Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer

Abstract

Recurrent chromosomal rearrangements have not been well characterized in common carcinomas. We used a bioinformatics approach to discover candidate oncogenic chromosomal aberrations on the basis of outlier gene expression. Two ETS transcription factors, ERG and ETV1, were identified as outliers in prostate cancer. We identified recurrent gene fusions of the 5' untranslated region of TMPRSS2 to ERG or ETV1 in prostate cancer tissues with outlier expression. By using fluorescence in situ hybridization, we demonstrated that 23 of 29 prostate cancer samples harbor rearrangements in ERG or ETV1. Cell line experiments suggest that the androgen-responsive promoter elements of TMPRSS2 mediate the overexpression of ETS family members in prostate cancer. These results have implications in the development of carcinomas and the molecular diagnosis and treatment of prostate cancer.

c-Jun enhancement of androgen receptor transactivation is associated with prostate cancer cell proliferation

“…Like PSA and hKLK2, TMPRSS2 is overexpressed in prostate cancer cells (Lin et al, 1999) and in a majority of prostate cancer patients (Vaarala et al, 2001). Recently, this gene was reported to undergo translocation with two ETs oncogenes in prostate cancer (Tomlins et al, 2005). Both Northern blot ( Figure 4a) and RT-PCR analyses ( Figure 4d) showed that DHT induced the expression of TMPRSS2 mRNA in our LNCaP stable lines, consistent with previous reports (Lin et al, 1999).…”

Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide

“…Expression of PSA (KLK3), KLK2, TMPRSS2, and FKBP5, which are direct AR targets, were all affected by 1. TMPRSS2 encodes a transmembrane protease and can undergo a chromosomal deletion in which a member of the ETS transcription factor family is placed under control of the strongly androgen-responsive TMPRSS2 5Ј regulatory region (27,32).…”

“…It is not known what proportions of these genes are direct targets of AR. Table 2 displays the effects of each treatment on the expression of a few selected genes that were observed to be induced by DHT and are known to be targets of AR (26,27). Effects on the expression of KLK2 and TMPRSS2 were verified by quantitative real-time RT-PCR (SI Fig.…”

Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

“…A discovery of great importance disclosed by genetic analysis of prostate tumors was the identification of gene rearrangements involving the promoter regions of androgen regulated genes. Most frequent among these genetic alterations in PCa are fusions of ETS transcription factor genes to 5′-regions of AR regulated genes, which results in androgen-stimulated overexpression of ETS proteins (Tomlins, et al, 2005). …”