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[775] TMPRSS2: ETS Gene Fusions in Androgen Independent Metastatic Prostate Cancers: An Association of TMPRSS2: ERG Fusions through Intronic Deletions and Molecular Evidence of Clonal Expansion

R Mehra, SA Tomlins, L Wang, A Menon, KJ Pienta, AM Chinnaiyan, RB Shah. University of Michigan, Ann Arbor, MI

Background: Recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS family transcription factors ERG, ETV1 and ETV4 have been identified as a critical molecular event in prostate cancer (PCA) carcinogenesis. The objective of this study was to comprehensively characterize frequency, mechanism, and significance of these gene fusions in a cohort of androgen independent lethal metastatic PCAs.
Design: A tissue microarray (TMA) was constructed representing 12 primary and 84 non-osseous metastatic samples from 30 rapid autopsies of men died of androgen independent metastatic PCA. Gene fusions between TMPRSS2 and three ETS family members were analyzed by fluorescence in situ hybridization (FISH) assay using 5 and 3 split probes flanking 4 genes. FISH signals were scored manually (100x oil immersion) in morphologically intact, non-overlapping nuclei and a minimum of 50 cancer cells from each site were recorded. Comparisons were made in between patients as well as within different metastatic sites of same patient.
Results: Rearrangement for TMPRSS2, ERG, ETV1 and ETV4 were seen in 48, 37, 11 and 4% of cases respectively. Overall, 37, 4, and 4% cases demonstrated TMPRSS2: ERG, TMPRSS2:ETV1 and TMPRSS2:ETV4 fusions respectively. As intronic loss of genomic DNA between TMPRSS2 and ERG has been identified as a mechanism of TMPRSS2: ERG fusion, our assays allowed us to detect deletion between them in 100% of rearranged cases for this molecular subtype. For each case demonstrating gene rearrangement, all metastatic sites and primary site when present uniformly maintained similar gene rearrangement.
Conclusions: Our results indicate that high level of TMPRSS2: ERG gene fusions is maintained during progression to androgen independent state however this fusion is seen exclusively thorough intronic deletions between two genes, indicating that this molecular subtype is associated with aggressive lethal PCAs. Metastatic PCAs maintain homogeneity of the respective molecular subtype of gene fusion, indicating that they arise through clonal expansion of seeded primary malignant cells in different metastatic sites.
Category: Genitourinary (including renal tumors)

Monday, March 3, 2008

Poster # 123, Monday Morning