Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories

Gerhäuser, Clarissa; Favero, Francesco; Risch, Thomas S.; Simon, Ronald; Feuerbach, Lars; Assenov, Yassen; Heckmann, Doreen; Sidiropoulos, Nikolaos; Waszak, Sebastian M.; Hübschmann, Daniel; Urbanucci, Alfonso; Girma, Etsehiwot G.; Kuryshev, Vladimir; Klimczak, Leszek J.; Saini, Natalie; Stütz, Adrian M.; Weichenhan, Dieter; Böttcher, Lisa Marie; Tóth, Réka; Hendriksen, Josephine D.; Koop, Christina; Lutsik, Pavlo; Matzk, Sören; Warnatz, Hans Jörg; Amstislavskiy, Vyacheslav; Feuerstein, Clarissa; Raeder, Benjamin; Bogatyrova, Olga; Schmitz, Eva Maria; Hube‐Magg, Claudia; Kluth, Martina; Huland, Hartwig; Graefen, Markus; Lawerenz, Chris; Henry, Gervaise H.; Yamaguchi, Takafumi N.; Malewska, Alicia; Meiners, Jan; Schilling, Daniela; Reisinger, Eva; Eils, Roland; Schlesner, Matthias; Strand, Douglas W.; Bristow, Robert G.; Boutros, Paul C.; Kalle, Christof von; Gordenin, Dmitry A.; Sültmann, Holger; Brors, Benedikt; Sauter, Guido; Plass, Christoph; Yaspo, Marie Laure; Korbel, Jan O.; Schlomm, Thorsten; Weischenfeldt, Joachim

doi:10.1016/j.ccell.2018.10.016

Cited by 230 publications

(265 citation statements)

References 89 publications

(77 reference statements)

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“…139 We applied our model to two independent PCa cohorts for validation of the good prediction 140 rate. We were able to validate our results using the ICGC PCa cohort of early and late onset 141 prostate cancer (n= 222) (Gerhauser et al, 2018). The AUC for the sensitivity analysis was 142 77.1% and the error rate was 35.1% ( Figure 3C).…”

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confidence: 59%

“…Recent high-resolution genome-wide studies have significantly improved our understanding 55 of chromosomal and genetic alterations associated with PCa development, such as the 56 androgen-driven formation of gene fusions between the transmembrane serine protease 57 TMPRSS2 and a member of the oncogenic ETS transcription factor family like ERG in about 58 50% of all PCa cases, and frequent loss of the tumour suppressor gene PTEN (Cancer 59 Genome Atlas Research, 2015;Fraser et al, 2017;Gerhauser et al, 2018;Taylor et al, 2010;60 Tomlins et al, 2005;Weischenfeldt et al, 2013). These events affect signalling pathways and 61 lead to alterations in gene expression programs that have been used for the development of 62 gene signatures (genomic classifiers) as biomarkers for the prediction of PCa prognosis.…”

Section: Introduction 40mentioning

confidence: 99%

“…117 Random forest model 118 We applied random forest-based modelling to rank the selected DMS according to their 119 discriminative power (for details see description in the Experimental section). In addition to 120 the DMS, the Purity-Adjusted Epigenetic Prostate Cancer Index (PEPCI) of tumor 121 aggressiveness (Gerhauser et al, 2018) was included in the model. Mean PEPCI was 122 significantly different between the two prognosis groups of the discovery cohort (t-test p-123 value=0.03).…”

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confidence: 99%

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Random forest-based modelling to detect biomarkers for prostate cancer progression

Tóth

Schiffmann

Hube‐Magg

et al. 2019

Preprint

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24The clinical course of prostate cancer (PCa) is highly variable, demanding an individualized 25 approach to therapy and robust prognostic markers for treatment decisions. We present a 26 random forest-based classification model to predict aggressive behaviour of PCa. DNA 27 methylation changes between PCa cases with good or poor prognosis (discovery cohort with 28 n=70) were used as input. The model was validated with data from two large independent 29

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confidence: 59%

Section: Introduction 40mentioning

confidence: 99%

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confidence: 99%

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Random forest-based modelling to detect biomarkers for prostate cancer progression

