TMPRSS2:ERG fusion by translocation or interstitial deletion is highly relevant in androgen-dependent prostate cancer, but is bypassed in late-stage androgen receptor-negative prostate cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 22; pp. 10658 - 10663
• Main Authors: HERMANS, Karin G, VAN MARION, Ronald, VAN DEKKEN, Herman, JENSTER, Guido, VAN WEERDEN, Wytske M, TRAPMAN, Jan
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.11.2006
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Chromosome aberrations; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; Down-Regulation; Humans; Male; Medical genetics; Medical sciences; Mice; Mice, Nude; Neoplasm Staging; Neoplasms, Hormone-Dependent - genetics; Neoplasms, Hormone-Dependent - metabolism; Neoplasms, Hormone-Dependent - pathology; Nephrology. Urinary tract diseases; Oncogene Proteins, Fusion - biosynthesis; Oncogene Proteins, Fusion - genetics; Pharmacology. Drug treatments; Polymerase Chain Reaction; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptors, Androgen - biosynthesis; Receptors, Androgen - deficiency; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Serine Endopeptidases - biosynthesis; Serine Endopeptidases - genetics; Trans-Activators - biosynthesis; Trans-Activators - genetics; Transcriptional Regulator ERG; Translocation, Genetic; Transplantation, Heterologous; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Chromosomal aberration; Hormonodependence; Urinary system disease; Prostate disease; Malignant tumor; Treatment; Bypass; Surgery; C-Onc gene; Androgen receptor; Cytogenetics; Deletion; Abnormal chromosome; Advanced stage; Interstitial; Male genital diseases; Prostate cancer; Protooncogene; Hormonal receptor; Chromosome translocation
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-06-1871

Recently, a unique fusion between the prostate-specific, androgen-regulated TMPRSS2 gene and the ETS genes ERG, ETV1, or ETV4 has been described in clinical prostate cancer. We investigated mechanisms of expression of four ETS genes, ERG, ETV1, ETV4, and FLI1, in 11 xenografts representing different stages of prostate cancer. All five androgen-dependent xenografts showed as major transcript overexpression of two splice variants of TMPRSS2:ERG, linking TMPRSS2 exon 1 or 2 sequences to ERG exon 4. In one of two androgen-sensitive xenografts, fusion transcripts of TMPRSS2 and ETV1 were detected. Array-based comparative genomic hybridization and interphase fluorescence in situ hybridization indicated both interstitial deletions and translocations as mechanisms of TMPRSS2:ERG gene fusion. Importantly, TMPRSS2 to ERG fusions were also observed in three of four androgen-independent, androgen receptor (AR)-negative xenografts and in two AR-negative clinical prostate cancer specimens; however, the fusion gene was not expressed. In almost all AR-negative tumor samples, overexpression of wild-type ETV4 or FLI1 was detected. Combined, our observations indicate a key role of fusion of TMPRSS2 and ETS genes in most androgen-regulated prostate cancers, which might be bypassed by androgen-independent expression of wild-type ETS factors in late-stage disease.