Clinico-pathological significance of the molecular alterations of the SPOP gene in prostate cancer

García-Flores, María; Casanova-Salas, Irene; Rubio‐Briones, J.; Calatrava, Ana; Domínguez-Escrig, José; Rubio, Luis; Ramírez‐Backhaus, M.; Fernández-Serra, Antonio; García-Casado, Zaida; Löpez‐Guerrero, José Antonio

doi:10.1016/j.ejca.2014.08.009

Cited by 43 publications

(46 citation statements)

References 24 publications

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“…To the best of our knowledge very few papers have previously investigated the impact of the deregulation of SPOP at mRNA or protein level in prostate carcinogenesis . In this regard, García‐Flores et al reported that SPOP was strongly downregulated in PrCa at mRNA level, and that expression was inversely associated with biochemical and clinical progression‐free survival and with Gleason score. Low levels of SPOP independently predicted a worse prognosis.…”

Section: Discussionmentioning

confidence: 96%

“…The percentage of SPOP mutations reported in the Catalogue of Somatic Mutations is 8% and that of TCGA Project is 11%. Other studies have also reported frequencies of 6%‐13% in primary and 14.5% in metastatic cancers . A comprehensive analysis of the SPOP gene in samples from six international cohorts, revealed SPOP mutations in 4.6% to 14.4% of the patients with PrCa, across different ethnic and demographic backgrounds, but without any association with ethnicity, clinical, or pathologic parameters .…”

Section: Discussionmentioning

confidence: 97%

“…17,21,32 In contrast with SPOP mutations, the role of SPOP gene To the best of our knowledge very few papers have previously investigated the impact of the deregulation of SPOP at mRNA or protein level in prostate carcinogenesis. 33,34 In this regard, García-Flores et al 35 ac.uk/cosmic) located in the substrate-binding cleft. 4,38 Despite this low percentage, there was a statistical association between these mutations and a shorter time to PSA recurrence.…”

Section: Discussionmentioning

confidence: 98%

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SPOP and FOXA1 mutations are associated with PSA recurrence in ERG wt tumors, and SPOP downregulation with ERG‐rearranged prostate cancer

et al. 2019

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Background ERG fusion‐related prostate cancer (PrCa) is the most prevalent oncogenic driver subclass. SPOP, FOXA1, and IDH1 mutations are other three main oncogenic driver subclasses in non–ETS‐fusion PrCa. ERG protein levels seem to be increased in SPOP‐mutated cases, and different studies reported that SPOP mutations and ERG fusions are mutually exclusive. The aim of this study has been to analyze the alterations in non–ETS‐oncogenic drivers in PrCa. Methods SPOP, FOXA1, and IDH mutations were investigated by polymerase chain reaction (PCR) and Sanger direct sequencing. ERG, SPOP, and TMPRSS2‐ERG messenger RNA expression was assessed by quantitative real‐time PCR from complementary DNA, and the presence of the fusion was also analyzed by nonquantitative PCR. The clinical pathological features were retrieved from the charts of the 111 patients included in the study (MARBiobanc, Barcelona, Spain). Results Loss of SPOP expression (25.2%) was associated with ERG overexpression (P = 0.0036). SPOP mutations were found in 5.4% cases, all with wild‐type (wt) ERG (P = 0.007). FOXA1 mutations were found in 8.2% cases, most of them ERG wt (P = 0.06). No IDH1 mutations were found. SPOP or FOXA1 mutations were found in 1.7% of ERG‐rearranged, and 34.2% of non–ERG‐rearranged cases (P < 0.0001). SPOP or FOXA1 alterations (mutations or expression loss) were significantly more common in GG5, while isolated ERG overexpression was more common in GG1 tumors (P = 0.042). SPOP‐or FOXA1‐mutated cases were associated with a shorter time to prostate‐specific antigen (PSA) recurrence in the univariate (P = 0.0009), and with the PSA recurrence risk in the multivariate (P = 0.023) analysis. Conclusions In conclusion, SPOP and FOXA1 mutations may have prognostic value in ERG wt tumors. Interestingly, in absence of SPOP mutations, downregulation of this gene is a feature of many ERG‐rearranged prostate tumors.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 98%

