Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer.

BACKGROUND: Androgen receptor (AR)-gene amplification, found in 20-30% of castration-resistant prostate cancer (CRPCa) is proposed to develop as a consequence of hormone-deprivation therapy and be a prime cause of treatment failure. Here we investigate AR-gene amplification in cancers before hormone deprivation therapy. METHODS: A tissue microarray (TMA) series of 596 hormone-naive prostate cancers (HNPCas) was screened for chromosome X and AR-gene locus-specific copy number alterations using four-colour fluorescence in situ hybridisation. RESULTS: Both high level gain in chromosome X (≥4 fold; n=4, 0.7%) and locus-specific amplification of the AR-gene (n=6, 1%) were detected at low frequencies in HNPCa TMAs. Fluorescence in situ hybridisation mapping whole sections taken from the original HNPCa specimen blocks demonstrated that AR-gene amplifications exist in small foci of cells (≤ 600 nm, ≤1% of tumour volume). Patients with AR gene-locus-specific copy number gains had poorer prostate cancer-specific survival. CONCLUSION: Small clonal foci of cancer containing high level gain of the androgen receptor (AR)-gene develop before hormone deprivation therapy. Their small size makes detection by TMA inefficient and suggests a higher prevalence than that reported herein. It is hypothesised that a large proportion of AR-amplified CRPCa could pre-date hormone deprivation therapy and that these patients would potentially benefit from early total androgen ablation.

Association between DNA methylation of HSPB1 and death in low Gleason score prostate cancer.

BACKGROUND: Heat shock protein 27 (Hsp-27) encoded by gene HSPB1 is a critical regulator of the behavioral phenotype of human prostate cancer (PCa) cells, enhanced expression being associated with highly aggressive disease and poor clinical outcome. In contrast, the protein is not expressed in PCas of low malignant potential. To gain insight into the mechanism regulating its expression, we tested the hypothesis that differential methylation of CpG islands within HSPB1 controls transcription and subsequent translation of the gene. METHODS: We studied prostate epithelial cell lines and tissue biopsies, including 59 BPH and 415 PCas, of which 367 were a cohort of men with up to 20 years of follow-up. Methylation across the gene (DNA methylation (DNAme)) was assayed by pyrosequencing. Hsp-27 expression was assessed by western blot and immunohistochemistry. RESULTS: In cancer tissues, methylation increased in a 3' direction (P < 0.0001) whereas in benign hyperplasia methylation was constantly below 5%, a cutoff giving a specificity of 100% and sensitivity of 50%. Although methylation of the promoter region was significantly discriminating between benign and malignant prostatic epithelia, it compared poorly with methylation of the first intron. The prognostic value of HSPB1 DNAme was confirmed by both univariate (hazard ratio 1.77 per 50% increment, P = 0.02) and multivariate models. Interaction between HSPB1 methylation and Gleason score revealed high DNAme to be a reliable prognostic marker of poor outcome in men with low Gleason score (P = 0.014). CONCLUSIONS: Our data indicate CpG methylation of the first HSPB1 intron to be an important biomarker that identifies aggressive PCas otherwise regarded as low risk by current clinical criteria but that, biologically, require immediate active management.

Splice variant PRKC-ζ(-PrC) is a novel biomarker of human prostate cancer.

