SPOP and FOXA1 mutations are associated with PSA recurrence in ERG wt tumors, and SPOP downregulation with ERG ‐rearranged prostate cancer (original) (raw)
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Journal of Clinical Pathology, 2007
Background: Recent reports indicate that prostate cancers (CaP) frequently over-express the potential oncogenes, ERG or ETV1. Many cases have chromosomal rearrangements leading to the fusion of the 59 end of the androgen-regulated serine protease TMPRSS2 (21q22.2) to the 39 end of either ERG (21q22.3) or ETV1 (7p21.3). The consequence of these rearrangements is aberrant androgen receptor-driven expression of the potential oncogenes, ETV1 or ERG. Aim: To determine the frequency of rearrangements involving TMPRSS2, ERG, or ETV1 genes in CaP of varying Gleason grades through fluorescence in situ hybridisation (FISH) on CaP tissue microarrays (TMAs). Methods: Two independent assays, a TMPRSS2 break-apart assay and a three-colour gene fusion FISH assay were applied to TMAs. FISH positive cases were confirmed by reverse transcriptase (RT) PCR and DNA sequence analysis. Results: A total of 106/196 (54.1%) cases were analysed by FISH. None of the five benign prostatic hyperplasia cases analysed exhibited these gene rearrangements. TMPRSS2:ERG fusion was found more frequently in moderate to poorly differentiated tumours (35/86, 40.7%) than in well differentiated tumours (1/15, 6.7%, p = 0.017). TMPRSS2:ETV1 gene fusions were not detected in any of the cases tested. TMPRSS2:ERG fusion product was verified by RT-PCR followed by DNA sequencing in 7/7 randomly selected positive cases analysed. Conclusion: This study indicates that TMPRSS2:ERG gene rearrangements in CaP may be used as a diagnostic tool to identify prognostically relevant sub-classifications of these cancers.
MP41-06 Spop Mutations in Prostate Cancer Across Demographically Diverse Patient Cohorts
The Journal of Urology, 2014
correlated with a higher Gleason sum and poorly differentiated phenotype, while lower ratios correlated with favorable prognosis. However, the functional significance of the ERG splice variants is not clearly understood. METHODS: ERG8 was ectopically expressed in TMPRSS2-ERG fusion harboring VCaP cells. Endogenous levels of the full-length ERG3 and its downstream target, C-MYC, were evaluated in response to ERG8 overexpression. ERG8 and ERG3 were co-transfected in various cell lines to examine subcellular localization and transcriptional regulatory functions using luciferase reporter assay. Interaction between ERG8 and ERG3 splice variants was assessed by using Chimeric Venus Reporter assay. Quantitative RNA expression data of C-MYC and ERG3/ERG8 ratios were assessed by the analysis of our previously published prostate cancer gene expression datasets. RESULTS: Expression of exogenous ERG8 in VCaP cells resulted in a decreases in ERG3 and C-MYC protein levels in a dose dependent manner. Attenuation of ERG3 and C-MYC protein levels in response to ERG8 overexpression was apparent in the prostate cancer derived cell line but was not observed in cell lines of non-prostatic origin. Venus Reporter assay revealed physical interaction between ERG8 and ERG3 proteins and ERG8 inhibited the transcriptional regulatory function of ERG3. Analysis of 45 cases in our prostate cancer gene expression datasets revealed a positive correlation between C-MYC expression and increased ratios of ERG3/ERG8. CONCLUSIONS: These findings support that altered ERG3 and ERG8 ratios in prostate tumor cells influence the overall oncogenic function of ERG. Consistently, increased ERG3 over ERG8 ratios associate with poor prognostic features of CaP. These data may aid in refining ERG targeted prognostic marker and therapeutic target strategies.
Systematic analysis reveals molecular characteristics of ERG-negative prostate cancer
Scientific reports, 2018
The TMPRSS2:ERG gene fusion is the most prevalent early driver gene activation in prostate cancers of European ancestry, while the fusion frequency is much lower in Africans and Asians. The genomic characteristics and mechanisms for patients lacking ERG fusion are still unclear. In this study, we systematically compared the characteristics of gene fusions, somatic mutations, copy number alterations and gene expression signatures between 201 ERG fusion positive and 296 ERG fusion negative prostate cancer samples. Both common and group-specific genomic alterations were observed, suggesting shared and different mechanisms of carcinogenesis in prostate cancer samples with or without ERG fusion. The genomic alteration patterns detected in ERG-negative group showed similarities with 77.5% of tumor samples of African American patients. These results emphasize that genomic and gene expression features of the ERG-negative group may provide a reference for populations with lower ERG fusion fr...
