TMPRSS2-ERG fusion

Transcriptomes distinguished ETS -fused tumors from SPOP mutants, and PTEN loss from PTEN/AKT1 mutations. Inferred relationships between specific genomic alterations and gene expression signatures of luminal/basal subtypes and of biological pathways/processes, including AR signaling, proliferation, and plasticity signatures, provide a basis to understand differences in treatment response and inform biomarker-guided treatment strategies.

This review underscores a multimodal diagnostic approach, merging molecular diagnostics with cytopathology, as a cornerstone in managing PCa effectively. This strategy promises a future where treatment is not only tailored to the individual's genetic makeup but also anticipates the disease's trajectory, offering hope for improved prognosis and quality of life for patients.

The TMPRSS2:ERG transcript product might be used as a PARPi resistance biomarker.

There is a significantly higher prevalence of ERG expression in our study compared to what is reported in other African-based studies. The expression of the ERG is independent of age, Gleason score, and serum PSA levels. A high proportion of our prostate cancer has high-grade disease at the time of diagnosis.

The estimated 5-year OS rates were 93.9%, 100%, 80.0%, and 78.7% for patients with ERG+/PTEN+, ERG-/PTEN+, ERG+/PTEN-, and ERG-/PTEN- phenotypes respectively. ERG rearrangements and PTEN deletions detected on biopsy samples are associated with poorer oncologic outcomes in prostate cancer patients treated with SBRT and merit further study in a dedicated prospective trial.

Bioinformatic analysis of the array outcomes indicated that the protective effect of NSAIDs was associated with reduced expression of (a) tumor promoting inflammatory molecules (M-CSF, IL-33, CCL22, CCL12, CX3CL1, CHI3L1, and CD93), (b) growth factors- growth signaling-associated molecules (Chemerin, FGF acidic, Flt-3 ligand, IGFBP-5, and PEDF), and (c) tumor microenvironment/stromal remodeling proteins MMP2 and MMP9. Overall, our findings corroborate the pathological findings that protective effects of NSAIDs in TMPSS2-ERG fusion-driven prostate tumorigenesis are associated with antiproliferative and anti-inflammatory effects and possible modulation of the immune cell enriched microenvironment.

Our study demonstrates that TRIM29 and TP63 are important regulators in maintaining the identity of the basal epithelium under physiological conditions. Furthermore, we uncover the role of TRIM29 in PRAD development.

The patient received docetaxel chemotherapy and pelvic radiotherapy. In a literature review, this case demonstrated the longest duration of effectiveness with olaparib alone without platinum-based chemotherapy. Additionally, the occurrence of relatively rare, fatal brain metastases in prostate cancer after a long period of CR suggests the necessity of regular brain imaging examinations.

TALA + ENZA improved outcomes compared with PBO + ENZA in patients with muts in specific non-HRR genes (regardless of HRR gene muts). TMPRSS2-ERG and RB1 emerged as candidate predictive biomarkers for differential efficacy favoring TALA + ENZA vs PBO + ENZA. PARP inhibitors may induce a synthetically lethal interaction with TMPRSS2-ERG-mediated inhibition of non-homologous end joining and help overcome RB1-mediated ENZA resistance.

Lastly, we identified novel positive associations between AMR and driver mutations in PIK3C3A (OR=1.12, p=0.0003) as well as small NS mutations or CNAs in the PI3K/AKT/mTOR pathway genes (OR=1.03, p=0.04). By analyzing a large, diverse real-world cohort and leveraging NGS-inferred genetic ancestry, our study confirms known associations between somatic alterations in PRAD cancer genes and race and ethnicity, while unveiling novel associations in understudied populations of potential significance for understanding disparities in disease outcomes.

GA in TP53, ATRX and RB1 were the most common GA identified in Bsarc and Psarc. Bsarc have more than 2-fold more GA compared to Psarc. Further study of both Bsarc and Psarc designed to further subclassify and design novel treatment for these rare tumors appears warranted.

Overall, 5-ERG-mRPs can robustly detect T2E fusion in PC at the individual level, which can be used on any gene measurement platform without specific normalization procedures. Hence, 5-ERG-mRPs may serve as an auxiliary tool for PC patient management.

This study underscores the potential of DL in deducing genetic alterations from routine slides and identifying their underlying morphological features which might harbor prognostic information. Implications: Our study illuminates the potential of deep learning in effectively inferring key prostate cancer genetic alterations from the tissue morphology depicted in routinely available histology slides, offering a cost-effective method that could revolutionize diagnostic strategies in oncology.

