ERG Rearrangement for Predicting Subsequent Cancer Diagnosis in High-Grade Prostatic Intraepithelial Neoplasia and Lymph Node Metastasis

Abstract

Purpose: We aimed to analyze whether ERG rearrangement in biopsies could be used to assess subsequent cancer diagnosis in high-grade prostatic intraepithelial neoplasia (HGPIN) and the risk of lymph node metastasis in early prostate cancer.Experimental Design: Samples from 523 patients (361 with early prostate cancer and 162 with HGPIN) were collected prospectively. On the basis of the cutoff value established previously, the 162 patients with HGPIN were stratified to two groups: one with an ERG rearrangements rate !1.6% (n ¼ 59) and the other with an ERG rearrangements rate <1.6% (n ¼ 103). For the 361 prostate cancer cases undergoing radical prostatectomy, 143 had pelvic lymph node dissection (node-positive, n ¼ 56 and node-negative, n ¼ 87). All ERG rearrangement FISH data were validated with ERG immunohistochemistry.Results: A total of 56 (of 59, 94.9%) HGPIN cases with an ERG rearrangements rate !1.6% and 5 (of 103, 4.9%) HGPIN cases with an ERG rearrangements rate <1.6% were diagnosed with prostate cancer during repeat biopsy follow-ups (P < 0.001). There were significant differences in ERG rearrangement rates between lymph node-positive and -negative prostate cancer (P < 0.001). The optimal cutoff value to predict lymph node metastasis by ERG rearrangement was established, being 2.6% with a sensitivity at 80.4% [95% confidence interval (CI), 67.6-89.8] and a specificity at 85.1% (95% CI, 75.8-91.8). ERG protein expression by immunohistochemistry was highly concordant with ERG rearrangement by FISH.Conclusions: The presence of ERG rearrangement in HGPIN lesions detected on initial biopsy warrants repeat biopsies and measuring ERG rearrangement could be used for assessing the risk of lymph node metastasis in early prostate cancer. Clin Cancer Res; 18(15); 4163-72. Ó2012 AACR.

Monoallelic expression of TMPRSS2/ERG in prostate cancer stem cells

“…However, if the local cellular microenvironment selected in favour of a particular gene set, for example, as a resistance response to hormone therapies in PCa 27 , then reversal of allelic silencing would provide a mechanism whereby both therapy resistance and even 'pre-tumour' progression 30 could rapidly occur. The importance of the ERG-activating rearrangement in the development of PCa has been demonstrated by tracking of the fused allele from positive high-grade prostatic intraepithelial neoplasia to development of primary tumours 31,32 . Additional studies have also matched TMPRSS2/ERG fusions in castrationresistant PCa lymph node metastases to localized primary tumours 33,34 , implying that early clonal expansion from a more primitive stem cell is indeed prevalent in PCa.…”

ERG rearrangement as a novel marker for predicting the extra-prostatic extension of clinically localised prostate cancer

“…The selection of slides for FISH analysis was performed by the pathologist conducting the diagnosis. The ERG rearrangement was calibrated with a dual-colour break-apart FISH assay (Beijing GP Medical Technologies, Ltd., Beijing, China) as previously described (16)(17)(18).…”

“…Our group has previously reported an initial scoring system for assessing ERG rearrangements in biopsy samples, based on the use of fluorescence in situ hybridisation (FISH), for the diagnosis of PCa and the risk assessment of lymph node metastasis. This proposed system has demonstrated excellent sensitivity and specificity (16,17). In clinical practice, an increase in ERG rearrangements was observed to be associated with more aggressive characteristics.…”

“…Subsequent to washing in deionised water for 5 min, the sections were boiled in deionised water at 100˚C for 27 min and then digested with Proteinase K (Beijing GP Medical Technologies, Ltd.) at 37˚C for 10 min. The sections on the slides were then dried, and hybridisation was performed as described previously (16,17). Next, the slides were counterstained and mounted with DAPI, examined under an oil objective at 100x magnification using an Olympus fluorescence microscope (BX51; Olympus Corp., Tokyo, Japan) and imaged with a CCD camera (DP70; Olympus Corp.) using the PathFinder CellScan software system (IMSTAR S.A., Paris, France).…”

“…ERG rearrangement rate in the patient was calculated using the following formula: ERG rearrangement rate (%) = number of cells exhibiting an abnormal signal pattern/number of cancer cells (16,17). All slices were independently assessed by three experienced researchers (Dr Li Lu, Dr Hao Zhang and Dr Guo-Liang Hou) who were blinded to the clinicopathological parameters, and any discordant results were reassessed until a consensus was achieved ( Fig.…”