BACKGROUND: Previously, using gene-knockdown techniques together with genome expression array analysis, we showed the gene protein Kinase C (PKC)-zeta (PRKCZ) to mediate the malignant phenotype of human prostate cancer. However, according to NCBI, the gene has undergone several major iterations. Therefore, to understand the relationship between its structure and biological activities, we have analysed its expressed sequence in prostate cancer cell lines and tissues. METHODS: Transcriptome-walking and targeted PCR were used to sequence the mRNA transcribed from PRKCZ. Hydropathy analysis was employed to analyse the hypothetical protein sequence subsequently translated and to identify an appropriate epitope to generate a specific monoclonal antibody. RESULTS: A novel sequence was identified within the 3'-terminal domain of human PRKCZ that, in prostate cancer cell lines and tissues, is expressed during transcription and thereafter translated into protein (designated PKC-ζ(-PrC)) independent of conventional PKC-ζ(-a). The monoclonal antibody detected expression of this 96 kD protein only within malignant prostatic epithelium. INTERPRETATION: Transcription and translation of this gene sequence, including previous intronic sequences, generates a novel specific biomarker of human prostate cancer. The presence of catalytic domains characteristic of classic PKC-ß and atypical PKC-ι within PKC-ζ(-PrC) provides a potential mechanism for this PRKCZ variant to modulate the malignant prostatic phenotype out-with normal cell-regulatory control.

Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort.

BACKGROUND: The natural history of prostate cancer is highly variable and it is difficult to predict. We showed previously that a cell cycle progression (CCP) score was a robust predictor of outcome in a conservatively managed cohort diagnosed by transurethral resection of the prostate. A greater need is to predict outcome in patients diagnosed by needle biopsy. METHODS: Total RNA was extracted from paraffin specimens. A CCP score was calculated from expression levels of 31 genes. Clinical variables consisted of centrally re-reviewed Gleason score, baseline prostate-specific antigen level, age, clinical stage, and extent of disease. The primary endpoint was death from prostate cancer. RESULTS: In univariate analysis (n=349), the hazard ratio (HR) for death from prostate cancer was 2.02 (95% CI (1.62, 2.53), P<10(-9)) for a one-unit increase in CCP score. The CCP score was only weakly correlated with standard prognostic factors and in a multivariate analysis, CCP score dominated (HR for one-unit increase=1.65, 95% CI (1.31, 2.09), P=3 × 10(-5)), with Gleason score (P=5 × 10(-4)) and prostate-specific antigen (PSA) (P=0.017) providing significant additional contributions. CONCLUSION: For conservatively managed patients, the CCP score is the strongest independent predictor of cancer death outcome yet described and may prove valuable in managing clinically localised prostate cancer.

Difluprednate for inflammatory eye disorders.

Uveitis is the third leading cause of preventable blindness in the U.S. Topical administration of corticosteroids remains the mainstay in the management of acute autoimmune anterior uveitis. Difluprednate 0.05% ophthalmic emulsion is a potent new topical corticosteroid that exhibits enhanced penetration, better bioavailability, rapid local metabolism and strong efficacy, with a low incidence of adverse effects. In June 2008, difluprednate ophthalmic emulsion 0.05% gained FDA approval in the U.S. for the treatment of postoperative ocular inflammation and pain. Recently, a multicenter, randomized clinical trial showed difluprednate to be noninferior to prednisolone acetate 1% dosed twice as often, the current standard of care for the acute management of endogenous uveitis in the U.S. Furthermore, difluprednate proved to have a comparable safety profile. Here, we review difluprednate pharmacokinetics, ocular indications, animal studies, as well as the results of the clinical trials conducted to date in the U.S.

Mycophenolate mofetil monotherapy in the management of paediatric uveitis.

PURPOSE: To evaluate effectiveness and safety of mycophenolate mofetil (MMF) monotherapy in paediatric autoimmune uveitis. METHODS: We reviewed medical records of patients, 18 years of age or younger, with autoimmune uveitis treated with MMF at our practice from 2005 to 2009. The dose and duration of MMF therapy, inflammation status, visual acuity, previous immunomodulatory therapies, and adverse effects were recorded. In addition, the following subgroups were defined: (1) Durable Disease Control: patients whose uveitis remained quiescent for at least 2 years on MMF monotherapy, with no more than two flare-ups successfully treated with an increase in MMF dosage and/or a short course (<1 month) of corticosteroids; (2) Short-term Inflammation Control: patients whose uveitis remained quiescent for less than 2 years, with no more than one flare-up successfully treated with an increase in MMF dosage and/or a short course of corticosteroids, or who initially achieved inflammation control but discontinued MMF because of significant adverse effects. RESULTS: A total of 38 out of 52 patients (73.1%) obtained inflammation control following 2 months of MMF monotherapy, achieving ≤ 0.5+ grading in anterior chamber cell/flare and vitreous haze. In the cross-sectional analysis, 25 patients (48.1%) met the criteria for Durable Disease Control, and 13 others (25.0%) qualified for Short-term Inflammation Control. Visual acuity remained stable or improved in 94.2% of the study population. Six patients (11.5%) discontinued MMF because of significant adverse effects, the most common of which was gastrointestinal disturbances. CONCLUSION: MMF monotherapy appears to be an effective and safe treatment in paediatric autoimmune uveitis.

Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study.

OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS: Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (± 5 years) who were negative for the familial mutation. RESULTS: In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47·6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS: The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.

The identification of chromosomal translocation, t(4;6)(q22;q15), in prostate cancer.

Our previous work identified a chromosomal translocation t(4;6) in prostate cancer cell lines and primary tumors. Using probes located on 4q22 and 6q15, the breakpoints identified in LNCaP cells, we performed fluorescence in situ hybridization analysis to detect this translocation in a large series of clinical localized prostate cancer samples treated conservatively. We found that t(4;6)(q22;q15) occurred in 78 of 667 cases (11.7%). The t(4;6)(q22;q15) was not independently associated with patient outcome. However, it occurs more frequently in high clinical T stage, high tumor volume specimens and in those with high baseline PSA (P=0.001, 0.001 and 0.01, respectively). The t(4;6)(q22;q15) occurred more frequently in samples with two or more TMPRSS2:ERG fusion genes caused by internal deletion than in samples without these genomic alterations, but this correlation is not statistically significant (P=0.0628). The potential role of this translocation in the development of human prostate cancer is discussed.

Elevated expression of Ki-67 identifies aggressive prostate cancers but does not distinguish BRCA1 or BRCA2 mutation carriers.

Prostate cancers in men with germline BRCA1 and BRCA2 mutations are more aggressive than morphologically similar cancers in men without these mutations. This study was performed to test the hypothesis that enhanced expression of Ki-67, as a surrogate of cell proliferation, is a characteristic feature of prostate cancers occurring in BRCA1 or BRCA2 mutation carriers. The study cohort comprised 20 cases of prostate cancer in mutation carriers and 126 control sporadic prostate cancers. Of the combined sample cohort, 65.7% stained only within malignant tissues while 0.7% stained in both malignant and benign tissues (p<0.001). Significantly increased expression of Ki-67 occurred in prostate cancers with higher Gleason score (p<0.001). Elevated Ki-67 expression was identified in 71% of prostate cancers in BRCA1 or BRCA2 mutation carriers and in 67% of the sporadic controls (p>0.5). Similar results were obtained when the data were analysed using a threshold set at 3.5 and 7.1%. This study shows that elevated expression of Ki-67 is associated both with aggressive prostate cancers and with high Gleason score irrespective of whether their occurrence is against a background of BRCA1 or BRCA2 mutations or as sporadic disease. The data suggest that, since elevated Ki-67 does not distinguish prostate cancers occurring in BRCA1 or BRCA2 mutation carriers from sporadic prostatic malignancies, the effects of these genetic mutations are probably independent. While all prostate cancers occurring in the presence of BRCA germline mutations are clinically aggressive, their potentially different phenotypes consistently involve maximal rates of cell proliferation.

Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer.