Tóth

Schiffmann

Hube‐Magg

et al. 2019

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“…ESRPs have previously been shown to have a dual role in carcinogenesis with both gain and loss associated with poor patient prognosis (36). ESRP1 has recently been shown to be amplified in an aggressive subgroup of early onset prostate cancer (54). ESRP1 expression is linked to poor survival and metastasis in lung cancer (64), and both ESRP1 and ESRP2 are upregulated in oral squamous cell carcinoma relative to normal epithelium (53).…”

Section: Discussionmentioning

confidence: 99%

“…Figure supplement 1C). While this manuscript was in preparation, another group used an alternative ESRP1 antibody to show upregulation of ESRP1 in 12,000 prostate cancer tissue microarray tumours(54).We next investigated the effects of ESRP1/2 expression on the biology of prostate cancer cells in vivo. Because of their normal endogenous expression profiles (Figures 1C and 1D), we selected PC3 and DU145 cells to study the effects of ESRP1/ESRP2 protein upregulation on prostate cancer cells.…”

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confidence: 99%

Androgen-regulated transcription ofESRP2drives alternative splicing patterns in prostate cancer

Munkley¹,

Krishnan³

et al. 2019

Preprint

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Prostate is the most frequent cancer in men. Prostate cancer progression is driven by androgen steroid hormones, and delayed by androgen deprivation therapy (ADT).Androgens control transcription by stimulating androgen receptor (AR) activity, yet also control pre-mRNA splicing through less clear mechanisms. Here we find androgens regulate splicing through AR-mediated transcriptional control of the epithelial-specific splicing regulator ESRP2. Both ESRP2 and its close paralog ESRP1 are highly expressed in primary prostate cancer. Androgen stimulation induces splicing switches in many endogenous ESRP2-controlled mRNA isoforms, including a key splicing switch in the metastatic regulator FLNB which is associated with disease relapse. ESRP2 expression in clinical prostate cancer is repressed by ADT, which may thus inadvertently dampen epithelial splice programmes. Supporting this, FLNB splicing was reciprocally switched by the AR antagonist bicalutamide (Casodex ® ). Our data reveal a new mechanism of splicing control in prostate cancer with important implications for metastatic disease progression. Key points: Transcriptional regulation of ESRP2 by the androgen receptor controls splice isoform patterns in prostate cancer cells.  Splicing switches regulated by the androgen-ESRP2 axis include a splice isoform in the FLNB gene that is a known metastatic driver.  Both ESRP1 and ESRP2 are highly expressed in prostate cancer tissue.  Ectopic expression of ESRP1 and 2 inhibits prostate cancer cell growth.  By repressing ESRP2 expression androgen deprivation therapy (ADT) may dampen epithelial splicing programmes to inadvertently prime disease progression towards metastasis.

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The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor

Legge

Moriarty

et al. 2021

Molecular Oncology

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Wilms tumour (WT), an embryonal kidney cancer, has been extensively characterised for genetic and epigenetic alterations, but a proportion of WTs still lack identifiable abnormalities. To uncover DNA methylation changes critical for WT pathogenesis, we compared the epigenome of foetal kidney with two WT cell lines, filtering our results to remove common cancer‐associated epigenetic changes and to enrich for genes involved in early kidney development. This identified four hypermethylated genes, of which ESRP2 (epithelial splicing regulatory protein 2) was the most promising for further study. ESRP2 was commonly repressed by DNA methylation in WT, and this occurred early in WT development (in nephrogenic rests). ESRP2 expression was reactivated by DNA methyltransferase inhibition in WT cell lines. When ESRP2 was overexpressed in WT cell lines, it inhibited cellular proliferation in vitro, and in vivo it suppressed tumour growth of orthotopic xenografts in nude mice. RNA‐seq of the ESRP2‐expressing WT cell lines identified several novel splicing targets. We propose a model in which epigenetic inactivation of ESRP2 disrupts the mesenchymal to epithelial transition in early kidney development to generate WT.

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Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories

Cited by 230 publications

References 89 publications

Random forest-based modelling to detect biomarkers for prostate cancer progression

Random forest-based modelling to detect biomarkers for prostate cancer progression

Androgen-regulated transcription ofESRP2drives alternative splicing patterns in prostate cancer

The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor

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