ORCID Profile
0000-0002-9128-0364
Current Organisations
Centre Hospitalier Universitaire Vaudois
,
Université de Lausanne
,
Universitat Bern
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-08-2016
Publisher: American Association for Cancer Research (AACR)
Date: 07-02-2023
DOI: 10.1158/0008-5472.CAN-22-2236
Abstract: DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633058.V1
Abstract: Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633061
Abstract: Supplementary Tables
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633061.V1
Abstract: Supplementary Tables
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.C.6599642
Abstract: Abstract Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy resulting from improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles have been shown to be associated with the mutually exclusive i SPOP /i -mutant or i TMPRSS2-ERG /i fusion genetic backgrounds. Using a cohort of prostate cancer brain metastases (PCBM) from 42 patients, with matched primary tumors for 17 patients, we carried out a DNA methylation analysis to examine the epigenetic distinction between primary prostate cancer and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM. Multiregion s ling of PCBM revealed epigenetic stability within metastases. Aberrant methylation in PCBM was associated with mutational background and PRC2 complex activity, an effect that is particularly pronounced in i SPOP /i -mutant PCBM. 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. Significance: DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases. /
Publisher: Springer Science and Business Media LLC
Date: 03-05-2022
DOI: 10.1038/S41467-022-30003-5
Abstract: Improved survival rates for prostate cancer through more effective therapies have also led to an increase in the diagnosis of metastases to infrequent locations such as the brain. Here we investigate the repertoire of somatic genetic alterations present in brain metastases from 51 patients with prostate cancer brain metastases (PCBM). We highlight the clonal evolution occurring in PCBM and demonstrate an increased mutational burden, concomitant with an enrichment of the homologous recombination deficiency mutational signature in PCBM compared to non-brain metastases. Focusing on known pathogenic alterations within homologous recombination repair genes, we find 10 patients (19.6%) fulfilling the inclusion criteria used in the PROfound clinical trial, which assessed the efficacy of PARP inhibitors (PARPi) in homologous recombination deficient prostate cancer. Eight (15.7%) patients show biallelic loss of one of the 15 genes included in the trial, while 5 patients (9.8%) harbor pathogenic alterations in BRCA1/2 specifically. Uncovering these molecular features of PCBM may have therapeutic implications, suggesting the need of clinical trial enrollment of PCBM patients when evaluating potential benefit from PARPi.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633058
Abstract: Supplementary Figures
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.C.6599642.V1
Abstract: Abstract Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy resulting from improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles have been shown to be associated with the mutually exclusive i SPOP /i -mutant or i TMPRSS2-ERG /i fusion genetic backgrounds. Using a cohort of prostate cancer brain metastases (PCBM) from 42 patients, with matched primary tumors for 17 patients, we carried out a DNA methylation analysis to examine the epigenetic distinction between primary prostate cancer and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM. Multiregion s ling of PCBM revealed epigenetic stability within metastases. Aberrant methylation in PCBM was associated with mutational background and PRC2 complex activity, an effect that is particularly pronounced in i SPOP /i -mutant PCBM. 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. Significance: DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases. /
Publisher: Springer Science and Business Media LLC
Date: 14-03-2018
DOI: 10.1038/NATURE26000
No related grants have been discovered for Ekkehard Hewer.