BACKGROUND: The discovery of ERG/ETV1 gene rearrangements and PTEN gene loss warrants investigation in a mechanism-based prognostic classification of prostate cancer (PCa). The study objective was to evaluate the potential clinical significance and natural history of different disease categories by combining ERG/ETV1 gene rearrangements and PTEN gene loss status. METHODS: We utilised fluorescence in situ hybridisation (FISH) assays to detect PTEN gene loss and ERG/ETV1 gene rearrangements in 308 conservatively managed PCa patients with survival outcome data. RESULTS: ERG/ETV1 gene rearrangements alone and PTEN gene loss alone both failed to show a link to survival in multivariate analyses. However, there was a strong interaction between ERG/ETV1 gene rearrangements and PTEN gene loss (P<0.001). The largest subgroup of patients (54%), lacking both PTEN gene loss and ERG/ETV1 gene rearrangements comprised a 'good prognosis' population exhibiting favourable cancer-specific survival (85.5% alive at 11 years). The presence of PTEN gene loss in the absence of ERG/ETV1 gene rearrangements identified a patient population (6%) with poorer cancer-specific survival that was highly significant (HR=4.87, P<0.001 in multivariate analysis, 13.7% survival at 11 years) when compared with the 'good prognosis' group. ERG/ETV1 gene rearrangements and PTEN gene loss status should now prospectively be incorporated into a predictive model to establish whether predictive performance is improved. CONCLUSIONS: Our data suggest that FISH studies of PTEN gene loss and ERG/ETV1 gene rearrangements could be pursued for patient stratification, selection and hypothesis-generating subgroup analyses in future PCa clinical trials and potentially in patient management.

Pars plana vitrectomy in the management of paediatric uveitis: the Massachusetts Eye Research and Surgery Institution experience.

PURPOSE: To assess the effectiveness and safety of pars plana vitrectomy (PPV) in the management of chronic paediatric uveitis. METHODS: We reviewed records of patients 16 years old or younger who underwent PPV due to persistent uveitis. Data including inflammatory status, ocular findings, visual acuity, dosage and duration of various medical therapies, surgical techniques and complications were collected. RESULTS: Twenty-eight eyes of 20 patients were included in the study. The diagnoses of uveitis included pars planitis in 15 eyes (54%), idiopathic panuveitis in 8 eyes (29%), and juvenile idiopathic arthritis-associated iridocyclitis in five eyes (18%). Six eyes presented with associated retinal vasculitis. The mean age at the time of PPV was 11.2 years. The mean follow-up after surgery was 13.5 months. All 28 eyes had active uveitis with or without medical therapy at the time of PPV. At last follow-up, uveitis control was achieved with or without adjuvant medical therapy in 27 eyes (96%). These included five of the six eyes with persistent retinal vasculitis. Two eyes that had 20-G PPV developed intra-operative retinal tears. Four eyes with pre-operative clear lenses developed cataract within the first 6 months after PPV. CONCLUSIONS: PPV is effective and safe in the management of chronic paediatric uveitis and its complications. It was able to reduce the amount of systemic medications required to control inflammation in this study. Patients with uveitis complicated by retinal vasculitis, however, are more likely to require long-term medical therapy to achieve inflammatory control.

Hsp-27 expression at diagnosis predicts poor clinical outcome in prostate cancer independent of ETS-gene rearrangement.

BACKGROUND: This study was performed to test the hypothesis that expression of small heat shock protein Hsp-27 is, at diagnosis, a reliable predictive biomarker of clinically aggressive prostate cancer. METHODS: A panel of tissue microarrays constructed from a well-characterised cohort of 553 men with conservatively managed prostate cancer was stained immunohistochemically to detect Hsp-27 protein. Hsp-27 expression was compared with a series of pathological and clinical parameters, including outcome. RESULTS: Hsp-27 staining was indicative of higher Gleason score (P<0.001). In tissue cores having a Gleason score >7, the presence of Hsp-27 retained its power to independently predict poor clinical outcome (P<0.002). Higher levels of Hsp-27 staining were almost entirely restricted to cancers lacking ERG rearrangements (chi2 trend=31.4, P<0.001), although this distribution did not have prognostic significance. INTERPRETATION: This study has confirmed that, in prostate cancers managed conservatively over a period of more than 15 years, expression of Hsp-27 is an accurate and independent predictive biomarker of aggressive disease with poor clinical outcome (P<0.001). These findings suggest that apoptotic and cell-migration pathways modulated by Hsp-27 may contain targets susceptible to the development of biologically appropriate chemotherapeutic agents that are likely to prove effective in treating aggressive prostate cancers.

