ERG

Gene Summary

Gene:ERG; ERG, ETS transcription factor
Aliases: p55, erg-3
Location:21q22.2
Summary:This gene encodes a member of the erythroblast transformation-specific (ETS) family of transcriptions factors. All members of this family are key regulators of embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis. The protein encoded by this gene is mainly expressed in the nucleus. It contains an ETS DNA-binding domain and a PNT (pointed) domain which is implicated in the self-association of chimeric oncoproteins. This protein is required for platelet adhesion to the subendothelium, inducing vascular cell remodeling. It also regulates hematopoesis, and the differentiation and maturation of megakaryocytic cells. This gene is involved in chromosomal translocations, resulting in different fusion gene products, such as TMPSSR2-ERG and NDRG1-ERG in prostate cancer, EWS-ERG in Ewing's sarcoma and FUS-ERG in acute myeloid leukemia. More than two dozens of transcript variants generated from combinatorial usage of three alternative promoters and multiple alternative splicing events have been reported, but the full-length nature of many of these variants has not been determined. [provided by RefSeq, Apr 2014]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcriptional regulator ERG
Source:NCBIAccessed: 13 March, 2017

Ontology:

What does this gene/protein do?
Show (13)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Prostate-Specific Antigen
  • Signal Transduction
  • Transcriptome
  • Biomarkers, Tumor
  • PTEN
  • Cell Proliferation
  • ERG
  • Prostate
  • Ultraviolet Rays
  • Prostatectomy
  • Validation Studies as Topic
  • Recurrence
  • Messenger RNA
  • Tissue Array Analysis
  • Cancer Gene Expression Regulation
  • Gene Rearrangement
  • Disease Progression
  • Gene Expression Profiling
  • Neoplasm Grading
  • Acute Myeloid Leukaemia
  • Trans-Activators
  • Immunohistochemistry
  • Gene Fusion
  • Chromosome 21
  • Proteomics
  • Neoplasm Recurrence, Local
  • Oncogene Fusion Proteins
  • Prostate Cancer
  • Synaptophysin
  • Adenocarcinoma
  • ROC Curve
  • FISH
  • DNA-Binding Proteins
  • TMPRSS2
  • Androgen Receptors
  • Staging
  • Estrogen Receptors
  • Ewing's Sarcoma
  • EWSR1
  • Radiotherapy, Image-Guided
  • Urinalysis
  • Mutation
  • Proto-Oncogene Proteins c-ets
  • Sensitivity and Specificity
  • Young Adult
Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Ewing's SarcomaERG and Ewing's Sarcoma View Publications105
Ewing's Sarcomat(21;22) EWSR1-ERG Translocations in Ewing's Sarcoma
Acute Myeloid Leukaemia (AML)t(16;21)(p11;q22) in Leukemia (ANLL)
Acute Myeloid Leukaemia (AML)t(16;21)(p11;q22) FUS-ERG in Acute Myelogenous Leukemia
Prostate CancerERG-TMPRSS2 Fusion in Prostate Cancer
The fusion of ERG and TMPRSS2 (21q22.3) is common in prostate cancer. It may be caused by intronic deletion or translocation.
See: More details below...

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

ERG-TMPRSS2 Fusion in Prostate Cancer

The fusion of ERG and TMPRSS2 (21q22.3) is common in prostate cancer. It may be caused by intronic deletion or translocation.

See also: Prostate Cancer - Clinical and Research information
See also: TMPRSS2.htm gene

Latest Publications

Berg KD
The prognostic and predictive value of TMPRSS2-ERG gene fusion and ERG protein expression in prostate cancer biopsies.
Dan Med J. 2016; 63(12) [PubMed] Related Publications
BACKGROUND: The clinical course of prostate carcinoma (PCa) is very heterogeneous. Consequently, a personalised approach for risk stratification and treatment planning is important. Recently, it has become evident that PCa, also at the genomic level, is heterogeneous. An early and common alteration is the gene fusion between the transmembrane protease serine 2 (TMPRSS2) gene and the v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) gene resulting in expression of the oncoprotein ERG. The gene fusion is present in approximately half of PCa patients and the resultant two subgroups demonstrate marked differences in their genomic signatures. It has been hypothesised that genomic alterations can explain some of the observed heterogeneity in the clinical course of PCa. In order to conduct an analysis of the prognostic and predictive value of ERG protein expression in PCa biopsies, the thesis sought to evaluate: 1) the concordance in ERG expression between biopsies and radical prostatectomies: 2) the association between expression of ERG protein and the risk of PCa progression during active surveillance (AS), and 3) the association between ERG protein expression and response to primary castration-based treatment for advanced PCa.
MATERIAL AND METHODS: The included patients derived from the institutional AS cohort and an institutional cohort of advanced PCa patients undergoing first line castration-based androgen deprivation therapy (ADT). The 265 patients in the AS cohort were enrolled prospectively between October 2002 and October 2012 and were followed with regular digital rectal examinations, PSA measurements, and repeated biopsies. The advanced PCa cohort comprised of 194 patients diagnosed between January 2000 and December 2011 and was established retrospectively by a standardised extraction of patient data. Immunohistochemical (IHC) assessment for ERG protein expression was performed in all tumours containing diagnostic specimens (AS cohort: n = 459; advanced PCa cohort: n = 968), re-biopsies during AS (n = 402), and deferred radical prostatectomy specimens following AS (n = 86). An anti-ERG rabbit monoclonal primary antibody (clone: EPR3864, dilution 23 μg/ml) was used. Fluorescence in situ hybridisation (FISH) for the TMPRSS2-ERG gene fusion was performed in 76 selected biopsies from the AS cohort using the ZytoLight TriCheck Probe, SPEC ERG/TMPRSS2.
RESULTS: Based on the AS cohort, Study 1 found a 97.3% concordance between the FISH assay and the IHC assay. The IHC assessments of ERG expression in diagnostic biopsies, re-biopsies, and radical prostatectomy specimens demonstrated a low proportion of temporal ERG reclassification. During four rounds of re-biopsies, 6.6% of the patients experienced ERG reclassification, and depending on the number biopsy specimens included 5.8-10.5% of the patients were ERG reclassified after radical prostatectomy. In Study 2, 46.4% of the AS patients were categorised as ERG-positive, whereas 53.6% were categorised as ERG-negative. After median 4.1 years follow-up, a significantly higher risk of disease progression was observed in men with ERG-positive tumours corresponding to a two-year cumulative incidence of 58.6% (95% CI: 48.7-68.5) and 21.7% (95% CI: 14.3-29.1) in the ERG-positive and the ERG-negative group, respectively. In the multiple causespecific Cox analyses, ERG expression was a strong and independent predictor of overall disease progression (HR: 2.45, 95% CI: 1.62-3.72) and histopathological progression in repeated biopsies (HR: 3.06, 95% CI: 1.78-5.26), and ERG status increased the discriminative ability for predicting disease progression significantly. Study 3 included 194 patients with advanced PCa treated with firstline ADT. In total, 54.1% had ERG-positive tumours and 45.9% had ERG-negative tumours. With a median of 6.8 years of follow-up, the risk of developing castration-resistant PCa (CRPC) did not differ between the ERG subgroups (p = 0.51). Finally, inclusion of ERG status in a multiple cause-specific Cox model did not increase the discriminative ability for predicting CRPC development during the first 8 years of ADT.
CONCLUSION: The thesis has demonstrated that assessment of ERG protein expression is feasible in biopsy specimens, and a high concordance was found between the IHC assay and FISH assessment of ERG rearrangement. The low proportion of ERG reclassification between biopsies and prostatectomies supports the use of ERG assessment in biopsies to characterise the individual patient's ERG status. ERG status harbours important prognostic value in terms of tumour progression for patients managed on AS, whereas ERG expression has no predictive value for ADT response in men with advanced PCa undergoing first-line castration-based ADT. The overall conclusion of the thesis is that ERG protein expression provides valuable prognostic information in low-risk PCa managed observationally, and ERG expression might be used to personalise follow-up regimens in future AS programmes.

Koo KM, Wee EJ, Trau M
High-speed biosensing strategy for non-invasive profiling of multiple cancer fusion genes in urine.
Biosens Bioelectron. 2017; 89(Pt 2):715-720 [PubMed] Related Publications
Aberrant chromosal rearrangements, such as the multiple variants of TMPRSS2:ERG fusion gene mutations in prostate cancer (PCa), are promising diagnostic and prognostic biomarkers due to their specific expression in cancerous tissue only. Additionally, TMPRSS2:ERG variants are detectable in urine to provide non-invasive PCa diagnostic sampling as an attractive surrogate for needle biopsies. Therefore, rapid and simplistic assays for identifying multiple urinary TMPRSS2:ERG variants are potentially useful to aid in early cancer detection, immediate patient risk stratification, and prompt personalized treatment. However, current strategies for simultaneous detection of multiple gene fusions are limited by tedious and prolonged experimental protocols, thus limiting their use as rapid clinical screening tools. Herein, we report a simple and rapid gene fusion strategy which expliots the specificity of DNA ligase and the speed of isothermal amplification to simultaneously detect multiple fusion gene RNAs within a short sample-to-answer timeframe of 60min. The method has a low detection limit of 2 amol (1000 copies), and was successfully applied for non-invasive fusion gene profiling in patient urine samples with subsequent validation by a PCR-based gold standard approach.

Jiang H, Mao X, Huang X, et al.
TMPRSS2:ERG fusion gene occurs less frequently in Chinese patients with prostate cancer.
Tumour Biol. 2016; 37(9):12397-12402 [PubMed] Related Publications
Prostate cancer is the commonest male malignancy in the Western world, but its morbidity is much lower in China. The principal aim of this study was to evaluate the frequency of TMPRSS2:ERG fusion in Chinese prostate cancer patients using immunohistochemistry and reverse transcription polymerase chain (RT-PCR). In addition, we compared the ERG protein expression with TMPRSS2:ERG fusion gene. The relationship between ERG expression and clinicopathologic features was also examined. Samples from patients who underwent radical prostatectomies in Changhai Hospital (Shanghai, China) were collected and stored in ethically approved tissue banks. One hundred seventy-four prostate cancer tissue samples and 10 normal tissues were marked on standard hematoxylin-eosin (HE) sections, punched out of the paraffin blocks and inserted into a recipient block using tissue arrayer instruments. Immunohistochemistry and RT-PCR were employed to detect TMPRSS2:ERG fusion gene. ERG was highly expressed in the nuclei of endothelial cells of vessels and weak cytoplasmic staining was occasionally observed. ERG positive staining was present in 14.9 % (26/174) of the tumor samples in microarray. All benign prostate samples were found to be negative. RT-PCR results revealed that 11.1 % (15/135) were TMPRSS2:ERG fusion positive. Altogether, there was a good agreement of ERG immunostaining with the presence of TMPRSS2:ERG. However, no correlation was observed between ERG expression and age, Gleason score, stage, surgical margin, and seminal vesicle involvement in Chinese patients. In the present study, we identified a high correlation between ERG expression and ERG TMPRSS2:ERG, with 100 % sensitivity and 88.9 % specificity. The expression level of ERG was unrelated to the age, Gleason score, stage, surgical margin, and seminal vesicle involvement. Therefore, the association between ERG expression and prostate cancer based on Chinese population should be further investigated in the future.

