Evaluation of PTEN and TMPRSS2-ERG abnormalities in prostate cancer by FISH and immunohistochemistry to address intra- and intertissue heterogeneity and disease progression.

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4651 Background: Gene fusions involving the ERGoncogene and deletions of the PTEN tumor suppressor are frequent alterations in prostate cancer. Recent reports highlighted the cooperation of these two pathways in prostate cancer progression using mouse models and human tumors. We developed a monoclonal antibody (CPDR ERG-MAb) that specifically recognizes the ERG oncoprotein in human prostate tumors. The objective of this study was to determine the frequency of ERG positive prostate cancer by immunohistochemistry (IHC) compared to ERG gene fusion frequency by FISH, their association with PTENdeletion, and correlation with parameters of disease progression. Methods: A tissue microarray (TMA) was constructed from 142 radical prostatectomy (RP) specimens with usual acinar-type prostate carcinoma obtained at University Health Network (UHN) between 2001 and 2002 comprising 742 spots. The TMA was constructed using up to six 0.6 mm donor cores from each RP specimen. In cases of multi focal and bilateral carcinoma, 3 donor cores were obtained from the largest foci in each lobe. Different Gleason patterns were also sampled within each focus. Standard clinical follow-up data, representing 7-9 years of follow-up, were compiled for each case. Results: Of the 742 cores, analysis was performed in 536 evaluable cores. Concordance between the ERG IHC and TMPRSS2 FISH in this multi-sampled TMA was 71%. Heterogeneity of the PTEN locus was widespread within tumor foci and between foci. The assay methodology influenced overall results. For example, FISH analysis showed wild type (wt) PTEN and wt ERG in 48% of tumor specimens in comparison to 31% by PTENFISH and ERG IHC. Higher association of PTENdeletion rate was noted in ERG IHC positive tumors. Of note, higher frequency of homozygous PTEN deletions associated with the ERG IHC positive tumors in comparison to ERG negative tumors. Conclusions: Comparison of FISH and IHC based assays to analyze ERG alterations in the prostate tumors need continued evaluations in independent studies. PTEN interaction with ERG status may reveal mechanistic insights in disease progression. Further validation studies are needed.