TMPRSS2-ERG Fusion Prostate Cancer: An Early Molecular Event Associated With Invasion

Abstract

Prostate cancer (PCA) is one of the most prevalent cancers and a major leading cause of morbidity and mortality in the Western world. The TMPRSS2-ERG fusion was recently identified as a common recurrent chromosomal aberration in this malignancy. 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 assay. Samples from hospital-based cohorts consisted of 237 clinically localized PCA, 34 hormone naive metastases, 9 hormone refractory metastases, 26 high grade prostatic intraepithelial neoplasia lesions, 15 samples of benign prostatic hyperplasia, 38 of proliferative inflammatory atrophy, and 47 of benign prostatic tissue. The TMPRSS2-ERG fusion was present in 48.5% of clinically localized PCA, 30% of hormone naive metastases, 33% of hormone refractory metastases, and in 19% of high grade prostatic intraepithelial neoplasia lesions in intermingling 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. If we consider the high incidence of PCA 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.

ETS rearrangements in prostate cancer

“…The study from Carver et al 47 looked at data from human samples and determined that high-grade PIN demonstrates ERG gene rearrangement in 10% of cases, whereas loss of PTEN as determined by immunohistochemistry was observed in 45% of cases. Similar to previous observations by our group on high-grade PIN with ERG rearrangement, 16,17 the associated prostate cancer also demonstrated the same gene fusion status. They interpret these data to be consistent with TMPRSS2:ERG fusion representing an early molecular event facilitating the transition from high-grade PIN to prostate cancer.…”

ERG immunohistochemistry is not predictive for PSA recurrence, local recurrence or overall survival after radical prostatectomy for prostate cancer

“…8,[19][20][21][22][23] This variability might be due to differences in study cohorts, clinical end points and methodologies for detecting gene fusion. For example, RT-PCR-detected TMPRSS2-ERG fusion was found in more than 70% of patients surgically treated by radical prostatectomy for prostate cancer.…”

ERG rearrangement is present in a subset of transition zone prostatic tumors

“…1,2,28 Two differentially labeled Bacterial Artificial Chromosome (BAC) FISH probes were used: the biotin-14-dCTP-labeled BAC clone RP11-24A11 (eventually conjugated to produce a red signal) for the neighboring 3 0 centromeric region of the ERG locus and the digoxigenin-dUTP-labeled BAC clone RP11-372O17 (eventually conjugated to produce a green signal), for the neighboring 5 0 telomeric region. According to this break-apart probe system, a nucleus without ERG rearrangement shows two pairs of juxtaposed red and green signals, forming yellow signals; a nucleus with ERG rearrangement through translocation shows one pair of still combined red and green signals (a yellow signal), whereas the other breaks into a single red and a single green signal (split signal); and a nucleus with ERG rearrangement through deletion shows one yellow signal and a single red signal, whereas the green signal (5 0 region) is lost (Figure 1).…”