Gao T, Mei Y, Sun H, et al.
The association of Phosphatase and tensin homolog (PTEN) deletion and prostate cancer risk: A meta-analysis.
Biomed Pharmacother. 2016; 83:114-121 [PubMed] Related Publications
OBJECTIVE: Phosphatase and tensin homolog (PTEN) deleted on chromosome 10, a tumor suppressor that negatively regulates the phosphoinositide-3-kinase(PI3K) which has been implicated in a number of human malignancies including prostate cancer. However the prognostic value of PTEN deletion in prostate cancer patient's diagnosis and the mechanism of PTEN deletion in prostate cancer development still remain unclear.
METHOD: A meta-analysis of 26 published studies including 8097 prostate cancer patients was performed.
RESULTS: Compared to PTEN normal patients, PTEN deletion patients showed a higher aggressive Gleason score(OR: 1.284, 95%CI=1.145-1.439) and pathological stage(OR: 1.628, 95%CI=1.270-2.087) which generally had a higher risk in prostate replace(HR: 1.738, 95%CI=1.264-2.390). Significant association between PTEN deletion and ERG rearrangements in prostate cancer development was also proved that compared to PTEN normal patients, patients with PTEN deletion showed a higher risk in ERG rearrangements(OR: 1.345, 95%CI=1.102-1.788).
CONCLUSION: This study indicated that patients with PTEN deletion were associated with higher pathological stage or Gleason score and a higher risk in prostate cancer replace potentially represent a novel clinically relevant event to identify individuals at increased risk for the occurrence, progression and prognosis of prostate cancer. Prostate cancer patients with PTEN deletion usually had a higher risk in ERG rearrangements than other patients may be a potential new area for identifying poor prognosis patients and selecting patients for targeted therapies which required confirmation through adequately designed prospective studies.

Kim H, Skowronski J, Den RB
Prognostic outlier genes for enhanced prostate cancer treatment.
Future Oncol. 2017; 13(3):249-261 [PubMed] Related Publications
AIM: To review the current landscape of outlier genes in the field of prostate cancer.
METHODS: A comprehensive review was performed.
RESULTS: Prostate cancer continues to be a significant worldwide health issue. In the era of personalized medicine, more emphasis is being placed on the ability to determine the timing, intensity and type of treatment, according to each patient's unique disease. Several commercial tests are available to determine the risk of aggressive prostate cancer based on genomic biomarkers and gene expression. Outlier genes represent a form of cancer classification that focuses on bimodal expression of a gene in a specific subset of patients. Outlier genes identified in prostate cancer include TMPRSS2-ERG, SPINK1, ScHLAP1, NVL, SMC4 and SQLE.
CONCLUSION: Classifying patient prostate cancers by outlier genes may allow for individualized cancer therapies and improved cancer therapy outcomes.

Kulda V, Topolcan O, Kucera R, et al.
Prognostic Significance of TMPRSS2-ERG Fusion Gene in Prostate Cancer.
Anticancer Res. 2016; 36(9):4787-93 [PubMed] Related Publications
BACKGROUND/AIM: Current research of prostate cancer (PCa) offers a promising way of identifying patients with adverse prognosis who do benefit from radical treatment that can affect quality of life as resections are associated with numerous side-effects. The aim of our study was to evaluate the relationship of TMPRSS2-ERG fusion gene status, tumor tissue prostate-specific antigen (PSA), prostate cancer antigen 3 (PCA3), miR-23b, miR-26a and miR-221 expression levels in combination with preoperative serum PSA level to the risk of PCa recurrence after radical prostatectomy.
PATIENTS AND METHODS: The study group consisted of 108 patients who underwent radical prostatectomy. PSA was measured in peripheral blood collected preoperativelly. The expression of TMPRSS2-ERG transcript and the expression of miR-23b, miR-26a and miR-221 in formalin-fixed, paraffin-embedded (FFPE) tumor tissues was analyzed by reverse transcription (RT) real-time polymerase chain reaction (PCR).
RESULTS: Significantly shorter time to recurrence was observed in patients with high expression of TMPRSS2-ERG (p=0.0020). High levels of preoperative PSA (>10.0 ng/ml) proved to be marker of shorter time to recurrence (p=0.0153). The most promising marker of the risk of recurrence after radical prostatectomy was a combination of high level of preoperative serum PSA and high expression of TMPRSS2-ERG fusion transcript in tumor tissue (p=0.0001).
CONCLUSION: A combination of high preoperative serum PSA and high expression of TMPRSS2-ERG could be promising in distinguishing those tumors that are aggressive and life-threatening.

Krstanoski Z, Vokac NK, Zagorac A, et al.
TMPRSS2:ERG gene aberrations may provide insight into pT stage in prostate cancer.
BMC Urol. 2016; 16(1):35 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: TMPRSS2:ERG gene aberration may be a novel marker that improves risk stratification of prostate cancer before definitive cancer therapy, but studies have been inconclusive.
METHODS: The study cohort consisted of 202 operable prostate cancer Slovenian patients who underwent laparoscopic radical prostatectomy. We retrospectively constructed tissue microarrays of their prostatic specimens for fluorescence in situ hybridization, with appropriate signals obtained in 148 patients for subsequent statistical analyses.
RESULTS: The following genetic aberrations were found: TMPRSS2:ERG fusion, TMPRSS2 split (a non-ERG translocation) and ERG split (an ERG translocation without involvement of TMPRSS2). TMPRSS2:ERG gene fusion happened in 63 patients (42 %), TMPRSS2 split in 12 patients and ERG split in 8 patients. Association was tested between TMPRSS2:ERG gene fusion and several clinicopathological variables, i.e., pT stage, extended lymph node dissection status, and Gleason score, correcting for multiple comparisons. Only the association with pT stage was significant at p = 0.05: Of 62 patients with pT3 stage, 34 (55 %) had TMPRSS2:ERG gene fusion. In pT3 stage patients, stronger (but not significant) association between eLND status and TMPRSS2:ERG gene fusion was detected. We detected TMPRSS2:ERG gene fusion in 64 % of the pT3 stage patients where we did not perform an extended lymph node dissection.
CONCLUSIONS: Our results indicate that it is possible to predict pT3 stage at final histology from TMPRSS2:ERG gene fusion at initial core needle biopsy. FISH determination of TMPRSS2:ERG gene fusion may be particularly useful for patients scheduled to undergo a radical prostatectomy in order to improve oncological and functional results.

Liu W
DNA alterations in the tumor genome and their associations with clinical outcome in prostate cancer.
Asian J Androl. 2016 Jul-Aug; 18(4):533-42 [PubMed] Free Access to Full Article Related Publications
Although most prostate cancer (PCa) cases are not life-threatening, approximately 293 000 men worldwide die annually due to PCa. These lethal cases are thought to be caused by coordinated genomic alterations that accumulate over time. Recent genome-wide analyses of DNA from subjects with PCa have revealed most, if not all, genetic changes in both germline and PCa tumor genomes. In this article, I first review the major, somatically acquired genomic characteristics of various subtypes of PCa. I then recap key findings on the relationships between genomic alterations and clinical parameters, such as biochemical recurrence or clinical relapse, metastasis and cancer-specific mortality. Finally, I outline the need for, and challenges with, validation of recent findings in prospective studies for clinical utility. It is clearer now than ever before that the landscape of somatically acquired aberrations in PCa is highlighted by DNA copy number alterations (CNAs) and TMPRSS2-ERG fusion derived from complex rearrangements, numerous single nucleotide variations or mutations, tremendous heterogeneity, and continuously punctuated evolution. Genome-wide CNAs, PTEN loss, MYC gain in primary tumors, and TP53 loss/mutation and AR amplification/mutation in advanced metastatic PCa have consistently been associated with worse cancer prognosis. With this recently gained knowledge, it is now an opportune time to develop DNA-based tests that provide more accurate patient stratification for prediction of clinical outcome, which will ultimately lead to more personalized cancer care than is possible at present.

Boutros PC, Fraser M, van der Kwast T, Bristow RG
Clonality of localized and metastatic prostate cancer.
Curr Opin Urol. 2016; 26(3):219-24 [PubMed] Related Publications
PURPOSE OF REVIEW: The influence of the long life-history of prostate cancer on the temporal and spatial variability of the tumour genome is now being elucidated. Multiregion sequencing to identify spatio-genomic differences in prostate tumour mutation profiles combined with computational approaches can map the evolution and transit of tumour cells throughout an individual patient.
RECENT FINDINGS: A series of recent studies have demonstrated that a prostate tumour is often composed of different subclones, with varying genetic similarity. As such, a single biopsy specimen may be insufficient to make accurate clinical predictions from molecular biomarkers, greatly complicating the application of biopsy-based tools for precision medicine. In addition, subclones that arise outside of the primary tumour can seed new metastases and circulate between sites within a patient.
SUMMARY: The mutational complexity of multiple tumour clones within the same individual, which respond differently to specific treatments, suggests the need for multimodal interventions.

Petrovics G, Li H, Stümpel T, et al.
A novel genomic alteration of LSAMP associates with aggressive prostate cancer in African American men.
EBioMedicine. 2015; 2(12):1957-64 [PubMed] Free Access to Full Article Related Publications
Evaluation of cancer genomes in global context is of great interest in light of changing ethnic distribution of the world population. We focused our study on men of African ancestry because of their disproportionately higher rate of prostate cancer (CaP) incidence and mortality. We present a systematic whole genome analyses, revealing alterations that differentiate African American (AA) and Caucasian American (CA) CaP genomes. We discovered a recurrent deletion on chromosome 3q13.31 centering on the LSAMP locus that was prevalent in tumors from AA men (cumulative analyses of 435 patients: whole genome sequence, 14; FISH evaluations, 101; and SNP array, 320 patients). Notably, carriers of this deletion experienced more rapid disease progression. In contrast, PTEN and ERG common driver alterations in CaP were significantly lower in AA prostate tumors compared to prostate tumors from CA. Moreover, the frequency of inter-chromosomal rearrangements was significantly higher in AA than CA tumors. These findings reveal differentially distributed somatic mutations in CaP across ancestral groups, which have implications for precision medicine strategies.

Silva MP, Barros-Silva JD, Vieira J, et al.
NCOA2 is a candidate target gene of 8q gain associated with clinically aggressive prostate cancer.
Genes Chromosomes Cancer. 2016; 55(4):365-74 [PubMed] Related Publications
Prostate carcinomas harboring 8q gains are associated with poor clinical outcome, but the target genes of this genomic alteration remain to be unveiled. In this study, we aimed to identify potential 8q target genes associated with clinically aggressive prostate cancer (PCa) using fluorescence in situ hybridization (FISH), genome-wide mRNA expression, and protein expression analyses. Using FISH, we first characterized the relative copy number of 8q (assessed with MYC flanking probes) of a series of 50 radical prostatectomy specimens, with available global gene expression data and typed for E26 transformation specific (ETS) rearrangements, and then compared the gene expression profile of PCa subsets with and without 8q24 gain using Significance Analysis of Microarrays. In the subset of tumors with ERG fusion genes (ERG+), five genes were identified as significantly overexpressed (false discovery rate [FDR], ≤ 5%) in tumors with relative 8q24 gain, namely VN1R1, ZNF417, CDON, IKZF2, and NCOA2. Of these, only NCOA2 is located in 8q (8q13.3), showing a statistically higher mRNA expression in the subgroup with relative 8q gain, both in the ERG+ subgroup and in the whole series (P = 0.000152 and P = 0.008, respectively). Combining all the cases with NCOA2 overexpression, either at the mRNA or at the protein level, we identified a group of tumors with NCOA2 copy-number increase, independently of ETS status and relative 8q24 gain. Furthermore, for the first time, we detected a structural rearrangement involving NCOA2 in PCa. These findings warrant further studies with larger series to evaluate if NCOA2 relative copy-number gain presents prognostic value independently of the well-established poor prognosis associated with MYC relative copy-number gain.