TMPRSS2:ERG fusion identifies a subgroup of prostate cancers with a favorable prognosis
Purpose: Our aim was to assess the frequency of ERG overexpression and TMPRSS2:ERG rearrangement in prostate cancer and their association with clinicopathologic variables and outcome. Experimental Design: The presence of theTMPRSS2:ERG rearrangement was studied by reverse transcription-PCR and fluorescence in situ hybridization in 19 prostate cancer xenografts and 7 prostate cancer cell lines.The expression of ERG was studied in the xenografts and cell lines and in 49 freshly frozen clinical prostate samples by quantitative reverse transcription-PCR. The frequency of the TMPRSS2:ERG fusion in clinical prostate cancer (n = 253) on tissue microarrays was assessed by three-color fluorescence in situ hybridization. Results: Seven of 19 (37%) of the xenografts overexpressed ERG and had TMPRSS2:ERG rearrangement. Two xenografts, representing small cell carcinomas, also contained the fusion but did not express ERG. In clinical tumor specimens, the overexpression of ERG was associated with the rearrangement (P = 0.0019). Fifty of 150 (33%) of the prostatectomy specimens and 28 of 76 (37%) of the hormone-refractory prostate cancers on the tissue microarrays carried the TMPRSS2:ERG rearrangement. It was associated with longer progression-free survival in patients treated by prostatectomy (P = 0.019), and according to multivariate analysis, it was an independent predictor of favorable outcome (relative risk, 0.54; 95% confidence interval, 0.30-0.98). The fusion was not associated with Gleason score, pT stage, diagnostic prostatespecific antigen, or cell proliferation activity in prostatectomy specimens nor with the AR gene amplification in hormone-refractory tumors. Conclusions: TheTMPRSS2:ERG rearrangement can be found in about one third of prostate cancers. A subgroup of prostate cancer patients with a good prognosis may be identified by the rearrangement.
Dual Functions of SPOP and ERG Dictate Androgen Therapy Responses in Prostate Cancer
bioRxiv (Cold Spring Harbor Laboratory), 2020
doi: bioRxiv preprint finding that mutant SPOP stabilizes the ERG oncoprotein 8,9 , more recent studies challenge 49 this view by showing descriptive evidence for divergence in tumorigenesis 3,10. 50 51 RESULTS 52 Activation of the ERG oncogene and missense mutation in SPOP are synthetic sick To shed light into the functional relationship of these recurrent driver genes, we 54 assessed the impact of SPOP mutations and ERG activation on the cellular growth of 55 mouse prostate epithelial organoids. In agreement with recent reports, lentiviral-transduced 56 point mutants of SPOP (SPOP-Y87C, SPOP-W131G) or a truncated version of ERG, 57 which typically results from gene fusion with androgen-regulated genes in prostate cancer 58 (ERG, amino acids 33-486), promoted cell growth (Fig. 1b, Extended Data Fig. 1b) 11-14. While SPOP mutant organoids displayed a round shape, the over-expression of ERG gave rise to characteristic finger-like protrusions. Surprisingly, the joint expression of both drivers considerably diminished cell growth and reduced finger-like protrusions, implying a synthetic sick relationship between the two genetic alterations. Cytological follow up analysis revealed reduced proliferation associated with senescence (evidenced by reduced Ki-67, increased p16 and P-HP1y positivity) rather than cell death as underlying cause (Extended Data Fig. 1c). We wondered if the observed synthetic sick relationship also applied to established cancer cells from advanced, castration-resistant metastatic disease. Forced expression of mutant SPOP (SPOP-Y87C, SPOP-W131G) promoted 3D growth of ERG fusion-negative LAPC-4 human prostate cancer cells. The oncogenic effect was paralleled by an increase in the expression of the oncogenic transcription factors MYC and HOXB13 and a decrease
Human Molecular Genetics, 2016
Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1,221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7,650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (p < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusionnegative (OR = 0.53, p = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, p = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.