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SPOP and FOXA1 mutations are associated with PSA recurrence in ERG wt tumors, and SPOP downregulation with ERG‐rearranged prostate cancer

et al. 2019

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“…A recent study found no association between SPOP mutation and clinical or pathological parameters 43 ; however, others have reported that mutations and decreased expression of the SPOP gene are associated with worse progression free survival 46 . Functionally, SPOP mutation has been shown to modulate carcinogenesis by preventing the degradation of oncogenic factors including ERG and the androgen receptor 47–51 .…”

Section: Introductionmentioning

confidence: 93%

Molecular subtyping of prostate cancer

Kaffenberger

Barbieri

2016

Current Opinion in Urology

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Purpose of Review The recent publication of The Cancer Genome Atlas molecular taxonomy of primary prostate cancer highlights the increased understanding of the genomic basis of human prostate cancer, but also emphasizes the complexity and heterogeneity of prostate cancer. Recent Findings 7 molecular subclasses have been defined on the basis of early genomic alterations, which are largely mutually exclusive. Summary We review the recent advances in the genomic understanding of human prostate cancer, with focus on molecular subclassification. Broadly, prostate cancer can be classified based upon whether specific genomic rearrangements, such as the TMPRSS2-ERG fusion occur or whether specific alterations such as SPOP and FOXA1 mutations occur. The molecular drivers remain to be identified in a further quarter of human prostate cancers. Depending upon the molecular subclassification and the coincident genomic alterations, specific clinical insights can be gained from this information, including associations with pathologic factors, race, and prognosis, as well as the possibility for future precision therapies.

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“…Thus, elevation of SRC-3 by a mutant SPOP may also contribute to the transcriptional activation of AR. In addition to mutations, SPOP can be downregulated in prostate cancer (27, 28), and this may provide another mechanism to increase AR stability and transcriptional activity. Additional studies will help clarify the role of SPOP in CRPC.…”

Section: Spop Regulates Transcriptional Output Of Ar By Controlling Gmentioning

confidence: 99%

Implications of ubiquitin ligases in castration-resistant prostate cancer

Fan

Hussain

2015

Current Opinion in Oncology

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Purpose of review Significant advances have been made in the study of ubiquitination-mediated regulation of androgen receptor (AR). This review will highlight the latest developments in the mechanisms by which E3 ubiquitin ligases control AR activity, with implications in castration-resistant prostate cancer (CRPC). Recent findings Several ubiquitin ligases have been identified to interact with and ubiquitinate AR, and consequently regulate positively or negatively e the AR transcriptional program.. Different ubiquitin ligases can use distinct mechanisms to modulate the expression of AR target genes, including local turnover of AR chromatin complex, recruitment of AR co-activators, and global AR stability. The expression or activity of ubiquitin ligases can be altered in prostate cancer and thus contribute to the growth of androgen-insensitive prostate cancer cells by modulating the AR transcriptional activity. Summary Understanding the regulation of AR transcriptional activity by ubiquitin ligases will contribute to the elucidation of mechanisms underlying AR re-activation that is believed to drive the development of CPPC. Ubiquitin ligases could potentially serve as promising targets for developing therapeutics in the treatment of advanced prostate cancers.

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Clinico-pathological significance of the molecular alterations of the SPOP gene in prostate cancer

Cited by 43 publications

References 24 publications

SPOP and FOXA1 mutations are associated with PSA recurrence in ERG wt tumors, and SPOP downregulation with ERG‐rearranged prostate cancer

SPOP and FOXA1 mutations are associated with PSA recurrence in ERG wt tumors, and SPOP downregulation with ERG‐rearranged prostate cancer

Molecular subtyping of prostate cancer

Implications of ubiquitin ligases in castration-resistant prostate cancer

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