Different FOXA1 alterations exhibit divergent molecular and clinical features, and should not be interpreted in aggregate. In particular, Class 1B mutations are associated with a unique molecular and immunological landscape with potentially better outcomes to ADT, while Class 2 mutations are associated with NEPC phenotype with inferior ADT sensitivity.

Fifty-three of 97 (54.6%) patients with SCCUPs presenting with I/P/RP involvement had at least one GA that could potentially guide targeted treatment decisions including entry into biomarker-driven clinical trials. I/P/RP SCCUP patients frequently demonstrated HPV infection and APOBEC mutation signatures. To our knowledge, this is the first report that describes the genomic landscape of SCCUPs presenting with I/P/RP metastases.

The homozygous adrenal-permissive HSD3B1 variant (c.1100 CC) is associated with distinct tumoral features characterized by elevated AR signaling and MAPK activation. It is also associated with a unique immune-cell regulatory landscape, with higher B7-H3 expression, increased intratumoral dendritic cells and decreased immunosuppressive neutrophils. This distinct molecular landscape of HSD3B1 c.1100 CC–associated prostate cancers warrants special therapeutic considerations, including possibly using B7-H3–targeted therapies.

Prostate sarcoma is an exceedingly rare primary cancer of the prostate with limited opportunities for targeted therapy or immunotherapy strategies. These tumors do not appear to be driven by “targetable� gene fusions and individual “targetable� mutations are uncommon.

TMPRSS2:ERG fusion positive status is associated with additional other genomic alterations in castrate resistant disease. In addition, CGP reveals significant differences in both targetable GA and markers of immunotherapy response between TMPRSS2:ERG positive and TMPRSS2:ERG negative CRPC. Given the higher levels of TMB and MSI-high status in TMPRSS2:ERG negative CRPC, TMPRSS2:ERG wild type may be a potential biomarker for immunotherapy response.

Notably, there were no moderately differentiated (MD) adenocarcinomas in the dorsolateral prostate of naproxen groups, and its incidence also decreased by ~79-91% in the aspirin cohorts. In contrast, NSAIDs showed little protective effect against prostate tumorigenesis in Hi-Myc mice, suggesting that NSAIDs exert a specific protective effect against TMPRSS2-ERG (fusion)-driven PCa.

Reduced PSAP expression is associated with aggressive prostate cancers. These findings make PSAP a candidate marker for prognostic multiparameter panels in ERG-negative prostate cancers.

Loss of FAM3B in PC, whether through the TMPRSS2-ERG translocation or epigenetic imprinting, causes an exit from this autoregulatory loop to unleash AR activity and PC progression.These findings establish FAM3B loss as a new driver of PC progression and support the utility of FAM3B loss as a biomarker to better define aggressive PC.

We demonstrated how TMPRSS2-ERG fusion reprograms the mesenchyme in the early phases of PCa; while, in advanced PCa models, transcriptional mesenchymal programs are associated with metastatic potential, and similar to the human bone microenvironment ones. Overall, these findings support mesenchymal changes as major contributors to PCa carcinogenesis and phenotypic heterogeneity, to a previously unrecognized level.

Our findings suggest that tumors with the TMPRSS2:ERG fusion exhibit a different germline genetic etiology compared to fusion negative cases.

β-Catenin inhibition by small molecule inhibitors or oligonucleotide-based PROTAC suppresses TMPRSS2-ERG- and p53 mutant-positive PCa cell growth in vitro and in mice. Our study identifies a gene transactivation function of GOF mutant p53 and reveals β-Catenin as a transcriptional target gene of p53 GOF mutants and a driver and therapeutic target of TMPRSS2-ERG- and p53 GOF mutant-positive PCa.

The inhibition of p300 has been shown to reduce the proliferation of prostate cancer cells with TMPRSS2:ETS (E26 transformation-specific) fusions, and combining p300 inhibitors with other targeted therapies may increase their efficacy. Overall, the interplay between the p300 and TMPRSS2 pathways is an active area of research.

TMPRSS2-ERG and androgen receptor RNA were detected down to 3x10 and 5x10 copies respectively in under 30 minutes. Administration of these assays onto the ISFET Lab-on-chip device was successful and the specificity of each marker was corroborated with mRNA extracted from prostate cancer cell lines.

Androgen receptor pathway inhibitors (ARPi; abiraterone and enzalutamide) and taxanes (docetaxel and cabazitaxel) were evaluated, using progression-free survival, by no longer clinically benefiting per PCWG3 criteria (PFS), as primary endpoint. Conclusions ARPi increases PFS and OS both compared to SOC and taxanes in patients with mCRPC. These are directly randomized data for ARPi and taxanes, showing the first evidence of a difference in PFS and OS for these agents in the mCRPC setting.