Qu X, Jeldres C, Glaskova L, et al.
Identification of Combinatorial Genomic Abnormalities Associated with Prostate Cancer Early Recurrence.
J Mol Diagn. 2016; 18(2):215-24 [PubMed] Free Access to Full Article Related Publications
Multiple biomarkers are needed to distinguish aggressive from indolent prostate cancer. We tested the prognostic utility of a three-marker fluorescent in situ hybridization (FISH) panel (TMPRSS2/ERG rearrangements, AR gain, and PTEN deletion) in a retrospective cohort (n = 210; median follow-up, 5.7 years). PTEN deletion was associated with an increased risk of biochemical recurrence (BcR; hazard ratio, 3.58; 95% CI, 1.39-9.22; P < 0.01) by multivariable Cox regression analyses and earlier BcR (P < 0.02) by Kaplan-Meier analysis. AR gain coexisted with X-chromosome gain and was associated with advanced tumor stage. When this panel was applied, two categories of combinatorial abnormalities proved clinically important. First, PTEN deletion without TMPRSS2/ERG rearrangement was enriched in pT3/4 tumors (70% versus 48%) and tumors with Gleason grades of 8 to 9 (60% versus 17%) compared with the entire cohort. These patients had earlier BcR than patients with normal FISH panel results (P < 0.01). In contrast, patients with PTEN deletion and ERG rearrangement had a BcR rate similar to patients who tested normal for all three markers (P > 0.1). Second, AR gain and concurrent trisomy 10 without TMPRSS2/ERG rearrangement were enriched in pT3/4 tumors and tumors with Gleason grades of 8 to 9. The three-marker FISH panel demonstrated prognostic utility and identified genomic aberrations associated with advanced disease state and early BcR in prostate cancer.

Metzger E, Willmann D, McMillan J, et al.
Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation.
Nat Struct Mol Biol. 2016; 23(2):132-9 [PubMed] Related Publications
Prostate cancer evolution is driven by a combination of epigenetic and genetic alterations such as coordinated chromosomal rearrangements, termed chromoplexy. TMPRSS2-ERG gene fusions found in human prostate tumors are a hallmark of chromoplexy. TMPRSS2-ERG fusions have been linked to androgen signaling and depend on androgen receptor (AR)-coupled gene transcription. Here, we show that dimethylation of KDM1A at K114 (to form K114me2) by the histone methyltransferase EHMT2 is a key event controlling androgen-dependent gene transcription and TMPRSS2-ERG fusion. We identified CHD1 as a KDM1A K114me2 reader and characterized the KDM1A K114me2-CHD1 recognition mode by solving the cocrystal structure. Genome-wide analyses revealed chromatin colocalization of KDM1A K114me2, CHD1 and AR in prostate tumor cells. Together, our data link the assembly of methylated KDM1A and CHD1 with AR-dependent transcription and genomic translocations, thereby providing mechanistic insight into the formation of TMPRSS2-ERG gene fusions during prostate-tumor evolution.

Kluth M, Meyer D, Krohn A, et al.
Heterogeneity and chronology of 6q15 deletion and ERG-fusion in prostate cancer.
Oncotarget. 2016; 7(4):3897-904 [PubMed] Free Access to Full Article Related Publications
Prostate cancer is notorious for its heterogeneity, which poses a problem for the applicability of diagnostic molecular markers. However, heterogeneity analysis can provide valuable information on the chronology in which molecular alterations arise. Here, we constructed a heterogeneity tissue microarray (TMA) comprising samples from 10 different tumor areas of 189 prostate cancers each in order to study the sequence of two frequent molecular alterations, i.e. 6q15 deletion and TMPRSS2:ERG fusion. Previous work shows a marked inverse relationship between these alterations, suggesting that presence of one of these alterations might impact development of the other. 6q15 deletion was analyzed by fluorescence in situ hybridization and ERG-expression by immunohistochemistry. Only 6.6% of 334 ERG-positive but 28.4% of 440 ERG-negative TMA spots showed 6q15 deletions (p < 0.0001). A breakdown of these data to the level of tumor foci revealed 6q deletions in 138 tumor foci that were large enough to have at least 3 analyzable TMA spots. These included 42 tumor foci with homogeneous ERG positivity and 16 with homogeneous 6q15 deletions. Remarkably, six of the 42 homogeneously ERG-positive tumor foci (14.3%) harbored small 6q15-deleted areas, but none of the 34 6q15-deleted foci showed areas of ERG positivity (p = 0.022). In conclusion, our data suggest that ERG-fusion can precede 6q15 deletion, but not vice versa. The complete absence of ERG-positive tumor areas in 6q15-deleted tumor foci further suggest that the functional consequences of 6q15 deletions may prevent the development of TMPRSS2:ERG fusions.

Meller S, Meyer HA, Bethan B, et al.
Integration of tissue metabolomics, transcriptomics and immunohistochemistry reveals ERG- and gleason score-specific metabolomic alterations in prostate cancer.
Oncotarget. 2016; 7(2):1421-38 [PubMed] Free Access to Full Article Related Publications
Integrated analysis of metabolomics, transcriptomics and immunohistochemistry can contribute to a deeper understanding of biological processes altered in cancer and possibly enable improved diagnostic or prognostic tests. In this study, a set of 254 metabolites was determined by gas-chromatography/liquid chromatography-mass spectrometry in matched malignant and non-malignant prostatectomy samples of 106 prostate cancer (PCa) patients. Transcription analysis of matched samples was performed on a set of 15 PCa patients using Affymetrix U133 Plus 2.0 arrays. Expression of several proteins was immunohistochemically determined in 41 matched patient samples and the association with clinico-pathological parameters was analyzed by an integrated data analysis. These results further outline the highly deregulated metabolism of fatty acids, sphingolipids and polyamines in PCa. For the first time, the impact of the ERG translocation on the metabolome was demonstrated, highlighting an altered fatty acid oxidation in TMPRSS2-ERG translocation positive PCa specimens. Furthermore, alterations in cholesterol metabolism were found preferentially in high grade tumors, enabling the cells to create energy storage. With this integrated analysis we could not only confirm several findings from previous metabolomic studies, but also contradict others and finally expand our concepts of deregulated biological pathways in PCa.

Murphy SJ, Karnes RJ, Kosari F, et al.
Integrated analysis of the genomic instability of PTEN in clinically insignificant and significant prostate cancer.
Mod Pathol. 2016; 29(2):143-56 [PubMed] Related Publications
Patients with clinically insignificant prostate cancer remain a major over-treated population. PTEN loss is one of the most recurrent alterations in prostate cancer associated with an aggressive phenotype, however, the occurrence of PTEN loss in insignificant prostate cancer has not been reported and its role in the separation of insignificant from significant prostate cancer is unclear. An integrated analysis of PTEN loss was, therefore, performed for structural variations, point mutations and protein expression in clinically insignificant (48 cases) and significant (76 cases) prostate cancers treated by radical prostatectomy. Whole-genome mate pair sequencing was performed on tumor cells isolated by laser capture microdissection to characterize PTEN structural alterations. Fluorescence in situ hybridization probes were constructed from the sequencing data to detect the spectrum of these PTEN alterations. PTEN loss by mate pair sequencing and fluorescence in situ hybridization occurred in 2% of insignificant, 13% of large volume Gleason score 6, and 46% of Gleason score 7 and higher cancers. In Gleason score 7 cancers with PTEN loss, PTEN alterations were detected in both Gleason pattern 3 and 4 in 57% of cases by mate pair sequencing, 75% by in situ hybridization and 86% by immunohistochemistry. PTEN loss by sequencing was strongly associated with TMPRSS2-ERG fusion, biochemical recurrence, PTEN loss by in situ hybridization and protein loss by immunohistochemistry. The complex nature of PTEN rearrangements was unveiled by sequencing, detailing the heterogeneous events leading to homozygous loss of PTEN. PTEN point mutation was present in 5% of clinically significant tumors and not in insignificant cancer or high-grade prostatic intraepithelial neoplasia. PTEN loss is infrequent in clinically insignificant prostate cancer, and is associated with higher grade tumors. Detection of PTEN loss in Gleason score 6 cancer in a needle biopsy specimen indicates a higher likelihood of clinically significant prostate cancer.


The Molecular Taxonomy of Primary Prostate Cancer.
Cell. 2015; 163(4):1011-25 [PubMed] Free Access to Full Article Related Publications
There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects.

Demidenko R, Razanauskas D, Daniunaite K, et al.
Frequent down-regulation of ABC transporter genes in prostate cancer.
BMC Cancer. 2015; 15:683 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: ATP-binding cassette (ABC) transporters are transmembrane proteins responsible for the efflux of a wide variety of substrates, including steroid metabolites, through the cellular membranes. For better characterization of the role of ABC transporters in prostate cancer (PCa) development, the profile of ABC transporter gene expression was analyzed in PCa and noncancerous prostate tissues (NPT).
METHODS: TaqMan Low Density Array (TLDA) human ABC transporter plates were used for the gene expression profiling in 10 PCa and 6 NPT specimens. ABCB1 transcript level was evaluated in a larger set of PCa cases (N = 78) and NPT (N = 15) by real-time PCR, the same PCa cases were assessed for the gene promoter hypermethylation by methylation-specific PCR.
RESULTS: Expression of eight ABC transporter genes (ABCA8, ABCB1, ABCC6, ABCC9, ABCC10, ABCD2, ABCG2, and ABCG4) was significantly down-regulated in PCa as compared to NPT, and only two genes (ABCC4 and ABCG1) were up-regulated. Down-regulation of ABC transporter genes was prevalent in the TMPRSS2-ERG-negative cases. A detailed analysis of ABCB1 expression confirmed TLDA results: a reduced level of the transcript was identified in PCa in comparison to NPT (p = 0.048). Moreover, the TMPRSS2-ERG-negative PCa cases showed significantly lower expression of ABCB1 in comparison to NPT (p = 0.003) or the fusion-positive tumors (p = 0.002). Promoter methylation of ABCB1 predominantly occurred in PCa and was rarely detected in NPT (p < 0.001).
CONCLUSIONS: The study suggests frequent down-regulation of the ABC transporter genes in PCa, especially in the TMPRSS2-ERG-negative tumors.

