Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer

Abstract

New predictive markers for managing prostate cancer are urgently required because of the highly variable natural history of this disease. At the time of diagnosis, Gleason score provides the gold standard for assessing the aggressiveness of prostate cancer. However, the recent discovery of TMPRSS2 fusions to the ERG gene in prostate cancer raises the possibility of using alterations at the ERG locus as additional mechanism-based prognostic indicators. Fluorescence in situ hybridization (FISH) assays were used to assess ERG gene status in a cohort of 445 prostate cancers from patients who had been conservatively managed. The FISH assays detected separation of 5 0 (labelled green) and 3 0 (labelled red) ERG sequences, which is a consequence of the TMPRSS2-ERG fusion, and additionally identify interstitial deletion of genomic sequences between the tandemly located TMPRSS2 and ERG gene sequences on chromosome 21. Cancers lacking ERG alterations exhibited favourable cause-specific survival (90% survival at 8 years). We identify a novel category of prostate cancers, characterized by duplication of the fusion of TMPRSS2 to ERG sequences together with interstitial deletion of sequences 5 0 to ERG (called '2 þ Edel'), which by comparison exhibited extremely poor cause-specific survival (hazard ratio ¼ 6.10, 95% confidence ratio ¼ 3.33-11.15, Po0.001, 25% survival at 8 years). In multivariate analysis, '2 þ Edel' provided significant prognostic information (P ¼ 0.003) in addition to that provided by Gleason score and prostate-specific antigen level at diagnosis. Other individual categories of ERG alteration were associated with intermediate or good prognosis. We conclude that determination of ERG gene status, including duplication of the fusion of TMPRSS2 to ERG sequences in 2 þ Edel, allows stratification of prostate cancer into distinct survival categories.

Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer

“…From a case -control study by Lapointe et al (2007), where 54 patients with localised cancer and 9 patients with metastasis were examined for fusion status, no correlations were found with stage, grade or recurrence. On the other hand, large cohort studies of patients managed with watchful waiting did show correlations with a positive fusion status being associated with reduced survival (Attard et al, 2007;Demichelis et al, 2007).…”

“…Several studies have compared clinicopathological parameters (Perner et al, 2006;Wang et al, 2006;Lapointe et al, 2007;Rajput et al, 2007;Tu et al, 2007) and prognostic significance (Wang et al, 2006;Attard et al, 2007;Demichelis et al, 2007;Lapointe et al, 2007;Nam et al, 2007) of this gene fusion with conflicting results. Two of these studies showed no correlation between histologic grade (Gleason score) (Lapointe et al, 2007;Tu et al, 2007), while others found positive associations (Attard et al, 2007;Rajput et al, 2007). Also, some studies have only shown correlation of fusion status with tumour stage (Perner et al, 2006;Wang et al, 2006).…”

“…watchful waiting) showed that men who had TMPRSS2:ERG fusion had lower prostate cancer-specific survival compared to men without fusion expression (Attard et al, 2007;Demichelis et al, 2007). Patients managed and selected for watchful waiting from these cohorts have different baseline distributions in grade, stage and PSA level to patients treated with surgery and may not be comparable.…”

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

“…Advantageously to routine detection of ERG fusion, FISH can give qualitative information on the type of gene fusion, resulting either from translocation or deletion, which is reported to be of clinical relevance. [5][6][7] Application of FISH, however, needs tissue-dependent optimization and can suffer from difficulty in interpretation, especially when only a few atypical glands are present. On the other hand, both quantitative and qualitative information on gene fusion can be obtained by QPCR.…”

Risk-Based Prostate Cancer Screening: Who and How?

“…Another RNA-based marker, TMPRESS2-ERG fusion gene, which is expressed in over half of the cases of clinically localized prostate cancer [74], has also shown recent promise as an prognostic factor. Several studies show associations with histological grade [75,76] and tumor stage [77,78]. Investigators reviewed tissue samples of 226 men who were treated with radical prostatectomy and found that in those for positive TMPRSS2-ERG fusion gene expression (N = 114, 50.4 %), PSA, Gleason sum, and margin status were independently associated with biochemical and progression-free survival [79].…”