions has been hampered by the presence of a truncated ERG protein product that is difficult to characterize with available antibodies. In the journal Neoplasia, Dr. Kyung Park and the research groups of Drs. Arul Chinnaiyan and Mark Rubin report development of a novel rabbit anti-ERG monoclonal antibody.

The antibody was tested in 131 men who underwent radical prostatectomy for prostate cancer as single therapy. Four tissue microarrays (TMAs) were established, representing tumors and benign tissue. TMPRSS2-ERG gene rearrangements do not occur in benign prostate tissue. Cases were selected in part based upon previous determination of ETS gene rearrangement status by FISH. FISH was performed in the microarrays, as was immunohistochemical (IHC) analysis using the new antibody. In total, 207 cases from two institutions were assessed for ERG rearrangements by FISH, and for ERG protein expression using IHC. Due to the truncated ERG protein that results from the TMPRSS2-ERG transcript isoform encoding, antibody-based detection would need to bind to the 3' end of ERG. While no presently commercially available antibody is capable of this, the novel rabbit monoclonal antibody was able to stain cell lines having a TMPRSS2-ERG gene rearrangement. Specificity was confirmed for the antibody-binding site on ERG by immunoblot analysis. The anti-ERG antibody was able to recognize ERG in ChIP assays using stable ERG expressing cell lines. Using an automated imaging system, ERG protein expression was confined to tumor cells, vessels and lymphocytes in the TMAs. No benign prostate glands demonstrated ERG expression. ERG staining by IHC was positive in two cases in which FISH and RT-PCR was negative. Three cases of ERG positivity by FISH had no significant ERG protein expression by IHC. There was near perfect correlation between automated IHC expression evaluation and that of the study pathologists. ERG protein expression by IHC was present in high-grade PIN that was associated with ERG-expressing prostate cancer. IHC found ERG rearrangement status positive in small vasculature regardless of surrounding tumor ERG status. FISH never detected ERG rearrangements in vessels or lymphocytes. There was 100% sensitivity for the detection of ERG rearrangements using IHC and only 1.5% of cases were determined to be false-positives.

Park K, Tomlins SA, Mudaliar KM, Chiu YL, Esgueva R, Mehra R, Suleman K, Varambally S, Brenner JC, MacDonald T, Srivastava A, Tewari AK, Sathyanarayana U, Nagy D, Pestano G, Kunju LP, Demichelis F, Chinnaiyan AM, Rubin MA

Neoplasia. 2010 Jul;12(7):590-8

UroToday Contributing Editor Christopher P. Evans, MD, FACS

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