1314 Recurrent Mutations in Spop Define a Distinct Molecular Class of Prostate Cancer

Barbieri, Christopher E.; Baca, Sylvan C.; Demichelis, Francesca; Lawrence, M; Blattner, Mija; Theurillat, Jean-Philippe; Boysen, Gunther; Stojanov, Petar; Allen, Eli Van; Stransky, N.; Nickerson, Elizabeth; Park, Kyung; Kitabayashi, Naoki; MacDonald, Theresa Y.; Vuong, Terry; Auclair, Daniel; Guiducci, Candace; Cibulskis, Kristian; Sivachenko, Andrey; Carter, Scott L.; Ambrogio, Lauren; Parkin, Melissa; White, Thomas A.; Saksena, Gordon; Voet, Douglas; Ramos, Alex H.; Winckler, Wendy; Hussain, Wasay; Wilkinson, Jane; Ardlie, Kristin; Banerjee, Samprit; Baldwin, Jennifer; Mosquera, Juan Miguel; Gabriel, Stacey; Golub, Todd R.; Meyerson, Matthew; Lander, Eric S.; Getz, Gad; Nelson, Peter S.; Garraway, Levi A.; Tewari, Ashutosh; Rubin, Mark A.

doi:10.1016/j.juro.2012.02.1661

Cited by 3 publications

(5 citation statements)

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“…Indeed, overall, we found 184 such promoters, several of which belong to known oncogenes and tumor suppressors such as TES or SPOP (Figures 4A-4C, S4A, and S4B; Table S5; FDR-adjusted p < 0.05, see STAR Methods for details) (Futreal et al, 2004). While these genes have been implied in cancer, the usage of an alternative promoter in cancer has not been described (Barbieri et al, 2012;Tobias et al, 2001). Tissue-specific promoter switching is more frequent, yet these events further demonstrate the prevalence of alternative-promoter regulation.…”

Section: Pan-cancer Deregulation Of Alternative Promotersmentioning

confidence: 95%

A Pan-cancer Transcriptome Analysis Reveals Pervasive Regulation through Alternative Promoters

Demircioğlu

Cukuroglu

Kindermans

et al. 2019

Cell

171

155

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Most human protein-coding genes are regulated by multiple, distinct promoters, suggesting that the choice of promoter is as important as its level of transcriptional activity. However, while a global change in transcription is recognized as a defining feature of cancer, the contribution of alternative promoters still remains largely unexplored. Here, we infer active promoters using RNA-seq data from 18,468 cancer and normal samples, demonstrating that alternative promoters are a major contributor to context-specific regulation of transcription. We find that promoters are deregulated across tissues, cancer types, and patients, affecting known cancer genes and novel candidates. For genes with independently regulated promoters, we demonstrate that promoter activity provides a more accurate predictor of patient survival than gene expression. Our study suggests that a dynamic landscape of active promoters shapes the cancer transcriptome, opening new diagnostic avenues and opportunities to further explore the interplay of regulatory mechanisms with transcriptional aberrations in cancer. 3 rd ≥4 th Rank of correlation (Spearman) Mean promoter activity (RNA-Seq) Mean log H3K4me3 (ChIP-Seq) read count Adrenal Gland Arterial Blood Vessel Blood Blood Vessel Brain

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Section: Pan-cancer Deregulation Of Alternative Promotersmentioning

confidence: 95%

A Pan-cancer Transcriptome Analysis Reveals Pervasive Regulation through Alternative Promoters

Demircioğlu

Cukuroglu

Kindermans

et al. 2019

Cell

171

155

View full text Add to dashboard Cite

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“…SPOP mutation alone alters the landscape of accessible enhancers in response to androgen SPOP mutations are present in $10% of PCa (Barbieri et al, 2012;The Cancer Genome Atlas Research Network, 2015;Li et al, 2020), occur early in the natural history of the disease, are relatively prostate specific, and affect AR activity through the deregulation of multiple substrates (Blattner et al, 2017;Geng et al, 2013;Theurillat et al, 2014). We previously developed a transgenic mouse with Cre-dependent, conditional expression of SPOP-F133V (Figure 2A) (Blattner et al, 2017).…”

Section: Resultsmentioning

confidence: 99%

“…We next looked in human PCas for evidence to support a relationship between SPOP mutation and FOXA1. FOXA1 is recurrently mutated in localized PCa, with mutations in the forkhead domain (FKHD)-altering pioneering activity being the most common (Adams et al, 2019;Barbieri et al, 2012;The Cancer Genome Atlas Research Network, 2015;Parolia et al, 2019). We hypothesized that if SPOP mutations acted in part through the modulation of FOXA1 activity, then SPOP mutant tumors and FOXA1 mutant tumors would display similar genomic and transcriptional features.…”