Ki-67 and outcome in clinically localised prostate cancer: analysis of conservatively treated prostate cancer patients from the Trans-Atlantic Prostate Group study.

Treatment decisions after diagnosis of clinically localised prostate cancer are difficult due to variability in tumour behaviour. We therefore examined one of the most promising biomarkers in prostate cancer, Ki-67, in a cohort of 808 patients diagnosed with prostate cancer between 1990 and 1996 and treated conservatively. Ki-67 expression was assessed immunohistochemically, in two laboratories, by two different scoring methods and the results compared with cancer-specific and overall survival. The power of the biomarker was compared with Gleason score and initial serum prostate-specific antigen (PSA). Both methods showed that Ki-67 provided additional prognostic information beyond that available from Gleason score and PSA: for the semi-quantitative method, Deltachi(2) (1 d.f.)=24.6 (P<0.0001), overall survival chi(2)=20.5 (P<0.0001), and for the quantitative method, Deltachi(2) (1 d.f.)=15.1 (P=0.0001), overall survival chi(2)=10.85 (P=0.001). Ki-67 is a powerful biomarker in localised prostate cancer and adds to a model predicting the need for radical or conservative therapy. As it is already in widespread use in routine pathology, it is confirmed as the most promising biomarker to be applied into routine practice.

Induction of durable remission in ocular inflammatory diseases.

PURPOSE: To describe a paradigm of care for patients with ocular inflammatory diseases aimed at induction of durable remission. METHODS: Retrospective cohort study. The records of 399 patients with ocular inflammatory diseases treated with systemic immunomodulatory therapy (IMT) at the Massachusetts Eye Research and Surgery Institution were reviewed. Durable remission was defined as control of inflammation in the absence of systemic IMT for at least 1 year. Fifty patients met the inclusion criteria. RESULTS: Mean age was 46+/-22.5 years (range 18-88). All the patients had corticosteroid therapy and failed this therapy before having IMT. Fifty-two percent of the patients had used methotrexate alone or in combination with other medications. Thirty percent of the patients required at least 2 years of therapy with systemic IMT to obtain durable remission, while 44% required 2 to 5 years of therapy to achieve the same. Twenty percent continued to stay in remission, off immunomodulatory drugs, between 2 and 5 years and 18% were in remission for more than 5 years after therapy discontinuation. CONCLUSIONS: IMT can be sight saving in patients. It can be tapered and discontinued successfully without the return of ocular inflammation. Durable drug-free remission is an achievable goal, and should be pursued by ocular inflammatory disease specialists.

Concepts of epigenetics in prostate cancer development.

Substantial evidence now supports the view that epigenetic changes have a role in the development of human prostate cancer. Analyses of the patterns of epigenetic alteration are providing important insights into the origin of this disease and have identified specific alterations that may serve as useful diagnostic and prognostic biomarkers. Examination of cancer methylation patterns supports a stem cell origin of prostate cancer. It is well established that methylation of GSTpi is a marker of prostate cancer, and global patterns of histone marking appear to be linked to cancer prognosis with levels of acetylated histones H3K9, H3K18, and H4K12, and of dimethylated H4R3 and H3K4, dividing low-grade prostate cancer (Gleason 6 or less) into two prognostically separate groups. Elevated levels of several components of the polycomb group protein complex, EZH2, BMI1, and RING1, can also act as biomarkers of poor clinical outcome. Many components of the epigenetic machinery, including histone deacetylase (whose expression level is linked to the TMPRSS2:ERG translocation) and the histone methylase EZH2, are potential therapeutic targets. The recent discovery of the role of small RNAs in governing the epigenetic status of individual genes offers exciting new possibilities in therapeutics and chemoprevention.