Fallahabadi ZR, Noori Daloii MR, Mahdian R, et al.
Frequency of PTEN alterations, TMPRSS2-ERG fusion and their association in prostate cancer.
Gene. 2016; 575(2 Pt 3):755-60 [PubMed] Related Publications
BACKGROUND: Phosphatase and tensin homolog (PTEN) gene aberration and trans membrane protease, serine 2 (TMPRSS2)-v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion are the most prevalent genomic events in prostate cancer. In this study we aimed to evaluate the frequency of PTEN alteration and TMPRSS2-ERG fusion and possible link between these two biomarkers in Iranian men.
METHODS: We assessed 42 fresh frozen tissue samples of prostate cancer (PCA) obtained by radical prostatectomy, interrogating the TMPRSS2-ERG fusion gene along with PTEN gene status using Real Time PCR and FISH methods.
RESULTS: Using Real Time PCR we identified the TMPRSS2-ERG fusion in 64% (27/42) of tumor samples, which was confirmed by FISH technique, giving 21 positive samples with deletion, suggesting the presence of TMPRSS2-ERG fusion gene. By contrast, PTEN deletion was detected in 52% (11/21) of PCA samples, which all showed low expression in Real Time. Concomitance of PTEN deletion or low expression and TMPRSS2-ERG fusion was present in PCA samples (P=0.005). All of the PTEN deletion samples showed TMPRSS2-ERG fusion, (11/11, 100%) while not all of the TMPRSS2-ERG fusion positive samples showed PTEN deletion. None of 29 cases of BPH and 8 cases of normal zone of tumor tissue showed TMPRSS2-ERG fusion.
CONCLUSIONS: These results indicate that PTEN loss occurs in cooperation with TMPRSS2-ERG fusion in PCA. While the majority of PCA samples harbor TMPRSS2-ERG fusion as well as PTEN gene deletion, normal tissues do not show these molecular aberrations.

Bu H, Narisu N, Schlick B, et al.
Putative Prostate Cancer Risk SNP in an Androgen Receptor-Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites.
Hum Mutat. 2016; 37(1):52-64 [PubMed] Free Access to Full Article Related Publications
Genome-wide association studies have identified genomic loci, whose single-nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the mechanisms of most of these variants are largely unknown. We integrated chromatin-immunoprecipitation-coupled sequencing and microarray expression profiling in TMPRSS2-ERG gene rearrangement positive DUCaP cells with the GWAS PCa risk SNPs catalog to identify disease susceptibility SNPs localized within functional androgen receptor-binding sites (ARBSs). Among the 48 GWAS index risk SNPs and 3,917 linked SNPs, 80 were found located in ARBSs. Of these, rs11891426:T>G in an intron of the melanophilin gene (MLPH) was within a novel putative auxiliary AR-binding motif, which is enriched in the neighborhood of canonical androgen-responsive elements. T→G exchange attenuated the transcriptional activity of the ARBS in an AR reporter gene assay. The expression of MLPH in primary prostate tumors was significantly lower in those with the G compared with the T allele and correlated significantly with AR protein. Higher melanophilin level in prostate tissue of patients with a favorable PCa risk profile points out a tumor-suppressive effect. These results unravel a hidden link between AR and a functional putative PCa risk SNP, whose allele alteration affects androgen regulation of its host gene MLPH.

Latest Publications: ERG (cancer-related)

Berg KD
The prognostic and predictive value of TMPRSS2-ERG gene fusion and ERG protein expression in prostate cancer biopsies.
Dan Med J. 2016; 63(12) [PubMed] Related Publications
BACKGROUND: The clinical course of prostate carcinoma (PCa) is very heterogeneous. Consequently, a personalised approach for risk stratification and treatment planning is important. Recently, it has become evident that PCa, also at the genomic level, is heterogeneous. An early and common alteration is the gene fusion between the transmembrane protease serine 2 (TMPRSS2) gene and the v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) gene resulting in expression of the oncoprotein ERG. The gene fusion is present in approximately half of PCa patients and the resultant two subgroups demonstrate marked differences in their genomic signatures. It has been hypothesised that genomic alterations can explain some of the observed heterogeneity in the clinical course of PCa. In order to conduct an analysis of the prognostic and predictive value of ERG protein expression in PCa biopsies, the thesis sought to evaluate: 1) the concordance in ERG expression between biopsies and radical prostatectomies: 2) the association between expression of ERG protein and the risk of PCa progression during active surveillance (AS), and 3) the association between ERG protein expression and response to primary castration-based treatment for advanced PCa.
MATERIAL AND METHODS: The included patients derived from the institutional AS cohort and an institutional cohort of advanced PCa patients undergoing first line castration-based androgen deprivation therapy (ADT). The 265 patients in the AS cohort were enrolled prospectively between October 2002 and October 2012 and were followed with regular digital rectal examinations, PSA measurements, and repeated biopsies. The advanced PCa cohort comprised of 194 patients diagnosed between January 2000 and December 2011 and was established retrospectively by a standardised extraction of patient data. Immunohistochemical (IHC) assessment for ERG protein expression was performed in all tumours containing diagnostic specimens (AS cohort: n = 459; advanced PCa cohort: n = 968), re-biopsies during AS (n = 402), and deferred radical prostatectomy specimens following AS (n = 86). An anti-ERG rabbit monoclonal primary antibody (clone: EPR3864, dilution 23 μg/ml) was used. Fluorescence in situ hybridisation (FISH) for the TMPRSS2-ERG gene fusion was performed in 76 selected biopsies from the AS cohort using the ZytoLight TriCheck Probe, SPEC ERG/TMPRSS2.
RESULTS: Based on the AS cohort, Study 1 found a 97.3% concordance between the FISH assay and the IHC assay. The IHC assessments of ERG expression in diagnostic biopsies, re-biopsies, and radical prostatectomy specimens demonstrated a low proportion of temporal ERG reclassification. During four rounds of re-biopsies, 6.6% of the patients experienced ERG reclassification, and depending on the number biopsy specimens included 5.8-10.5% of the patients were ERG reclassified after radical prostatectomy. In Study 2, 46.4% of the AS patients were categorised as ERG-positive, whereas 53.6% were categorised as ERG-negative. After median 4.1 years follow-up, a significantly higher risk of disease progression was observed in men with ERG-positive tumours corresponding to a two-year cumulative incidence of 58.6% (95% CI: 48.7-68.5) and 21.7% (95% CI: 14.3-29.1) in the ERG-positive and the ERG-negative group, respectively. In the multiple causespecific Cox analyses, ERG expression was a strong and independent predictor of overall disease progression (HR: 2.45, 95% CI: 1.62-3.72) and histopathological progression in repeated biopsies (HR: 3.06, 95% CI: 1.78-5.26), and ERG status increased the discriminative ability for predicting disease progression significantly. Study 3 included 194 patients with advanced PCa treated with firstline ADT. In total, 54.1% had ERG-positive tumours and 45.9% had ERG-negative tumours. With a median of 6.8 years of follow-up, the risk of developing castration-resistant PCa (CRPC) did not differ between the ERG subgroups (p = 0.51). Finally, inclusion of ERG status in a multiple cause-specific Cox model did not increase the discriminative ability for predicting CRPC development during the first 8 years of ADT.
CONCLUSION: The thesis has demonstrated that assessment of ERG protein expression is feasible in biopsy specimens, and a high concordance was found between the IHC assay and FISH assessment of ERG rearrangement. The low proportion of ERG reclassification between biopsies and prostatectomies supports the use of ERG assessment in biopsies to characterise the individual patient's ERG status. ERG status harbours important prognostic value in terms of tumour progression for patients managed on AS, whereas ERG expression has no predictive value for ADT response in men with advanced PCa undergoing first-line castration-based ADT. The overall conclusion of the thesis is that ERG protein expression provides valuable prognostic information in low-risk PCa managed observationally, and ERG expression might be used to personalise follow-up regimens in future AS programmes.

Koo KM, Wee EJ, Trau M
High-speed biosensing strategy for non-invasive profiling of multiple cancer fusion genes in urine.
Biosens Bioelectron. 2017; 89(Pt 2):715-720 [PubMed] Related Publications
Aberrant chromosal rearrangements, such as the multiple variants of TMPRSS2:ERG fusion gene mutations in prostate cancer (PCa), are promising diagnostic and prognostic biomarkers due to their specific expression in cancerous tissue only. Additionally, TMPRSS2:ERG variants are detectable in urine to provide non-invasive PCa diagnostic sampling as an attractive surrogate for needle biopsies. Therefore, rapid and simplistic assays for identifying multiple urinary TMPRSS2:ERG variants are potentially useful to aid in early cancer detection, immediate patient risk stratification, and prompt personalized treatment. However, current strategies for simultaneous detection of multiple gene fusions are limited by tedious and prolonged experimental protocols, thus limiting their use as rapid clinical screening tools. Herein, we report a simple and rapid gene fusion strategy which expliots the specificity of DNA ligase and the speed of isothermal amplification to simultaneously detect multiple fusion gene RNAs within a short sample-to-answer timeframe of 60min. The method has a low detection limit of 2 amol (1000 copies), and was successfully applied for non-invasive fusion gene profiling in patient urine samples with subsequent validation by a PCR-based gold standard approach.

Burdelski C, Dieckmann T, Heumann A, et al.
p16 upregulation is linked to poor prognosis in ERG negative prostate cancer.
Tumour Biol. 2016; 37(9):12655-12663 [PubMed] Related Publications
Altered expression of the p16 tumor suppressor is frequently found in prostate cancer, but its role for tumor development and patient prognosis is disputed. In order to clarify the prognostic role of p16 and to draw conclusions on interactions with key molecular features of prostate cancer, we studied p16 expression in a tissue microarray (TMA) with more than 12,400 prostate cancers and attached clinical, pathological, and molecular data such as ERG status and deletions of 3p13, 5q21, 6q15, and PTEN. p16 immunostaining was absent in non-neoplastic prostate cells but was found in 37 % of 9627 interpretable prostate cancers. Finding p16 expression in 58 % of ERG positive but in only 22 % of ERG negative cancers (p < 0.0001), highlights the known androgen-dependence of both genes. Significant associations between p16 upregulation and tumor phenotype or patient prognosis were strictly limited to the subset of ERG negative cancers. For example, p16 positivity increased from 15 % in Gleason ≤3 + 3 to 38 % in Gleason ≥4 + 4 cancers (p < 0.0001) and was associated with early PSA recurrence (p < 0.0001). p16 upregulation was strongly linked to deletions of PTEN (p < 0.0001), highlighting the interaction of both genes in growth control. In conclusion, p16 upregulation is a strong prognostic factor in ERG negative cancers. The strict limitation of its prognostic impact to a molecularly defined subgroup challenges the concept of molecular prognosis testing without considering molecular subtypes.

