Three-Color FISH Analysis of TMPRSS2/ERG Fusions in Prostate Cancer Indicates That Genomic Microdeletion of Chromosome 21 Is Associated with Rearrangement

Abstract

The recent description of novel recurrent gene fusions in approximately 80% of prostate cancer (PCa) cases has generated increased interest in the search for new translocations in other epithelial cancers and emphasizes the importance of understanding the origins and biologic implications of these genomic rearrangements. Analysis of 15 PCa cases by reverse transcription-polymerase chain reaction was used to detect six ERG-related gene fusion transcripts with TMPRSS2. No TMPRSS2/ETV1 chimeric fusion was detected in this series. Three-color fluorescence in situ hybridization confirms that TMPRSS2/ERG fusion may be accompanied by a small hemizygous sequence deletion on chromosome 21 between ERG and TMPRSS2 genes. Analysis of genomic architecture in the region of genomic rearrangement suggests that tracts of microhomology could facilitate TMPRSS2/ERG fusion events.

Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: frequency and transcript variant analysis by RT-PCR and FISH on paraffin-embedded tissues

“…First demonstrated by Yoshimoto et al 15 with three-color FISH, Perner and co-workers showed deletion in B70% of cases, similar to our observation (21/27, 81%). This finding raises the possibility that the TMPRSS2-ERG fusion event, in addition to ERG activation, is often accompanied by variable losses of intervening genes.…”

“…All but one case were negative for TMPRSS2-ETV1 fusion, and similar ETV1 downstream mRNA levels were seen in all but three fusion-negative cases. 14 Soller et al 13 Yoshimoto et al 15 Tomlins et al 6 Current study (#) Table 3. Tumors with TMPRSS2-ERG fusions more frequently had focal intraluminal mucin, amphophilic cytoplasm and cribriform architecture.…”

“…10,11 In prostate cancer, multiple TMPRSS2-ERG fusion variants have been identified at the transcript level, most of them involving only the 5 0 untranslated sequence of TMPRSS2. 6,[12][13][14][15] The TMPRSS2-ETS fusions thus lead to overexpression of the ERG or ETV protein induced by the TMPRSS2 promoter. In contrast to other translocations involving the ERG gene, for example, EWS-ERG fusion, no fusion protein is expected in most TMPRSS2-ERG fusions.…”

“…Unlike the TMPRSS2-ETV1 fusion, which involves a t(7;21) translocation, the TMPRSS2 and ERG genes are located close to each other on chromosome 21, approximately 3 Mb apart. 15 Thus, the TMPRSS2-ERG fusion could result either from balanced or unbalanced translocation, or from deletion of the intervening DNA segment, and the literature to date suggests deletion as the more frequent event. 16,17 In the present study, we evaluated a series of 82 formalin-fixed paraffin-embedded prostate cancer specimens, by RT-PCR and by FISH analyses.…”

A variant TMPRSS2 isoform and ERG fusion product in prostate cancer with implications for molecular diagnosis

“…The higher-MW PCR product from sample PT335 corresponds to fusion of TMPRSS2 (exon1) to ERG (exon3), and a lower-MW PCR product from sample PT316 (not shown) corresponds to fusion of TMPRSS2 (exon2) to ERG (exon5); both variants have been previously reported. 15,17 Variant TMPRSS2-ERG in prostate cancer J Lapointe et al…”