Anticancer research, 2012
Shortcomings of current methods of prostate cancer detection call for improved biomarkers. The transmembrane protease, serine 2:ets-related gene (TMPRSS2:ERG) gene fusion leads to the overexpression of ERG, an E-twenty six (ETS) family transcription factor, and is the most prevalent genetic lesion in prostate cancer, but its clinical utility remains unclear. Two radical prostatectomy samples were analysed by next-generation whole-transcriptome sequencing. The chosen samples differed in fusion gene status, as previously determined by reverse transcription polymerase chain reaction (RT-PCR). Next-generation sequencing identified the involvement of novel and previously reported prostate cancer-related transcripts, the WNT signalling pathway, evasion of p53-mediated anti-proliferation and several ETS-regulated pathways in the prostate cancer cases examined. Overexpression of Rho GDP-dissociation inhibitor (RhoGDIB), a gene associated with fusion-positive prostate cancer, was found to el...
TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort
Oncogene, 2007
The identification of the TMPRSS2:ERG fusion in prostate cancer suggests that distinct molecular subtypes may define risk for disease progression. In surgical series, TMPRSS2:ERG fusion was identified in 50% of the tumors. Here, we report on a population-based cohort of men with localized prostate cancers followed by expectant (watchful waiting) therapy with 15% (17/111) TMPRSS2:ERG fusion. We identified a statistically significant association between TMPRSS2:ERG fusion and prostate cancer specific death (cumulative incidence ratio ¼ 2.7, Po0.01, 95% confidence interval ¼ 1.3-5.8). Quantitative reverse-transcription-polymerase chain reaction demonstrated high estrogen-regulated gene (ERG) expression to be associated with TMPRSS2:ERG fusion (Po0.005). These data suggest that TMPRSS2:ERG fusion prostate cancers may have a more aggressive phenotype, possibly mediated through increased ERG expression.
Morphological features ofTMPRSS2–ERG gene fusion prostate cancer
The Journal of Pathology, 2007
The TMPRSS2-ETS fusion prostate cancers comprise 50-70% of the prostate-specific antigen (PSA)-screened hospital-based prostate cancers examined to date, making it perhaps the most common genetic rearrangement in human cancer. The most common variant involves androgen-regulated TMPRSS2 and ERG, both located on chromosome 21. Emerging data from our group and others suggests that TMPRSS2-ERG fusion prostate cancer is associated with higher tumour stage and prostate cancer-specific death. The goal of this study was to determine if this common somatic alteration is associated with a morphological phenotype. We assessed 253 prostate cancer cases for TMPRSS2-ERG fusion status using an ERG break-apart FISH assay. Blinded to gene fusion status, two reviewers assessed each tumour for presence or absence of eight morphological features. Statistical analysis was performed to look for significant associations between morphological features and TMPRSS2-ERG fusion status. Five morphological features were associated with TMPRSS2-ERG fusion prostate cancer: blue-tinged mucin, cribriform growth pattern, macronucleoli, intraductal tumour spread, and signet-ring cell features, all with p-values &amp;amp;amp;lt; 0.05. Only 24% (n=30/125) of tumours without any of these features displayed the TMPRSS2-ERG fusion. By comparison, 55% (n=38/69) of cases with one feature (RR=3.88), 86% (n=38/44) of cases with two features (RR=20.06), and 93% (n=14/15) of cases with three or more features (RR=44.33) were fusion positive (p&amp;amp;amp;lt;0.001). To our knowledge, this is the first study that demonstrates a significant link between a molecular alteration in prostate cancer and distinct phenotypic features. The strength of these findings is similar to microsatellite unstable colon cancer and breast cancer involving BRCA1 and BRCA2 mutations. The biological effect of TMPRSS2-ERG overexpression may drive pathways that favour these common morphological features that pathologists observe daily. These features may also be helpful in diagnosing TMPRSS2-ERG fusion prostate cancer, which may have both prognostic and therapeutic implications.
British journal of cancer, 2010
Recent studies have indicated that prostate cancer patients with the TMPRSS2-ERG gene fusion have a higher risk of recurrence. To identify markers associated with TMPRSS2-ERG fusion and prognostic of biochemical recurrence, we analysed a cohort of 139 men with prostate cancer for 502 molecular markers. RNA from radical prostatectomy tumour specimens was analysed using cDNA-mediated, annealing, selection, extension and ligation (DASL) to determine mRNAs associated with TMPRSS2-ERG T1/E4 fusion and prognostic of biochemical recurrence. Differentially expressed mRNAs in T1/E4-positive tumours were determined using significance analysis of microarrays (false discovery rate (FDR) <5%). Univariate and multivariate Cox regression determined genes, gene signatures and clinical factors prognostic of recurrence (P-value <0.05, log-rank test). Analysis of two prostate microarray studies (GSE1065 and GSE8402) validated the findings. In the 139 patients from this study and from a 455-patie...