SPOP mutation

Notably, this observation was correlated with the protein levels of ELK3. Taken together, our study reveals the precise mechanism of SPOP-mediated degradation of ELK3 and provides evidence that SPOP mutations contribute to docetaxel resistance in PCa.

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.

SPOP-M35L promotes HCC cell proliferation and metastasis, suggesting that M35L mutation possibly reprograms SPOP from a tumor suppressor to an oncoprotein. Taken together, this study uncovers mutations in SPOP's MATH lead to distinct functional consequences in context-dependent manners, rather than simply disrupting its interactions with substrates, raising a noteworthy concern that we should be prudent to select SPOP as therapeutic target for cancers.

Notably, SPOP protein were negatively associated with TIAM1 protein in human gastric cancer tissue specimens. In conclusion, our results elucidate a molecular mechanism by which SPOP regulates the stability of TIAM1, and further demonstrate that SPOP inhibits the progression of gastric cancer by promoting the ubiquitination and degradation of TIAM1 protein.

Our hypothesis generating data support that SPOP-mutated prostate cancer likely represents a unique molecular subtype of prostate cancer that may confer prolonged survival. Future studies of novel androgen-receptor targeting treatments should be tested in this molecular population.

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.

WSP-act prostate cancer demonstrated a pronounced upregulation of ROR1 gene expression, underscoring its potential involvement in the crosstalk between the canonical and non-canonical Wnt signaling pathways. Additionally, the augmented levels of M2 macrophages in WSP-act tumors, combined with the reported role of ROR1 in tumor immunosuppression, suggests that ROR1 may contribute to immune evasion in WSP-act mPCa. Our findings may provide rationale for developing novel therapeutic strategies targeting Wnt-activated prostate cancers.

In this retrospective analysis, PARP inhibitors appeared more effective in patients with BRCA2mut/SPOPmut than in patients with BRCA2mut/SPOPwt mCRPC. This may be related to an increase in HRR defects in coaltered disease.

Molecular alterations that may predispose a person to the development of IDC-P include the loss of BRCA2 and PTEN as well as mutations in SPOP. However, the causative nature of these genetic alterations is yet to be validated.

Patients with M1PCa demonstrated characteristic genetic mutations compared to M0PCa, which most often influenced androgen receptor signaling and is associated with worse survival. In addition, we identified distinct genetic mutations between castration sensitive and resistant M1PCa. These findings may be used to further our understanding and management of men with PCa.

P2, N=20, Recruiting, National Cancer Institute (NCI) | Initiation date: Apr 2024 --> Oct 2023

Moreover, liver cancer-associated SPOP mutant S119N disrupts the SPOP-CREB5 interactions and impairs the ubiquitination of CREB5.This disruption ultimately leads to the activation of the MET signaling pathway and enhances metastatic properties of hepatoma cells both in vitro and in vivo. In conclusion, our findings highlight the functional significance of the SPOP-CREB5-MET axis in liver cancer metastasis.

No abstract available

Our findings also suggest that tuning of linear SPOP self-association could be used by the cell to modulate activity and provide insights into the mechanisms underlying hypermorphic SPOP mutations. The characteristics of cancer-associated SPOP mutations suggest a route for designing separation-of-function mutations in other phase-separating systems.

We provide evidence that SPOP is critical in regulating immunosuppressive versus anti-tumor activity downstream of DNA damage-induced STING activation in prostate cancer. PARPi treatment of SPOPmut CRPC alters this NC-STING signaling toward canonical, anti-tumor cGAS-STING-IFN-β signaling, highlighting a novel biomarker-informed treatment strategy for prostate cancer.

The mutational results represented a possible subgroup characterized by carrying the novel variants in SPOP and AR in pT3 PCa patients. In addition to the significant clinicopathological parameters, the mutational results provide a better understanding of the molecular structure of pathologically advanced PCa in the SPOP and AR aspects.

Prostate cancer patients with CDH1 mutations had long disease courses that were managed aggressively with overall survival that ranged from 2 to 16 years from the time of diagnosis. CDH1 variants are an uncommon but recurrently mutated gene in prostate cancer that overlaps with mutations in TP53 and no other tumor suppressor genes. These findings suggest an alternative mechanism for loss-of-function mutations in advanced prostate cancers.

These data indicate that SPOP mutations drive opposing molecular and immune landscapes in prostate and endometrial cancers-suggesting a loss-of-function mechanism in prostate cancer and gain-of-function mechanism in endometrial cancer-and provide a rationale for tailored therapeutic approaches.

Distinct recurrent PCa genomic and transcriptomic features are observed after CHT exposure. Tumor fraction assessed by DNA sequencing quantifies pathologic response and could be a useful trial endpoint or prognostic biomarker. TP53 mutations and high cell cycle transcriptomic activity are linked with aggressive residual disease despite potent CHT.

