A variant TMPRSS2 isoform and ERG fusion product in prostate cancerwith implications for molecular diagnosis.
<p>Prostate cancer is the most commonly diagnosed cancer among men in the United States. Recently, fusion of <em>TMPRSS2</em> with ETS family oncogenic transcription factors has been identified as a common molecular alteration in prostate cancer, where most often the rearrangement places <em>ERG</em> under the androgen-regulated transcriptional control of <em>TMPRSS2</em>. Here, we carried out rapid amplification of cDNA ends (RACE) on a prostate cancer specimen carrying an atypical aberration discovered by array-based comparative genomic hybridization (array CGH), suggesting an alternative fusion partner of <em>ERG</em>. We identified novel transcribed sequences fused to <em>ERG</em>, mapping 4 kb upstream of the <em>TMPRSS2</em> start site. The sequences derive from an apparent second <em>TMPRSS2</em> isoform, which we found also expressed in some prostate tumors, suggesting similar androgen-regulated control. In a reverse transcription-polymerase chain reaction (RT-PCR)-based survey of 63 prostate tumor specimens (54 primary and nine lymph node metastases), 44 (70%) cases expressed either the known or novel variant <em>TMPRSS2</em>-<em>ERG</em> fusion, 28 (44%) expressed both, 10 (16%) expressed only the known, and notably six (10%) expressed only the variant isoform fusion. In this specimen set, the presence of a <em>TMPRSS2</em>-<em>ERG</em> fusion showed no statistical association with tumor stage, Gleason grade or recurrence-free survival. Nonetheless, the discovery of a novel variant <em>TMPRSS2</em> isoform-<em>ERG</em> fusion adds to the characterization of ETS-family rearrangements in prostate cancer, and has important implications for the accurate molecular diagnosis of <em>TMPRSS2</em>-<em>ETS</em> fusions.</p>