TMPRSS2-ERG fusion prostate cancer: An early molecular event associated with invasion.

PR-10

Prostate cancer (PCA) is one of the most prevalent cancers and a major leading cause of morbidity and mortality in the Western world. The recent identification of the common gene fusions of the 5'-untranslated region of TMPRSS2 (21q22.3) with the ETS transcription factor family members, either ERG (21q22.2), ETV1 (7p21.2), or ETV4(17q21) suggests a mechanism for over expression of the ETS genes in the majority of PCA. In our study we interrogated a broad spectrum of benign, precursor and malignant prostatic lesions to assess the TMPRSS2-ERG fusion status using a multicolor interphase fluorescence in-situ hybridization (FISH) assay. Samples from hospital based cohorts consisted of 237 localized prostate cancers, 34 hormone naïve metastases, 9 hormone refractory metastases, 26 high grade prostatic intraepithelial neoplasia (PIN) lesions, 15 samples of benign prostatic hyperplasia, 38 of proliferative inflammatory atrophy (PIA), and 47 of normal prostatic tissue. The TMPRSS2-ERG fusion was present in 48.5% of localized PCA, 30% of hormone naïve metastases, 33% of hormone refractory metastases, and in 19% of high grade PIN lesions in close proximity to cancer foci. Almost all these fusion positive cases show a homogenous distribution of the fusion pattern. In contrast, none of the other samples harbored this genetic aberration. Furthermore, the FISH assay detected that in about 60% of fusion positive primary PCA cases, an intronic deletions between ERG and TMPRSS2 is the underlying mechanism for fusion. Using 100K oligonucleotide SNP arrays, a homogeneous deletion site between ERG and TMPRSS2 on chromosome 21q22.2-3 was verified. The other underlying mechanism for gene fusion is a translocation of these genes. A significant association was observed between tumors with TMPRSS2-ERG fusion through deletions and higher tumor stage and the presence of metastatic disease involving pelvic lymph nodes. If we consider the high incidence of prostate cancer and the high frequency of this gene fusion, TMPRSS2-ERG is the most common genetic aberration so far described in human malignancies. Furthermore, its clinical application as a biomarker and ancillary diagnostic test is promising given its high specificity.