Original Article

Modern Pathology (2007) 20, 467–473. doi:10.1038/modpathol.3800759; published online 2 March 2007

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

Jacques Lapointe1,2,*,, Young H Kim1,*, Melinda A Miller3, Chunde Li4,5, Gulsah Kaygusuz1,, Matt van de Rijn1, David G Huntsman3, James D Brooks2 and Jonathan R Pollack1

  1. 1Department of Pathology, Stanford University, Stanford, CA, USA
  2. 2Department of Urology, Stanford University, Stanford, CA, USA
  3. 3Department of Pathology, British Columbia Cancer Agency, Vancouver, BC, Canada
  4. 4Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
  5. 5Department of Oncology, Karolinska University Hospital, Stockholm, Sweden

Correspondence: Dr JR Pollack, MD, PhD, Department of Pathology, Stanford University School of Medicine, 269 Campus Drive, CCSR-3245A, Stanford, CA 94305-5176, USA. E-mail: pollack1@stanford.edu

*These authors contributed equally to this work.

Current address: Urology Division, Department of Surgery, McGill University, Montreal, QC, Canada.

Current address: Department of Pathology, Ankara University School of Medicine, Ankara, Turkey.

Received 29 November 2006; Revised 16 January 2007; Accepted 17 January 2007; Published online 2 March 2007.

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Abstract

Prostate cancer is the most commonly diagnosed cancer among men in the United States. Recently, fusion of TMPRSS2 with ETS family oncogenic transcription factors has been identified as a common molecular alteration in prostate cancer, where most often the rearrangement places ERG under the androgen-regulated transcriptional control of TMPRSS2. 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 ERG. We identified novel transcribed sequences fused to ERG, mapping 4 kb upstream of the TMPRSS2 start site. The sequences derive from an apparent second TMPRSS2 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 TMPRSS2-ERG 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 TMPRSS2-ERG fusion showed no statistical association with tumor stage, Gleason grade or recurrence-free survival. Nonetheless, the discovery of a novel variant TMPRSS2 isoform-ERG fusion adds to the characterization of ETS-family rearrangements in prostate cancer, and has important implications for the accurate molecular diagnosis of TMPRSS2-ETS fusions.

Keywords:

prostate cancer, TMPRSS2-ERG fusion, molecular diagnosis