SPOP mutation leads to genomic instability in prostate cancer

Boysen, Gunther; Barbieri, Christopher E.; Prandi, Davide; Blattner, Mirjam; Chae, Sung-Suk; Dahija, Arun; Nataraj, Srilakshmi; Huang, Dennis; Marotz, Clarisse; Xu, Limei; Huang, Julie; Lecca, Paola; Chhangawala, Sagar; D, Liu; Zhou, Pengbo; Sboner, Andrea; Bono, Johann S. de; Demichelis, Francesca; Houvras, Yariv; Rubin, Mark A.

doi:10.7554/elife.09207

Cited by 158 publications

(197 citation statements)

References 35 publications

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“…SPOP mutations define a distinct and key molecular class of prostate cancer, with characteristic genomic alterations, patterns of genomic rearrangements, gene expression profiles and methylation patterns (Barbieri et al, 2012; Blattner et al, 2014; Boysen et al, 2015; Cancer Genome Atlas Research, 2015). SPOP mutations occur early in the natural history of prostate cancer solely as heterozygous missense mutations with dominant negative, selective loss of function towards the remaining wild-type allele (Baca et al, 2013; Boysen et al, 2015; Prandi et al, 2014; Theurillat et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

et al. 2017

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Summary Recurrent point mutations in SPOP define a distinct molecular subclass of prostate cancer. Here, we describe a mouse model showing that mutant SPOP drives prostate tumorigenesis in vivo. Conditional expression of mutant SPOP in the prostate dramatically altered phenotypes in the setting of Pten loss, with early neoplastic lesions (high-grade prostatic intraepithelial neoplasia) with striking nuclear atypia, and invasive poorly differentiated carcinoma. In mouse prostate organoids, mutant SPOP drove increased proliferation and a transcriptional signature consistent with human prostate cancer. Using these models and human prostate cancer samples, we show that SPOP mutation activates both PI3K/mTOR and androgen receptor (AR) signaling, effectively uncoupling the normal negative feedback between these two pathways.

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Section: Introductionmentioning

confidence: 99%

SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

et al. 2017

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“…These three genes are also in our CONIM gene list. Several other studies investigated relations between point mutations and CNA numbers in single cancer types: a higher number of CNAs has been reported in SPOP-mutated prostate cancer (Boysen et al, 2015). Lower CNA numbers have been detected in CASP8-mutated oral squamous cell carcinoma (Pickering et al, 2013) and in CTNNB1-mutated endometrial cancer (Kandoth et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the length distribution of CNAs reflects chromosomal interactions (Fudenberg et al, 2011). The observation that certain genes tend to be mutated in CNA-rich (TP53 and SPOP [Ciriello et al, 2013; Boysen et al, 2015]) or CNA-poor (CTCF and ARID1A [Ciriello et al, 2013]) cancers implies that, besides epigenetic factors, the genetic background of the cell influences CNA variation.…”

Section: Introductionmentioning

confidence: 99%

A network of epigenetic modifiers and DNA repair genes controls tissue-specific copy number alteration preference

Cramer

Serrano

Schaefer

2016

eLife

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Copy number alterations (CNAs) in cancer patients show a large variability in their number, length and position, but the sources of this variability are not known. CNA number and length are linked to patient survival, suggesting clinical relevance. We have identified genes that tend to be mutated in samples that have few or many CNAs, which we term CONIM genes (COpy Number Instability Modulators). CONIM proteins cluster into a densely connected subnetwork of physical interactions and many of them are epigenetic modifiers. Therefore, we investigated how the epigenome of the tissue-of-origin influences the position of CNA breakpoints and the properties of the resulting CNAs. We found that the presence of heterochromatin in the tissue-of-origin contributes to the recurrence and length of CNAs in the respective cancer type.DOI: http://dx.doi.org/10.7554/eLife.16519.001

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“…Concordant with this, SPOP- mutant tumors have been found to have among the highest androgen receptor transcriptional activity 5 . Importantly, it has been recently demonstrated that SPOP modulates DNA double strand break (DSB) repair, is associated with genomic instability, and sensitizes to DNA damaging agents such as PARP inhibitors 52 .…”

Section: Introductionmentioning

confidence: 99%

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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SPOP mutation leads to genomic instability in prostate cancer

Cited by 158 publications

References 35 publications

SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling

A network of epigenetic modifiers and DNA repair genes controls tissue-specific copy number alteration preference

Molecular subtyping of prostate cancer

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