Jiang H, Mao X, Huang X, et al.
TMPRSS2:ERG fusion gene occurs less frequently in Chinese patients with prostate cancer.
Tumour Biol. 2016; 37(9):12397-12402 [PubMed] Related Publications
Prostate cancer is the commonest male malignancy in the Western world, but its morbidity is much lower in China. The principal aim of this study was to evaluate the frequency of TMPRSS2:ERG fusion in Chinese prostate cancer patients using immunohistochemistry and reverse transcription polymerase chain (RT-PCR). In addition, we compared the ERG protein expression with TMPRSS2:ERG fusion gene. The relationship between ERG expression and clinicopathologic features was also examined. Samples from patients who underwent radical prostatectomies in Changhai Hospital (Shanghai, China) were collected and stored in ethically approved tissue banks. One hundred seventy-four prostate cancer tissue samples and 10 normal tissues were marked on standard hematoxylin-eosin (HE) sections, punched out of the paraffin blocks and inserted into a recipient block using tissue arrayer instruments. Immunohistochemistry and RT-PCR were employed to detect TMPRSS2:ERG fusion gene. ERG was highly expressed in the nuclei of endothelial cells of vessels and weak cytoplasmic staining was occasionally observed. ERG positive staining was present in 14.9 % (26/174) of the tumor samples in microarray. All benign prostate samples were found to be negative. RT-PCR results revealed that 11.1 % (15/135) were TMPRSS2:ERG fusion positive. Altogether, there was a good agreement of ERG immunostaining with the presence of TMPRSS2:ERG. However, no correlation was observed between ERG expression and age, Gleason score, stage, surgical margin, and seminal vesicle involvement in Chinese patients. In the present study, we identified a high correlation between ERG expression and ERG TMPRSS2:ERG, with 100 % sensitivity and 88.9 % specificity. The expression level of ERG was unrelated to the age, Gleason score, stage, surgical margin, and seminal vesicle involvement. Therefore, the association between ERG expression and prostate cancer based on Chinese population should be further investigated in the future.

Box A, Alshalalfa M, Hegazy SA, et al.
High alpha-methylacyl-CoA racemase (AMACR) is associated with ERG expression and with adverse clinical outcome in patients with localized prostate cancer.
Tumour Biol. 2016; 37(9):12287-12299 [PubMed] Related Publications
Alpha-methylacyl-CoA racemase (AMACR) is a well-characterized marker extensively utilized in prostate cancer (PCA) diagnosis. However, the prognostic value of AMACR expression and its relation to TMPRSS2-ERG gene rearrangement as one of the most common molecular alterations in PCA is not fully explored. AMACR expression was investigated in a cohort of 218 men with localized PCA treated by radical prostatectomy and correlated with ERG and various clinical and pathological parameters. In vitro studies assessed AMACR changes to ERG knockdown and other related genes. In addition, bioinformatics validated the significance of AMACR/ERG expression and assessed relevant genetic signatures in relation to AMACR/ERG expression. AMACR expression was significantly associated with disease progression and with ERG (p ∼0). Seventeen percent of cancer foci showed negative/weak AMACR expression while being ERG positive. High AMACR expression was significantly associated with positive surgical margins (p = 0.01), specifically in tumors with lower Gleason score <7, with ∼95 % exhibiting positive surgical margin (p = 0.008). High AMACR showed marginal association with PSA biochemical recurrence (BCR) (p = 0.06) which was slightly more pronounced in ERG-positive tumors (p = 0.04). This was validated in other public cohorts. However, in this cohort, the association with BCR was not statistically significant in multivariate analysis (p = 0.09). Using in vitro cellular models, AMACR messenger RNA (mRNA) expression, but not protein levels, showed an association with ERG expression. We report for the first time a significant association between AMACR and ERG with prognostic implication. Patients with high AMACR/ERG-positive PCA may be at higher risk for disease progression, and additional studies in larger cohorts are needed to confirm the above findings. Functional studies investigating the molecular pathways connecting AMACR and ERG may provide an additional insight into PCA progression pathways.

Gao T, Mei Y, Sun H, et al.
The association of Phosphatase and tensin homolog (PTEN) deletion and prostate cancer risk: A meta-analysis.
Biomed Pharmacother. 2016; 83:114-121 [PubMed] Related Publications
OBJECTIVE: Phosphatase and tensin homolog (PTEN) deleted on chromosome 10, a tumor suppressor that negatively regulates the phosphoinositide-3-kinase(PI3K) which has been implicated in a number of human malignancies including prostate cancer. However the prognostic value of PTEN deletion in prostate cancer patient's diagnosis and the mechanism of PTEN deletion in prostate cancer development still remain unclear.
METHOD: A meta-analysis of 26 published studies including 8097 prostate cancer patients was performed.
RESULTS: Compared to PTEN normal patients, PTEN deletion patients showed a higher aggressive Gleason score(OR: 1.284, 95%CI=1.145-1.439) and pathological stage(OR: 1.628, 95%CI=1.270-2.087) which generally had a higher risk in prostate replace(HR: 1.738, 95%CI=1.264-2.390). Significant association between PTEN deletion and ERG rearrangements in prostate cancer development was also proved that compared to PTEN normal patients, patients with PTEN deletion showed a higher risk in ERG rearrangements(OR: 1.345, 95%CI=1.102-1.788).
CONCLUSION: This study indicated that patients with PTEN deletion were associated with higher pathological stage or Gleason score and a higher risk in prostate cancer replace potentially represent a novel clinically relevant event to identify individuals at increased risk for the occurrence, progression and prognosis of prostate cancer. Prostate cancer patients with PTEN deletion usually had a higher risk in ERG rearrangements than other patients may be a potential new area for identifying poor prognosis patients and selecting patients for targeted therapies which required confirmation through adequately designed prospective studies.

Kim H, Skowronski J, Den RB
Prognostic outlier genes for enhanced prostate cancer treatment.
Future Oncol. 2017; 13(3):249-261 [PubMed] Related Publications
AIM: To review the current landscape of outlier genes in the field of prostate cancer.
METHODS: A comprehensive review was performed.
RESULTS: Prostate cancer continues to be a significant worldwide health issue. In the era of personalized medicine, more emphasis is being placed on the ability to determine the timing, intensity and type of treatment, according to each patient's unique disease. Several commercial tests are available to determine the risk of aggressive prostate cancer based on genomic biomarkers and gene expression. Outlier genes represent a form of cancer classification that focuses on bimodal expression of a gene in a specific subset of patients. Outlier genes identified in prostate cancer include TMPRSS2-ERG, SPINK1, ScHLAP1, NVL, SMC4 and SQLE.
CONCLUSION: Classifying patient prostate cancers by outlier genes may allow for individualized cancer therapies and improved cancer therapy outcomes.

Kulda V, Topolcan O, Kucera R, et al.
Prognostic Significance of TMPRSS2-ERG Fusion Gene in Prostate Cancer.
Anticancer Res. 2016; 36(9):4787-93 [PubMed] Related Publications
BACKGROUND/AIM: Current research of prostate cancer (PCa) offers a promising way of identifying patients with adverse prognosis who do benefit from radical treatment that can affect quality of life as resections are associated with numerous side-effects. The aim of our study was to evaluate the relationship of TMPRSS2-ERG fusion gene status, tumor tissue prostate-specific antigen (PSA), prostate cancer antigen 3 (PCA3), miR-23b, miR-26a and miR-221 expression levels in combination with preoperative serum PSA level to the risk of PCa recurrence after radical prostatectomy.
PATIENTS AND METHODS: The study group consisted of 108 patients who underwent radical prostatectomy. PSA was measured in peripheral blood collected preoperativelly. The expression of TMPRSS2-ERG transcript and the expression of miR-23b, miR-26a and miR-221 in formalin-fixed, paraffin-embedded (FFPE) tumor tissues was analyzed by reverse transcription (RT) real-time polymerase chain reaction (PCR).
RESULTS: Significantly shorter time to recurrence was observed in patients with high expression of TMPRSS2-ERG (p=0.0020). High levels of preoperative PSA (>10.0 ng/ml) proved to be marker of shorter time to recurrence (p=0.0153). The most promising marker of the risk of recurrence after radical prostatectomy was a combination of high level of preoperative serum PSA and high expression of TMPRSS2-ERG fusion transcript in tumor tissue (p=0.0001).
CONCLUSION: A combination of high preoperative serum PSA and high expression of TMPRSS2-ERG could be promising in distinguishing those tumors that are aggressive and life-threatening.

Liu YF, Wang BY, Zhang WN, et al.
Genomic Profiling of Adult and Pediatric B-cell Acute Lymphoblastic Leukemia.
EBioMedicine. 2016; 8:173-83 [PubMed] Free Access to Full Article Related Publications
Genomic landscapes of 92 adult and 111 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) were investigated using next-generation sequencing and copy number alteration analysis. Recurrent gene mutations and fusions were tested in an additional 87 adult and 93 pediatric patients. Among the 29 newly identified in-frame gene fusions, those involving MEF2D and ZNF384 were clinically relevant and were demonstrated to perturb B-cell differentiation, with EP300-ZNF384 inducing leukemia in mice. Eight gene expression subgroups associated with characteristic genetic abnormalities were identified, including leukemia with MEF2D and ZNF384 fusions in two distinct clusters. In subgroup G4 which was characterized by ERG deletion, DUX4-IGH fusion was detected in most cases. This comprehensive dataset allowed us to compare the features of molecular pathogenesis between adult and pediatric B-ALL and to identify signatures possibly related to the inferior outcome of adults to that of children. We found that, besides the known discrepancies in frequencies of prognostic markers, adult patients had more cooperative mutations and greater enrichment for alterations of epigenetic modifiers and genes linked to B-cell development, suggesting difference in the target cells of transformation between adult and pediatric patients and may explain in part the disparity in their responses to treatment.

Bachurska SY, Staykov DG, Ivanov GP, Belovezhdov VT
Lack of ERG-antibody in Benign Mimickers of Prostate Cancer.
Folia Med (Plovdiv). 2016; 58(1):48-53 [PubMed] Related Publications
INTRODUCTION: Prostate carcinoma (PC) is the second most diagnosed cancer in men worldwide. Prostate tissue in needle biopsy expresses a wide variety of architectural patterns some of which are difficult to interpret. Immunohistochemical markers, such as AMACR, p63 and 34βE12 that are currently used in diagnosing prostate cancer, are of great value, but often their interpretation is ambiguous. In 2005 Tomlins et al. identified an emerging marker, erythroblastosis E26 rearrangement gene (ERG), which is a member of the family of genes encoding erythroblast-transformation specific transcription factors (ETS) with frequent expression in PC.
AIM: The aim of this study was to investigate the expression of ERG in benign mimickers of PC in needle biopsies and its diagnostic value alone and in combination with AMACK and 34βE12.
RESULTS: Of the selected 46 biopsies, two were eventually diagnosed as PC Gleason score 6 as they were simultaneously ERG and AMACR-positive and 34βE12-negative. One case was considered atypical. The remaining 43 biopsies were diagnosed as benign cases: simple atrophy in 13 cases, partial atrophy in 11, adenosis in 9, basal cell hyperplasia in 3, post-atrophic hyperplasia in 3, clear cell hyperplasia in 2 and sclerotic adenosis in 2 cases. None of the 43 benign cores showed evidence of ERG expression.
CONCLUSION: ERG could be preferably used in diagnosing prostate needle biopsies, lesions that are hard to interpret and controversial expression of AMACR/34βE12.