Primary intraocular lymphoma: another great masquerader.

PURPOSE: To describe diverse and atypical presentations of the most common masquerader in neoplastic masquerade syndromes. METHODS: Retrospective interventional case series. The authors identified three patients who presented with atypical and diagnostically challenging masquerading manifestations. These patients were eventually found to have primary intraocular lymphoma (PIOL). Their case histories, presenting signs and symptoms, diagnostic tests, and treatments are described. RESULTS: Patient 1 masqueraded as viral retinitis and branch retinal vein occlusion but was resistant to 5 weeks of oral and intravenous acyclovir. Patient 2 presented with choroidal infiltrates and vision loss. This patient had had breast carcinoma for the last 25 years and secondary metastasis was suspected. Patient 3 had chronic uveo-retinitis and a chronic Propionibacterium acnes infection was suspected. All three patients were diagnosed with PIOL. CONCLUSIONS: PIOL is an aggressive masquerader and not only presents clinical diagnostic difficulties but also requires expert tissue handling and analysis, so that early diagnosis can be made and therapy can be instituted.

Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype.

There is a high and rising prevalence of prostate cancer (PRCA) within the male population of the United Kingdom. Although the relative risk of PRCA is higher in male BRCA2 and BRCA1 mutation carriers, the histological characteristics of this malignancy in these groups have not been clearly defined. We present the histopathological findings in the first UK series of BRCA1 and BRCA2 mutation carriers with PRCA. The archived histopathological tissue sections of 20 BRCA1/2 mutation carriers with PRCA were collected from histopathology laboratories in England, Ireland and Scotland. The cases were matched to a control group by age, stage and serum PSA level of PRCA cases diagnosed in the general population. Following histopathological evaluation and re-grading according to current conventional criteria, Gleason scores of PRCA developed by BRCA1/2 mutation carriers were identified to be significantly higher (Gleason scores 8, 9 or 10, P=0.012) than those in the control group. Since BRCA1/2 mutation carrier status is associated with more aggressive disease, it is a prognostic factor for PRCA outcome. Targeting screening to this population may detect disease at an earlier clinical stage which may therefore be beneficial.

Complex patterns of ETS gene alteration arise during cancer development in the human prostate.

An ERG gene 'break-apart' fluorescence in situ hybridization (FISH) assay has been used to screen whole-mount prostatectomy specimens for rearrangements at the ERG locus. In cancers containing ERG alterations the observed pattern of changes was often complex. Different categories of ERG gene alteration were found either together in a single cancerous region or within separate foci of cancer in the same prostate slice. In some cases the juxtaposition of particular patterns of ERG alterations suggested possible mechanisms of tumour progression. Prostates harbouring ERG alterations commonly also contained cancer that lacked rearrangements of the ERG gene. A single trans-urethral resection of the prostate specimen examined harboured both ERG and ETV1 gene rearrangements demonstrating that the observed complexity may, at least in part, be explained by multiple ETS gene alterations arising independently in a single prostate. In a search for possible precursor lesions clonal ERG rearrangements were found both in high grade prostatic intraepithelial neoplasia (PIN) and in atypical in situ epithelial lesions consistent with the diagnosis of low grade PIN. Our observations support the view that ERG gene alterations represent an initiating event that promotes clonal expansion initially to form regions of epithelial atypia. The complex patterns of ERG alteration found in prostatectomy specimens have important implications for the design of experiments investigating the clinical significance and mechanism of development of individual prostate cancers.

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

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' (labelled green) and 3' (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' to ERG (called '2+Edel'), which by comparison exhibited extremely poor cause-specific survival (hazard ratio=6.10, 95% confidence ratio=3.33-11.15, P<0.001, 25% survival at 8 years). In multivariate analysis, '2+Edel' provided significant prognostic information (P=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+Edel, allows stratification of prostate cancer into distinct survival categories.