Section: Spop Mutant Prostate Organoids Display An Oncogenic Ar Cistromementioning

confidence: 99%

“…Recurrent missense mutations in SPOP (speckle type BTB/ POZ protein) occur in $10% of localized primary PCa cases (The Cancer Genome Atlas Research Network, 2015;Li et al, 2020) and are highly prostate specific; they are rarely observed in other cancer types. SPOP mutations nominate a distinct molecular subtype of human PCa (Barbieri et al, 2012;The Cancer Genome Atlas Research Network, 2015;Shoag et al, 2018), with defined genomic alterations, DNA methylation, transcriptional signatures, and clinical characteristics (Barbieri et al, 2012;Boy-sen et al, 2015;The Cancer Genome Atlas Research Network, 2015;Liu et al, 2018). Furthermore, a variety of data suggest that SPOP mutations occur early in the process of prostate tumorigenesis (Baca et al, 2013;Boysen et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Reshaping of the androgen-driven chromatin landscape in normal prostate cells by early cancer drivers and effect on therapeutic sensitivity

Grbeša

Augello²,

Liu³

et al. 2021

Cell Reports

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SUMMARY The normal androgen receptor (AR) cistrome and transcriptional program are fundamentally altered in prostate cancer (PCa). Here, we profile the chromatin landscape and AR-directed transcriptional program in normal prostate cells and show the impact of SPOP mutations, an early event in prostate tumorigenesis. In genetically normal mouse prostate organoids, SPOP mutation results in accessibility and AR binding patterns similar to that of human PCa. Consistent with dependence on AR signaling, castration of SPOP mutant mouse models results in the loss of neoplastic phenotypes, and human SPOP mutant PCa shows a favorable response to AR-targeted therapies. Together, these data validate mouse prostate organoids as a robust model for studying epigenomic and transcriptional alterations in normal prostate, provide valuable datasets for further studies, and show that a single genomic alteration may be sufficient to reprogram the chromatin of normal prostate cells toward oncogenic phenotypes, with potential therapeutic implications for AR-targeting therapies.

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“…Although the complex is often described as a tumor suppressor in multiple cancer types (Jones et al, 2010;Versteege et al, 1998;Witkowski et al, 2014), there is also increasing evidence for tumor-promoting functions of SWI/SNF in other malignancies, including leukemia, breast, liver, and pancreas cancer, melanoma, glioblastoma, neuroblastoma, and synovial sarcoma (Buscarlet et al, 2014;Clark et al, 1994;Hiramatsu et al, 2017;Jubierre et al, 2016;Laurette et al, 2020;Wu et al, 2016). Mutations in SWI/SNF genes are very rare in PCa (Abida et al, 2019;Armenia et al, 2018;Baca and Garraway, 2012;Barbieri et al, 2012;Beltran et al, 2016;Cancer Genome Atlas Research Network, 2015;Muthuswami et al, 2019), in contrast to several other cancer types Shain and Pollack, 2013). From the functional perspective, inhibition of the SWI/SNF subunits BAF57 (SMARCE1) or BAF53A (ACTL6A) in PCa cells has shown to abrogate androgen-dependent cell proliferation (Jin et al, 2018;Link et al, 2008).…”

Section: Emergent Directions In the Search For Lineage Plasticity Driversmentioning

confidence: 99%

Impact of Lineage Plasticity to and from a Neuroendocrine Phenotype on Progression and Response in Prostate and Lung Cancers

et al. 2020

Self Cite

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Intratumoral heterogeneity can occur via phenotype transitions, often after chronic exposure to targeted anticancer agents. This process, termed lineage plasticity, is associated with acquired independence to an initial oncogenic driver, resulting in treatment failure. In non-small cell lung cancer (NSCLC) and prostate cancers, lineage plasticity manifests when the adenocarcinoma phenotype transforms into neuroendocrine (NE) disease. The exact molecular mechanisms involved in this NE transdifferentiation remain elusive. In small cell lung cancer (SCLC), plasticity from NE to nonNE phenotypes is driven by NOTCH signaling. Herein we review current understanding of NE lineage plasticity dynamics, exemplified by prostate cancer, NSCLC, and SCLC.

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1314 Recurrent Mutations in Spop Define a Distinct Molecular Class of Prostate Cancer

Cited by 3 publications

References 0 publications

A Pan-cancer Transcriptome Analysis Reveals Pervasive Regulation through Alternative Promoters

A Pan-cancer Transcriptome Analysis Reveals Pervasive Regulation through Alternative Promoters

Reshaping of the androgen-driven chromatin landscape in normal prostate cells by early cancer drivers and effect on therapeutic sensitivity

Impact of Lineage Plasticity to and from a Neuroendocrine Phenotype on Progression and Response in Prostate and Lung Cancers

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