Krstanoski Z, Vokac NK, Zagorac A, et al.
TMPRSS2:ERG gene aberrations may provide insight into pT stage in prostate cancer.
BMC Urol. 2016; 16(1):35 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: TMPRSS2:ERG gene aberration may be a novel marker that improves risk stratification of prostate cancer before definitive cancer therapy, but studies have been inconclusive.
METHODS: The study cohort consisted of 202 operable prostate cancer Slovenian patients who underwent laparoscopic radical prostatectomy. We retrospectively constructed tissue microarrays of their prostatic specimens for fluorescence in situ hybridization, with appropriate signals obtained in 148 patients for subsequent statistical analyses.
RESULTS: The following genetic aberrations were found: TMPRSS2:ERG fusion, TMPRSS2 split (a non-ERG translocation) and ERG split (an ERG translocation without involvement of TMPRSS2). TMPRSS2:ERG gene fusion happened in 63 patients (42 %), TMPRSS2 split in 12 patients and ERG split in 8 patients. Association was tested between TMPRSS2:ERG gene fusion and several clinicopathological variables, i.e., pT stage, extended lymph node dissection status, and Gleason score, correcting for multiple comparisons. Only the association with pT stage was significant at p = 0.05: Of 62 patients with pT3 stage, 34 (55 %) had TMPRSS2:ERG gene fusion. In pT3 stage patients, stronger (but not significant) association between eLND status and TMPRSS2:ERG gene fusion was detected. We detected TMPRSS2:ERG gene fusion in 64 % of the pT3 stage patients where we did not perform an extended lymph node dissection.
CONCLUSIONS: Our results indicate that it is possible to predict pT3 stage at final histology from TMPRSS2:ERG gene fusion at initial core needle biopsy. FISH determination of TMPRSS2:ERG gene fusion may be particularly useful for patients scheduled to undergo a radical prostatectomy in order to improve oncological and functional results.

Kirby R
The role of PSA in detection and management of prostate cancer.
Practitioner. 2016; 260(1792):17-21, 3 [PubMed] Related Publications
The prostate specific antigen (PSA) test clearly provides the opportunity for clinically relevant prostate cancer to be detected at a stage when treatment options are greater and outcomes may be improved. However, in some patients the PSA test may lead to investigations which can identify clinically insignificant cancers which would not have become evident in a man's lifetime. In addition, a raised PSA may often indicate benign prostatic enlargement, and this may provide an opportunity for treatment of this condition before complications develop. The lack of sensitivity and specificity that characterises PSA testing in the initial diagnosis of prostate cancer largely disappears after treatment of localised prostate cancer, especially after surgery. Three monthly PSA measurement is usually recommended for the first year after primary treatment. Subsequently less frequent testing is required. A PSA rise after primary treatment usually indicates biochemical recurrence and often the need for further therapy. There are two promising urinary RNA biomarkers, prostate cancer antigen 3 (PCA3) and fusion gene TMPRSS2:ERG, both of which aim to distinguish between men with low-risk (indolent) and those with aggressive (clinically significant) cancers.

Beltran H, Antonarakis ES, Morris MJ, Attard G
Emerging Molecular Biomarkers in Advanced Prostate Cancer: Translation to the Clinic.
Am Soc Clin Oncol Educ Book. 2016; 35:131-41 [PubMed] Related Publications
Recent clinical and preclinical studies focused on understanding the molecular landscape of castration-resistant prostate cancer (CRPC) have provided insights into mechanisms of treatment resistance, disease heterogeneity, and potential therapeutic targets. This work has served as a framework for several ongoing clinical studies focused on bringing novel observations into the clinic in the form of tissue, liquid, and imaging biomarkers. Resistance in CRPC typically is driven through reactivation of androgen receptor (AR) signaling, which can occur through AR-activating point mutations, amplification, splice variants (such as AR-V7), or other bypass mechanisms. Detection of AR aberrations in the circulation negatively impacts response to subsequent AR-directed therapies such as abiraterone and enzalutamide. Other potentially clinically relevant alterations in CRPC include defects in DNA damage repair (at either the somatic or germline level) in up to 20% of patients (with implications for PARP1 inhibitor therapy), PI3K/PTEN/Akt pathway activation, WNT signaling pathway alterations, cell cycle gene alterations, and less common but potentially targetable alterations involving RAF and FGFR2. Imaging biomarkers that include those focused on incorporating overexpressed androgen-regulated genes/proteins, such as prostate-specific membrane antigen (PSMA) and dihydrotestosterone (DHT) in combination with CT, can noninvasively identify patterns of AR-driven distribution of CRPC tumor cells, monitor early metastatic lesions, and potentially capture heterogeneity of response to AR-directed therapies and other therapeutics. This article focuses on the current state of clinical biomarker development and future directions for how they might be implemented into the clinic in the near term to improve risk stratification and treatment selection for patients.

Zhang HY, Firempong CK, Wang YW, et al.
Ergosterol-loaded poly(lactide-co-glycolide) nanoparticles with enhanced in vitro antitumor activity and oral bioavailability.
Acta Pharmacol Sin. 2016; 37(6):834-44 [PubMed] Free Access to Full Article Related Publications
AIM: Ergosterol is a plant sterol with anti-tumor and anti-angiogenic activities, but is poorly soluble. In this study, we attempted to enhance its anti-tumor action and oral bioavailability via poly(lactide-co-glycolide) (PLGA) nanoparticle encapsulation.
METHODS: Ergosterol-loaded PLGA nanoparticles (NPs/Erg) were prepared using the emulsion/solvent evaporation technique. Their physicochemical properties were characterized, and their cytotoxicity against human cancer cell lines was evaluated with MTT assay. The pharmacokinetics and tissue distribution of NPs/Erg were investigated in rats and mice, respectively.
RESULTS: NPs/Erg were spherical in shape with a particle size of 156.9±4.8 nm and a Zeta potential of -19.27±1.13 mV, and had acceptable encapsulation efficiency and loading capacity. NPs/Erg exerted much stronger cytotoxicity against human cancer cells than the free ergosterol, and showed significantly reduced IC50 values (14.69±0.48 μg/mL in glioma U251 cells; 9.43±0.52 μg/mL in breast cancer MCF-7 cells; 4.70±0.41 μg/mL in hepatoma HepG2 cells). After oral administration of a single dose in rats, NPs/Erg displayed a prolonged plasma circulation with a 4.9-fold increase of oral bioavailability compared with the free ergosterol. After mice received NPs/Erg, the ergosterol in NPs/Erg was rapidly distributed in stomach, kidneys, liver, brain, spleen, and virtually non-existent in heart and lungs. The presence of NPs/Erg in brain was particularly improved compared with the free ergosterol.
CONCLUSION: The PLGA nanoparticles serve as a promising carrier for the poorly soluble ergosterol and significantly improve its bioavailability, biodistribution and in vitro anti-tumor activities.

Merz C, von Mässenhausen A, Queisser A, et al.
IL-6 Overexpression in ERG-Positive Prostate Cancer Is Mediated by Prostaglandin Receptor EP2.
Am J Pathol. 2016; 186(4):974-84 [PubMed] Related Publications
Prostate cancer is the most diagnosed cancer in men and multiple risk factors and genetic alterations have been described. The TMPRSS2-ERG fusion event and the overexpression of the transcription factor ERG are present in approximately 50% of all prostate cancer patients, however, the clinical outcome is still controversial. Prostate tumors produce various soluble factors, including the pleiotropic cytokine IL-6, regulating cellular processes such as proliferation and metastatic segregation. Here, we used prostatectomy samples in a tissue microarray format and analyzed the co-expression and the clinicopathologic data of ERG and IL-6 using immunohistochemical double staining and correlated the read-out with clinicopathologic data. Expression of ERG and IL-6 correlated strongly in prostate tissue samples. Forced expression of ERG in prostate tumor cell lines resulted in significantly increased secretion of IL-6, whereas the down-regulation of ERG decreased IL-6 secretion. By dissecting the underlying mechanism in prostate tumor cell lines we show the ERG-mediated up-regulation of the prostanoid receptors EP2 and EP3. The prostanoid receptor EP2 was overexpressed in human prostate cancer tissue. Furthermore, the proliferation rate and IL-6 secretion in DU145 cells was reduced after treatment with EP2-receptor antagonist. Collectively, our study shows that the expression of ERG in prostate cancer is linked to the expression of IL-6 mediated by the prostanoid receptor EP2.

Graff RE, Meisner A, Ahearn TU, et al.
Pre-diagnostic circulating sex hormone levels and risk of prostate cancer by ERG tumour protein expression.
Br J Cancer. 2016; 114(8):939-44 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
BACKGROUND: Experimental studies have shown androgen receptor stimulation to facilitate formation of the TMPRSS2:ERG gene fusion in prostate cell lines. No study has tested whether higher pre-diagnostic circulating sex hormone levels in men increase risk of developing TMPRSS2:ERG-positive prostate cancer specifically.
METHODS: We conducted a nested case-control study of 200 prostate cancer cases and 1057 controls from the Physicians' Health Study and Health Professionals Follow-up Study. We examined associations between pre-diagnostic circulating levels of total testosterone, free testosterone, DHT, androstanediol glucuronide, estradiol, and SHBG and risk of prostate cancer by TMPRSS2:ERG status. TMPRSS2:ERG was estimated by ERG immunohistochemistry. We used multivariable unconditional polytomous logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of ERG-positive (n=94) and, separately, ERG-negative (n=106) disease.
RESULTS: Free testosterone was significantly associated with the risk of ERG-positive prostate cancer (OR: 1.37, 95% CI: 1.05-1.77), but not ERG-negative prostate cancer (OR: 1.09, 95% CI: 0.86-1.38) (Pdiff=0.17). None of the remaining hormones evaluated showed clear differential associations with ERG-positive vs ERG-negative disease.
CONCLUSIONS: These findings provide some suggestive evidence that higher pre-diagnostic free testosterone levels are associated with an increased risk of developing TMPRSS2:ERG-positive prostate cancer.

Liu W
DNA alterations in the tumor genome and their associations with clinical outcome in prostate cancer.
Asian J Androl. 2016 Jul-Aug; 18(4):533-42 [PubMed] Article available free on PMC after 12/04/2017 Related Publications
Although most prostate cancer (PCa) cases are not life-threatening, approximately 293 000 men worldwide die annually due to PCa. These lethal cases are thought to be caused by coordinated genomic alterations that accumulate over time. Recent genome-wide analyses of DNA from subjects with PCa have revealed most, if not all, genetic changes in both germline and PCa tumor genomes. In this article, I first review the major, somatically acquired genomic characteristics of various subtypes of PCa. I then recap key findings on the relationships between genomic alterations and clinical parameters, such as biochemical recurrence or clinical relapse, metastasis and cancer-specific mortality. Finally, I outline the need for, and challenges with, validation of recent findings in prospective studies for clinical utility. It is clearer now than ever before that the landscape of somatically acquired aberrations in PCa is highlighted by DNA copy number alterations (CNAs) and TMPRSS2-ERG fusion derived from complex rearrangements, numerous single nucleotide variations or mutations, tremendous heterogeneity, and continuously punctuated evolution. Genome-wide CNAs, PTEN loss, MYC gain in primary tumors, and TP53 loss/mutation and AR amplification/mutation in advanced metastatic PCa have consistently been associated with worse cancer prognosis. With this recently gained knowledge, it is now an opportune time to develop DNA-based tests that provide more accurate patient stratification for prediction of clinical outcome, which will ultimately lead to more personalized cancer care than is possible at present.

