TMPRSS2:ERG Gene Fusion Predicts Subsequent Detection of Prostate Cancer in Patients With High-Grade Prostatic Intraepithelial Neoplasia

Abstract

A B S T R A C T PurposeHigh-grade prostatic intraepithelial neoplasia (HGPIN) is considered a precursor lesion of prostate cancer (PCa). The predictive value of ERG gene fusion in HGPIN for PCa was interrogated as a post hoc analysis in the context of a randomized clinical trial. Patients and MethodsThe GTx Protocol G300104 randomly assigned 1,590 men with biopsy-diagnosed HGPIN to receive toremifene or placebo for 3 years or until a diagnosis of PCa was made on prostate biopsy. As part of this phase III clinical trial, a central pathologist evaluated biopsies of patients with isolated HGPIN at baseline and 12, 24, and 36 months of follow-up. ERG immunohistochemistry was performed on biopsies from 461 patients and evaluated for protein overexpression. ResultsERG expression was detected in 11.1% of patients (51 of 461 patients) with isolated HGPIN. In the first year and during the 3-year clinical trial, 14.7% and 36.9% of 461 patients were diagnosed with PCa, respectively. Patients with ERG expression were more likely to develop PCa, with 27 (53%) of 51 ERG-positive and 143 (35%) of 410 ERG-negative patients experiencing progression to PCa (P ϭ .014, Fisher's exact test). ERG expression was not associated with age, baseline PSA, Gleason score, or tumor volume. ConclusionThis study underscores the necessity of more stringent follow-up for men with HGPIN that is also positive for ERG overexpression. Clinicians should consider molecular characterization of HGPIN as a means to improve risk stratification.

TMPRSS2:ERG fusion gene occurs less frequently in Chinese patients with prostate cancer

“…As for prostate cancer, TMPRSS2:ERG may be a key step in the early stage of prostate cancer development. It was reported that the patients with high-grade prostatic intraepithelial neoplasia (HGPIN) who overexpressed ERG were more vulnerable to prostate cancer than their counterparts without ERG expression [30]. Over the past decade, accumulating evidence demonstrated that TMPRSS2:ERG fusion gene can be a potential tumor biomarker for detecting prostate cancer, particularly in Western countries [31,32].…”

Androgen Signaling in Prostate Cancer

“…TMPRSS2-ERG fusions are the most common molecular alteration in prostate cancer, occur-ring in 40% -50% of tumors The Cancer Genome Atlas Research Network 2015). These fusions are also recognized in isolated high-grade prostatic intraepithelial neoplasia (HGPIN) lesions (Park et al 2014), lesions associated with cancer (Perner et al 2007), as well as benign prostatic epithelial cells after extended exposure to DHT (Berger et al 2011), suggesting that the acquisition of TMPRSS2-ETS fusions is likely an early carcinogenic event. Moreover, some evidence suggests that androgens themselves can provoke nonrandom fusion events (Lin et al 2009;Mani et al 2009).…”

Precursor Lesions of Urologic Malignancies

“…[45][46][47] There is potential clinical significance to these findings, since isolated HGPIN with ERG overexpression on biopsy has been shown to have a higher rate of cancer on repeated biopsy than isolated HGPIN without ERG overexpression. 48,49 While most HGPIN cases likely represent a precursor lesion, a recent and robust study by Haffner et al 50 has shifted this paradigm; by examining ERG rearrangements in addition to PTEN deletion to track the temporal evolution of HGPIN and invasive carcinoma, the authors demonstrated that in some cases, HGPIN arises from nearby invasive cancers, likely through retrograde colonization. Distinguishing such cases where HGPIN may represent progression of disease is clinically important and further work likely is needed in this area.…”