title: A variant TMPRSS2 isoform and ERG fusion product in prostate cancer with implications for molecular diagnosis.
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.
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA 94305-5176, USA.
authors.forename: Jacques
authors.initials: J
authors.lastname: Lapointe
authors.forename: Young H
authors.initials: YH
authors.lastname: Kim
authors.forename: Melinda A
authors.initials: MA
authors.lastname: Miller
authors.forename: Chunde
authors.initials: C
authors.lastname: Li
authors.forename: Gulsah
authors.initials: G
authors.lastname: Kaygusuz
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: James D
authors.initials: JD
authors.lastname: Brooks
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Pollack
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D001483:Base Sequence; D018572:Disease-Free Survival; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D025202:Molecular Diagnostic Techniques; D008969:Molecular Sequence Data; D021141:Nucleic Acid Amplification Techniques; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; C515553:TMPRSS2-ERG fusion protein, human; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human