Importantly, these findings also reveal potential avenues for the detection and treatment of prostate cancer through the profiling and modulation of the host microbiota. The latter could involve approaches such as the use of faecal microbiota transplantation, prebiotics, probiotics, postbiotics or antibiotics, which can be used independently or combined with existing treatments to reverse therapeutic resistance and improve clinical outcomes in patients with prostate cancer.

We tested the performance of FTAS-seq with well-characterized prostate cancer cell lines and utilized the technique for the analysis of patient RNA samples. FTAS-seq chemistry combined with appropriate primer panels holds great potential as a tool for biomarker discovery that can support the development of personalized cancer therapies.

In 10% of cases, an increase in the number of copies of the EGFR and KRAS genes was found, and in 10% of cases, a fusion gene (RNA) MET- MET.M13M15, TMPRSS2-ERG.The identified genome changes were processed by the server through the FDA, NCCN, EMA, ESMO registries to search for the most appropriate therapy options that exist in world practice for a specific type and localization of the established mutation.ConclusionConclusion. For personalized prescription of targeted drugs, it is more efficient to use multigene diagnostics for a comprehensive study of the mutational status of a tumor.

Although, at some degree, ERG expression seems to be associated with the morphological features of prostate cancer, different studies reported controversial results. However, expression of PTEN is more clearly associated with the pathology and clinical course of the disease. More research is required to elucidate the role of these molecules in the molecular pathology of prostate cancer, as well as their potential use as therapeutic targets.

P=N/A | N=14 | Active, not recruiting | Sponsor: Medical University of South Carolina | Trial completion date: Jun 2023 ➔ Sep 2023 | Trial primary completion date: Mar 2023 ➔ Jun 2023

Across four BRCA-associated cancers, TP53 muts are enriched in BRCA1 pts and depleted in gATM pts. In breast/ovarian cancers, PIK3CA muts are depleted in gBRCA1/2 pts, while ESR1 muts are enriched in gATM pts. KRAS muts are enriched in gBRCA1/2-altered pancreas cancers, but are depleted in gBRCA1/2-altered ovarian cancers.

While PCBM displayed a CpG island hypermethylator phenotype, hypomethylation at the promoters of genes involved in neuroactive ligand-receptor interaction and cell adhesion molecules such as GABRB3, CLDN8, and CLDN4 was also observed, suggesting that cells from primary tumors may require specific reprogramming to form brain metastasis. This study revealed the DNA methylation landscapes of PCBM and the potential mechanisms and effects of PCBM-associated aberrant DNA methylation.

Agent Orange exposure may contribute to tumor genomic alterations in AR and FGFR in prostate cancer. These findings hold potential prognostic and therapeutic implications for U.S. Veterans with metastatic prostate cancer.

Molecular alterations in 3 samples showed a microsatellite-stable disease with low tumor mutation burden and variable PTEN, PTCH1, KDM6A, ARv7, and PIK3CA loss/alteration, TP53 mutation, TMPRSS2-ERG fusion, and MYC, PIK3CB, RICTOR, or IRS2 amplification. Our findings suggest that PGCC is a rare and aggressive subtype of prostate carcinoma whose recognition may steer clinicians to adopt more aggressive treatments and investigate new therapeutic strategies.

Overall, we observed that the genomic, epigenomic, and transcriptomic alterations evaluated between AA and EA prostate cancer patients varied between studies, highlighting the impact of using different methods and sample sizes. The reported genomic, epigenomic, and transcriptomic alterations do not only uncover molecular mechanisms of tumorigenesis but also provide researchers and clinicians valuable resources to identify novel biomarkers and treatment modalities to improve the disparity of clinical outcomes between AA and EA patients.

P=N/A, N=243, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2022 --> Dec 2023

We were able to establish IDCP cases from past high-grade PIN cases. As a number of HRR gene mutations of unknown pathological significance were detected, IDCP cases could be retrieved from past cases and genetic abnormalities could be identified efficiently. The findings of the study provide a possible approach to diagnose prostate cancer cases with genetic mutations at an early stage.

Nifuroxazide blocked this interaction, and overly activated PARP1, leading to cell death that was reduced by olaparib, a PARP1 inhibitor. These results show that nifuroxazide inhibits ERG, leading to parthanatic cell death.

Less frequent ETS fusion events other than TMPRSS2-ERG such as TMPRSS2-ETV5 and non-ETS fusion events such as SLC45A3-SKIL may be more common in PCa in Nigerian men. This study provides useful working transcriptomic signatures that characterize oncogenic states representative of specific gene fusion events in PCa from Nigerian men.

P=N/A, N=120, Active, not recruiting, CHU de Quebec-Universite Laval | Trial primary completion date: Dec 2022 --> Dec 2023