TMPRSS2:ETV4 Gene Fusions Define a Third Molecular Subtype of Prostate Cancer

Abstract

Although common in hematologic and mesenchymal malignancies, recurrent gene fusions have not been well characterized in epithelial carcinomas. Recently, using a novel bioinformatic approach, we identified recurrent gene fusions between TMPRSS2 and the ETS family members ERG or ETV1 in the majority of prostate cancers. Here, we interrogated the expression of all ETS family members in prostate cancer profiling studies and identified marked overexpression of ETV4 in 2 of 98 cases. In one such case, we confirmed the overexpression of ETV4 using quantitative PCR, and by rapid amplification of cDNA ends, quantitative PCR, and fluorescence in situ hybridization, we show that the TMPRSS2 (21q22) and ETV4 (17q21) loci are fused in this case. This result defines a third molecular subtype of prostate cancer and supports the hypothesis that dysregulation of ETS family members through fusions with TMRPSS2 may be an initiating event in prostate cancer development. (Cancer Res 2006; 66(7): 3396-400)

TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort

“…In early studies, the gene fusions of the 5 0 -untranslated region of TMPRSS2 (21q22.3) with the ETS transcription factor family members, estrogen-regulated gene (ERG) (21q22.2), ETV1 (7p21.2) (Tomlins et al, 2005), or ETV4 (Tomlins et al, 2006) provide a mechanism for the overexpression of the ETS genes in prostate cancers. Furthermore, the fusion of an androgen-regulated gene, TMPRSS2, and an oncogene suggests that disease progression may vary based on these molecular subtypes.…”

Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: frequency and transcript variant analysis by RT-PCR and FISH on paraffin-embedded tissues

“…We identified six variants in the present study, including two novel variants T1-4/E4 and T1-4/E5. Compiling our and other recent RT-PCR studies, a total of 19 transcript variants have been identified to date, variably and confusingly named types I-VIII, 14 [1][2][3][4][5][6][7][8][9][10][11][12][13][14]12 etc, by investigators. In light of this complexity, we would propose that a generic nomenclature system be used, and these variants would be named as T1/E4, T1/E5, T1-4/E4, etc, as was first used by Clark et al 12 From Table 2, it is clear that T1/E4 is the predominant transcript observed in all studies, and other common variants are T1/E5, T1/E2, T2/E4 and T2/E5.…”

“…ETV4, another member of the ETS family, was later identified as another minor partner in this gene fusion. 7 The high prevalence of prostate cancer in western societies, in combination with the reported frequency of fusion between TMPRSS2 and ETS family genes, would make this one of the most common genetic alterations identified in human malignancy.…”

Diversity of TMPRSS2-ERG fusion transcripts in the human prostate

“…Recently, fusion of the TMPRSS2 gene to three members of the ETS family of transcription factor genes, ERG, ETV1 and ETV4, has been reported and confirmed in human prostate cancer (Tomlins et al, 2005(Tomlins et al, , 2006Soller et al, 2006). ERG is the ETS family gene most commonly altered, with Tomlins et al (2005) reporting the fusion of exon 1 of TMPRSS2 to either exon 2 or 4 of ERG.…”