Penney KL, Pettersson A, Shui IM, et al.
Association of Prostate Cancer Risk Variants with TMPRSS2:ERG Status: Evidence for Distinct Molecular Subtypes.
Cancer Epidemiol Biomarkers Prev. 2016; 25(5):745-9 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
BACKGROUND: Numerous genetic variants have been confirmed as prostate cancer risk factors. These variants may confer susceptibility to the development of specific molecular alterations during tumor initiation and progression. The TMPRSS2:ERG gene fusion occurs in roughly 50% of prostate cancers. Genetic risk variants may influence the development of this fusion. We sought to determine whether prostate cancer risk variants are differentially associated with TMPRSS2:ERG fusion-positive and negative cancer.
METHODS: In the Health Professionals Follow-up Study and Physicians' Health Study Tumor Cohort, we evaluated the associations of 39 prostate cancer risk SNPs with TMPRSS2:ERG fusion status, measured by ERG protein expression. Logistic regression was performed to generate OR and 95% confidence intervals. The primary outcome was ERG(+) (n = 227) versus ERG(-) (n = 260) prostate cancer. A secondary outcome was ERG(+) or ERG(-) cancer versus controls without cancer.
RESULTS: Six of 39 SNPs were significantly associated (P < 0.05) with ERG(+) versus ERG(-) disease. Three SNPs were exclusively associated with the risk of ERG(+), one with risk of ERG(-), and two with associations trending in opposite directions for ERG(+) and ERG(-) Only two significant SNPs would be expected by chance.
CONCLUSIONS: Prostate cancer genetic risk variants are differentially associated with the development of ERG(+) and ERG(-) prostate cancer.
IMPACT: Our findings suggest the molecular process of prostate carcinogenesis may be distinct for men with different underlying genetic predisposition. When examining risk factors for prostate cancer, the integration of molecular subtypes may enhance understanding of the etiology of this disease. Cancer Epidemiol Biomarkers Prev; 25(5); 745-9. ©2016 AACR.

Duren RP, Boudreaux SP, Conneely OM
Genome Wide Mapping of NR4A Binding Reveals Cooperativity with ETS Factors to Promote Epigenetic Activation of Distal Enhancers in Acute Myeloid Leukemia Cells.
PLoS One. 2016; 11(3):e0150450 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Members of the NR4A subfamily of orphan nuclear receptors regulate cell fate decisions via both genomic and non-genomic mechanisms in a cell and tissue selective manner. NR4As play a key role in maintenance of hematopoietic stem cell homeostasis and are critical tumor suppressors of acute myeloid leukemia (AML). Expression of NR4As is broadly silenced in leukemia initiating cell enriched populations from human patients relative to normal hematopoietic stem/progenitor cells. Rescue of NR4A expression in human AML cells inhibits proliferation and reprograms AML gene signatures via transcriptional mechanisms that remain to be elucidated. By intersecting an acutely regulated NR4A1 dependent transcriptional profile with genome wide NR4A binding distribution, we now identify an NR4A targetome of 685 genes that are directly regulated by NR4A1. We show that NR4As regulate gene transcription primarily through interaction with distal enhancers that are co-enriched for NR4A1 and ETS transcription factor motifs. Using a subset of NR4A activated genes, we demonstrate that the ETS factors ERG and FLI-1 are required for activation of NR4A bound enhancers and NR4A target gene induction. NR4A1 dependent recruitment of ERG and FLI-1 promotes binding of p300 histone acetyltransferase to epigenetically activate NR4A bound enhancers via acetylation at histone H3K27. These findings disclose novel epigenetic mechanisms by which NR4As and ETS factors cooperate to drive NR4A dependent gene transcription in human AML cells.

Wu J, Chi L, Chen Z, et al.
Functional analysis of the TMPRSS2:ERG fusion gene in cisplatin‑induced cell death.
Mol Med Rep. 2016; 13(4):3173-80 [PubMed] Related Publications
The TMPRSS2:E‑twenty‑six (ETS) gene fusion occurs frequently in a high proportion of patients with prostate cancer (PCa) in Western countries, and the aberrant expression of TMPRSS2: v‑ETS avian erythroblastosis virus E26 oncogene homolog (ERG), the most common form of the corresponding protein, can regulate cell migration and contribute to tumor invasion and metastasis. However, its association with other cellular events, and in particular, cell death, remain unknown. To examine the function of such fusion genes, an expression plasmid containing the TMPRSS2:ERG (T1/E5) sequence (ΔERG) from a patient sample was constructed and transiently transfected into DU145 cells, which do not express the fusion gene. It was found that the overexpression of ΔERG significantly inhibited the ability of cisplatin to induce apoptosis in DU145 cells. By contrast, VCaP cells, which do contain TMPRSS2:ERG, were sensitized to cisplatin‑induced apoptosis through siRNA inhibition of the fusion gene. To elucidate the underlying mechanism, a stable cell line expressing the ΔERG gene was constructed. Expression of ΔERG did not affect cell migration, but did protect cells from DNA damage and apoptosis induced by cisplatin. Furthermore, knockdown of ΔERG by short interfering RNA resulted in cells regaining their sensitivity to cisplatin. Finally, the gene coding for activating transcription factor 5, which is important for cell survival, may be upregulated by ΔERG. Taken together, these data point to a new function of the TMPRSS2:ERG fusion gene in regulating the apoptotic pathway.

Varinot J, Furudoï A, Drouin S, et al.
HOXB13 protein expression in metastatic lesions is a promising marker for prostate origin.
Virchows Arch. 2016; 468(5):619-22 [PubMed] Related Publications
The HOXB13 gene is a member of the homeobox gene family, and prostate development depends on HOXB13 function. HOXB13 is a very sensitive and specific marker of prostate tissue and prostate cancer. When the origin of a tumor in a resection specimen or in biopsy material is unclear, it allows determining the prostate as the primary. Our aim was to determine whether HOXB13 has similar sensitivity for determining prostate origin of lymph node and bone metastases. We retrieved cases of lymph node and bone metastases of histologically confirmed prostate cancer (PCa) and selected lymph node metastases of urothelial carcinoma (UCa). A panel of antibodies against HOXB13, PSA, ERG, Androgen receptors, p504S, p63, GATA-3, CK7, and Uroplakin 2 and 3 was tested on these tissue samples. Two pathologists analysed and scored staining as either 0 (negative) or + (positive). The selected cohort consisted of 74 cases of lymph node and 15 of bone metastases of PCa and 15 of lymph node metastases of UCa. HOXB13 was expressed in 93 % of lymph node and in 33 % of bone metastases of PCa. All lymph node metastases of UCa were negative. Sensitivity of HOXB13 as a marker for prostate origin in lymph node metastases was 93 % and for bone metastases 33 %. Inter-observer variability in assessment of staining was good, as only two (1.9 %) of lymph node metastasis of PCa were discordant. HOXB13 is a useful marker for prostate origin when doubt exists regarding the site of the primary of a metastatic lesion. On bone metastases, HOXB13 immunohistochemistry performed less well, probably due to the use of tissue decalcification.

Xu B, Naughton D, Busam K, Pulitzer M
ERG Is a Useful Immunohistochemical Marker to Distinguish Leukemia Cutis From Nonneoplastic Leukocytic Infiltrates in the Skin.
Am J Dermatopathol. 2016; 38(9):672-7 [PubMed] Article available free on PMC after 01/09/2017 Related Publications
Leukemia cutis (LC) and reactive myeloid infiltrates in the skin may be difficult to distinguish pathologically, sometimes even after an extensive immunohistochemical work-up. This poses a serious clinical dilemma, as the prognosis and treatment of either condition are markedly different. Although most reactive myeloid infiltrates require a simple course of corticosteroids before the symptoms regress, the development of LC may require chemotherapeutic or transplant-variant interventions. Erythroblast transformation specific regulated gene-1 (ERG) is a member of the erythroblast transformation specific family of transcription factors, which are downstream effectors of mitogenic signaling transduction pathways. ERG is a key regulator of cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis and has recently been found to be overexpressed in acute myeloid and lymphoblastic leukemia. In this study, the authors aimed to explore the diagnostic utility of ERG immunohistochemistry in LC by comparing the frequency and expression level of ERG immunostain in 32 skin biopsies, 16 with LC and 16 with reactive leukocytic infiltrates. A significantly higher frequency of ERG positivity was detected in LC (13/16, 81.4%), compared with reactive conditions (0/16). In addition, the expression level of ERG in LC, calculated using H score (mean ± standard error of mean, 188 ± 24), was significantly higher than that in nonneoplastic leukocytic infiltrate (28 ± 8). Our results strongly suggest that ERG expression is potentially an extremely useful marker to distinguish between cases of LC from those of reactive myeloid infiltrates in the skin with a positive predictive value of 100% and negative predictive value of 84.2%.

Bakkar A, Alshalalfa M, Petersen LF, et al.
microRNA 338-3p exhibits tumor suppressor role and its down-regulation is associated with adverse clinical outcome in prostate cancer patients.
Mol Biol Rep. 2016; 43(4):229-40 [PubMed] Related Publications
MicroRNAs (miRNAs) are small non-coding RNAs that function in transcriptional and post-transcriptional regulation of gene expression. Several miRNAs have been implicated in regulating prostate cancer (PCa) progression. Deregulations of miRNA regulatory networks have been reported in ERG positive PCa, which accounts for ~50 % of PCa and have been suggested to affect tumor aggressiveness. The function of miR338-3p, its prognostic significance, and its association with ERG positive PCa has not been fully investigated. Using microarray expression profiling, we identified miRNA338-3p as among the top deregulated miRNAs associated with ERG status in PCa. We investigated miR338-3p function using in vitro and in vivo experimental models and its expression was assessed and validated in clinical samples and a public cohort of localized and metastatic prostate cancer. miR338-3p was significantly down-regulated with disease progression from benign prostate tissue to primary and metastatic lesions. In localized disease, patients with lower miR338-3p expression levels showed increased association to biochemical recurrence and several adverse pathological parameters compared to patients with higher miRNA338-3p tissue expression levels. Using in vitro PCa cell models, overexpression of miR338-3p resulted in a decrease in cell invasion and expression of chemokine signalling genes CXCL12, CXCR4, and CXCR7. In vivo, orthotropic implantation of PC3 cells stably expressing miR338-3p was associated with a significant decrease in tumor weights compared to control cells. miR338-3p has anti-proliferative and anti-invasive properties. It affects CXCR4 axis, and its down-regulation is associated with adverse clinical outcomes in PCa patients.

Petrovics G, Li H, Stümpel T, et al.
A novel genomic alteration of LSAMP associates with aggressive prostate cancer in African American men.
EBioMedicine. 2015; 2(12):1957-64 [PubMed] Article available free on PMC after 01/09/2017 Related Publications
Evaluation of cancer genomes in global context is of great interest in light of changing ethnic distribution of the world population. We focused our study on men of African ancestry because of their disproportionately higher rate of prostate cancer (CaP) incidence and mortality. We present a systematic whole genome analyses, revealing alterations that differentiate African American (AA) and Caucasian American (CA) CaP genomes. We discovered a recurrent deletion on chromosome 3q13.31 centering on the LSAMP locus that was prevalent in tumors from AA men (cumulative analyses of 435 patients: whole genome sequence, 14; FISH evaluations, 101; and SNP array, 320 patients). Notably, carriers of this deletion experienced more rapid disease progression. In contrast, PTEN and ERG common driver alterations in CaP were significantly lower in AA prostate tumors compared to prostate tumors from CA. Moreover, the frequency of inter-chromosomal rearrangements was significantly higher in AA than CA tumors. These findings reveal differentially distributed somatic mutations in CaP across ancestral groups, which have implications for precision medicine strategies.