In vitro, CPSF4 knockdown reduced cell invasion and migration while also causing G1 and G2 arrest in PC3 cell lines. Our findings demonstrate that CPSF4 may be used as a possible biomarker in PCa and support its oncogenic function in cellular proliferation and metastasis.

P2, N=20, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Aug 2023 --> Apr 2024

A significant link is found between promoter hyper methylation and protein expression in all mutant cases of APC and SPOP, suggesting that both genes may be associated in the development of colorectal cancer in people of Indian decent. Hypermethylation of APC gene and loss of SPOP expression have shown an association with disease prognosis and could be further studied looking at its potential role in planning adjuvant treatment in CRC patients.

The genomic mutational landscape of PCa differs based on HPV infection status. This work adds evidence for the direct involvement of HPV in PCa etiology. Different genomic features render HPV-positive PCa a unique subpopulation that might benefit from virus-targeted therapy.

P2, N=30, Recruiting, Mayo Clinic | Not yet recruiting --> Recruiting

African American patients with metastatic prostate adenocarcinoma might have a higher prevalence of mutant SPOP (30%), compared to ∼10% in unselected cohorts with lower expressions of SPOP substrates. In our study, in patients with mutant SPOP, the mutation was associated with decreased SPOP substrate expression and androgen receptor signaling, raising concern for suboptimal efficacy of androgen deprivation therapy in this subset of patients.

Analysis of a large real-world cohort leveraging genetic ancestry inferred from NGS data confirms previously known associations between the presence of somatic alterations in prostate cancer genes and race/ethnicity, and identifies novel associations of potential precision therapeutic relevance.

P2, N=30, Not yet recruiting, Mayo Clinic | Initiation date: Mar 2023 --> Jun 2023

P2, N=20, Not yet recruiting, National Cancer Institute (NCI)

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.

The synonym SNP rs11554137 IDH1 was found in tumor tissue but not in the normal tissue in one case. A larger cohort of Colombian PCa patients is needed for future studies to validate these findings and gain a better understanding of the molecular profile of this cancer in our population and if there are any differences by Colombian regions.

Inactivating mutations in SPOP are associated with better response to ARSI treatment in mCRPC overall. Additional analysis with a larger cohort is needed to evaluate the association of SPOP status and outcomes with docetaxel. Race-associated clinical outcomes and molecular features were observed, suggesting the benefit of biomarker-directed therapy selection for individualized patient subsets in guiding treatment decisions for mCRPC patients.

Gene Set Enrichment Analysis (GSEA) of GARS through the TCGA PRAD database provided evidence for upregulation of biological processes such as cellular proliferation. Our findings support the oncogenic role of GARS involved in cellular proliferation and poor clinical outcome and provide further evidence for its use as a potential biomarker in PCa.

Our data illustrate for the first time a critical role for SPOP in the growth and survival of the prostate epithelium and prostate cancer cell. Our findings further validates SPOP as a important therapeutic target for the treatment of prostate cancer.

Herein, we present the first structure of SPOP in its oligomeric form, uncovering several new interfaces important for SPOP self-assembly and normal function. Given that many previously unaccounted-for cancer mutations are localized in these newly identified interfaces, we uncover molecular mechanisms underlying dysregulation of SPOP function, with effects ranging from gross structural changes to enhanced self-association, and heightened stability and activity.

CDT1 and CDC6 downregulation induced p21 expression without p53 activation. Our results suggest that SPOP is essential for DNA replication licensing in non-cancerous keratinocyte HaCaT cells.

EC-associated SPOP mutations accelerate xenograft tumor growth partially by increasing IRF1 and PD-L1 expression. Together, we identify SPOP as a negative regulator of the IRF1-PD-L1 axis and characterize the critical roles of IRF1 and PD-L1 in SPOP mutation-driven tumor immune evasion in EC.

P2, N=30, Not yet recruiting, Mayo Clinic

In SPOPMT PCs, inactivation of APC is a common event and associated with more aggressive disease (higher metastatic potential and faster progression to castration resistance). This observation may help identify SPOPMT PC patients who are at higher risk for early castration resistance and could benefit from more intensive treatment.

Background: Androgen deprivation therapy (ADT) plus either Abiraterone, Docetaxel or Enzalutamide (ADE) improves overall survival (OS) of men with metastatic M1 castrate-sensitive prostate cancer (mCSPC), compared to ADT alone and is currently standard of care. In this real-world study within KPNC, we confirmed the durable benefit of ADT based therapy in patients with mutSPOP. Patients with mutSPOP derived similar benefit regardless of 1st line therapy (ADT vs ADT + ADE). We also noted durable responses to abiraterone or enzalutamide for CRPC after initial treatment with ADE for CSPC.

In a cohort of aggressive PCa, oncogenic driver mutations were associated with significant differences in prognosis. ETS fusions and SPOP mutations correlated with improved outcomes for men with localized disease at presentation. TP53 loss was associated with worse prognosis, as was the combination with RB1 loss, across the disease spectrum.