Graff RE, Pettersson A, Lis RT, et al.
Dietary lycopene intake and risk of prostate cancer defined by ERG protein expression.
Am J Clin Nutr. 2016; 103(3):851-60 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There is limited evidence that supports etiologically distinct molecular subtypes of prostate cancer, the identification of which may improve prevention. Given their antioxidant properties, we hypothesized that lycopene and tomato sauce may be especially protective against diseases harboring the common gene fusion transmembrane protease, serine 2 (TMPRSS2):v-ets avian erythroblastosis virus E26 oncogene homolog (ERG).
OBJECTIVE: We aimed to examine associations between estimated lycopene and tomato sauce intake and the risk of prostate cancer defined by ERG protein expression subtype.
DESIGN: Our study population consisted of a prospective cohort of 46,719 men from the Health Professionals Follow-Up Study. TMPRSS2:ERG was assessed by ERG immunohistochemistry on tumor tissue microarrays constructed from radical prostatectomy specimens. We used multivariable competing risk models to calculate HRs and 95% CIs for the risk of ERG-positive and, separately, ERG-negative disease. We implemented inverse probability weighting to account for evaluating ERG status only in surgically treated cases.
RESULTS: During 23 y of follow-up, 5543 men were diagnosed with prostate cancer, among whom 884 were assayed for ERG (426 ERG-positive). With inclusion of only the latter cases, increasing cumulative average tomato sauce intake was associated with a decreased risk of prostate cancer overall (≥2 servings/wk compared with <1 serving/mo; multivariable HR: 0.70; 95% CI: 0.52, 0.95; P-trend = 0.002). With respect to molecular subtypes, cumulative average tomato sauce intake was associated with a decreased risk of ERG-positive disease (HR: 0.54; 95% CI: 0.37, 0.81; P-trend = 0.004) but not with ERG-negative disease (HR: 0.96; 95% CI: 0.62, 1.50; P-trend = 0.10) (P-heterogeneity = 0.04). Increasing quintiles of lycopene intake were associated with a decreased risk of both subtypes (P-heterogeneity = 0.79). Inverse probability weighting did not materially change the results.
CONCLUSIONS: Our results lend some support to the hypothesis that prostate cancers that harbor TMPRSS2:ERG may be etiologically distinct from fusion-negative cancers. In particular, tomato sauce consumption may play a role in reducing TMPRSS2:ERG-positive disease.

Mizutani N, Omori Y, Kawamoto Y, et al.
Resveratrol-induced transcriptional up-regulation of ASMase (SMPD1) of human leukemia and cancer cells.
Biochem Biophys Res Commun. 2016; 470(4):851-6 [PubMed] Related Publications
Resveratrol (RSV) is a plant-derived phytoalexin present in plants, whose pleiotropic effects for health benefits have been previously reported. Its anti-cancer activity is among the current topics for novel cancer treatment. Here, effects of RSV on cell proliferation and the sphingolipid metabolism of K562, a human leukemia cell line, were analyzed. Some experiments were also performed in HCT116, a human colon cancer cell line. RSV inhibited cell proliferation of both cell lines. Increased cellular ceramide and decreased sphingomyelin and S1P by RSV were observed in RSV-treated K562 cells. Further analysis revealed that acid sphingomyelinase mRNA and enzyme activity levels were increased by RSV. Desipramine, a functional ASMase inhibitor, prevented RSV-induced ceramide increase. RSV increased ATF3, EGR1, EGR3 proteins and phosphorylated c-Jun and FOXO3. However, co-transfection using these transcription factor expression vectors and ASMase promoter reporter vector revealed positive effects of EGR1 and EGR3 but not others. Electrophoresis mobility shift assay (EMSA) and Chromatin immunoprecipitation (ChIP) assay demonstrated the direct binding of EGR1/3 transcription factors with ASMase 5'-promoter. These results indicate that increased EGR1/3 and ASMase expression play an important role in cellular ceramide increase by RSV treatment.

Almami A, Hegazy SA, Nabbi A, et al.
ING3 is associated with increased cell invasion and lethal outcome in ERG-negative prostate cancer patients.
Tumour Biol. 2016; 37(7):9731-8 [PubMed] Related Publications
The inhibitor of growth family member 3 (ING3) is a member of the ING tumor suppressor family. Although its expression has been reported in various types of cancers, the role of ING3 and its prognostic value in prostate cancer (PCa) has not been investigated. ING3 expression and prognostic value was assessed in a cohort of PCa patients (n = 312) treated with transurethral resection of prostate using immumoflourescent automated quantitative analysis (AQUA) system. In vitro studies were carried out in conjunction to investigate its expression in various PCa cell lines. ING3 knockdown was also carried out in DU145 cell lines to assess for any changes in invasion and migration. ING3 expression was highest in benign prostate tissues (mean 3.2 ± 0.54) compared to PCa (mean 2.5 ± 0.26) (p = 0.437), advanced prostate cancer (AdvPCa) (mean 1.5 ± 0.32) (p = 0.004), and castration-resistant prostate cancer (CRPC) (mean 2.28 ± 0.32) (p = 0.285). ING3 expression was inversely correlated to Gleason score (p = 0.039) and ETS-related gene (ERG) expression (p = 0.019). Higher ING3 expression was marginally associated with lethal disease (p = 0.052), and this was more pronounced in patients with ERG-negative status (p = 0.018). Inhibition of ING3 in DU145 PCa cells using small interfering RNA (siRNA) was associated with decreased cell invasion (p = 0.0016) and cell migration compared to control cells. ING3 is significantly associated with PCa disease progression and cancer-specific mortality. To our knowledge, this is the first report suggesting an oncogenic function of ING3, previously well known as a tumor suppressor protein. Further studies should investigate potential-related pathways in association to ING3.

Silva MP, Barros-Silva JD, Vieira J, et al.
NCOA2 is a candidate target gene of 8q gain associated with clinically aggressive prostate cancer.
Genes Chromosomes Cancer. 2016; 55(4):365-74 [PubMed] Related Publications
Prostate carcinomas harboring 8q gains are associated with poor clinical outcome, but the target genes of this genomic alteration remain to be unveiled. In this study, we aimed to identify potential 8q target genes associated with clinically aggressive prostate cancer (PCa) using fluorescence in situ hybridization (FISH), genome-wide mRNA expression, and protein expression analyses. Using FISH, we first characterized the relative copy number of 8q (assessed with MYC flanking probes) of a series of 50 radical prostatectomy specimens, with available global gene expression data and typed for E26 transformation specific (ETS) rearrangements, and then compared the gene expression profile of PCa subsets with and without 8q24 gain using Significance Analysis of Microarrays. In the subset of tumors with ERG fusion genes (ERG+), five genes were identified as significantly overexpressed (false discovery rate [FDR], ≤ 5%) in tumors with relative 8q24 gain, namely VN1R1, ZNF417, CDON, IKZF2, and NCOA2. Of these, only NCOA2 is located in 8q (8q13.3), showing a statistically higher mRNA expression in the subgroup with relative 8q gain, both in the ERG+ subgroup and in the whole series (P = 0.000152 and P = 0.008, respectively). Combining all the cases with NCOA2 overexpression, either at the mRNA or at the protein level, we identified a group of tumors with NCOA2 copy-number increase, independently of ETS status and relative 8q24 gain. Furthermore, for the first time, we detected a structural rearrangement involving NCOA2 in PCa. These findings warrant further studies with larger series to evaluate if NCOA2 relative copy-number gain presents prognostic value independently of the well-established poor prognosis associated with MYC relative copy-number gain.

Nagaishi T, Watabe T, Jose N, et al.
Epithelial Nuclear Factor-x03BA;B Activation in Inflammatory Bowel Diseases and Colitis-Associated Carcinogenesis.
Digestion. 2016; 93(1):40-6 [PubMed] Related Publications
Prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). Previous studies had shown that nuclear factor-x03BA;B (NF-x03BA;B) activation in both macrophages and epithelia in inflamed colonic tissue is associated with CAC development. However, the mechanism by which epithelial NF-x03BA;B activation leading to CAC development had not previously been rigorously studied. We and others had observed the increased expression of the type 2 receptor for tumor necrosis factor (TNFR2/TNFRSF1b/p75) in IBD models. Myosin light chain kinase (MLCK) is suggested to be associated with epithelial permeability via TNF signaling. Therefore, the relationship between epithelial MLCK expression and NF-x03BA;B activation via TNFR2 signaling on CAC development was investigated. Pro-tumorigenic cytokines such as interleukin (IL)-1β, IL-6 and macrophage inflammatory protein-2 at the lamina propria were increased in the setting of colitis and further increased in tumor tissues with upregulated epithelial TNFR2 and MLCK expressions in an animal model of CAC. The upregulated MLCK expression was also observed in TNF-stimulated colonic epithelial cells in vitro in association with the upregulation of TNFR2 but not TNFR1/TNFRSF1a/p55. Gene silencing of tnfrsf1b, but not tnfrsf1a, resulted in restoration of epithelial tight junction (TJ) associated with decreased MLCK expression. The presence of anti-TNF antibody also resulted in restoration of TJ in association with suppressed MLCK expression, and interestingly, similar results including the suppressed TNFR2 and MLCK expressions were observed by inhibiting MLCK in the epithelial cells. MLCK silencing also led to suppressed TNFR2 expression, suggesting that the restored TJ leads to reduced TNFR2 signaling. Such suppression of MLCK as well as blockade of TNFR2 signaling resulted in reduced CAC development, restored TJ, and decreased pro-tumorigenic cytokines. These imply that TNF-induced NF-x03BA;B activation and MLCK expression may be a potential target for the prevention of IBD-associated carcinogenesis.

Seipel AH, Samaratunga H, Delahunt B, et al.
Immunohistochemistry of ductal adenocarcinoma of the prostate and adenocarcinomas of non-prostatic origin: a comparative study.
APMIS. 2016; 124(4):263-70 [PubMed] Related Publications
Ductal adenocarcinoma of the prostate (DAC) has morphological similarities to adenocarcinomas of other organs. DAC behaves in an aggressive manner and may present with metastases. These metastases may occur at unusual sites, which itself may cause diagnostic difficulties. It is important for therapeutic decisions that a prostatic origin of these metastases be established. Our aim was to compare the protein expression of DAC and adenocarcinomas of colon, endometrium, lung, pancreas, stomach and urinary bladder. A tissue microarray was constructed using 60 DAC, 6 colonic, 7 endometrial, 7 lung, 5 pancreatic, 5 gastric, and 9 urinary bladder adenocarcinomas. Slides were stained for estrogen, progesterone and androgen receptor, prolactin, PSA, prostein, PSMA, PSAP, CDX2, lysozyme, villin, monoclonal CEA, CK7, CK20, HMWCK, p63, p504s, c-Myc, EGFR, Ki-67, p16, p21, p27, p53, PTEN, ERG, and PAX-8. Androgen receptor, prostein, PSA, and PSAP were almost invariably expressed in DAC. Ki-67-labeling index was lower in DAC than in other adenocarcinomas. The expression patterns of intestinal markers and cytokeratins in DAC were less specific and may lead to diagnostic errors if not combined with prostate-specific markers.

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