DNA methylation landscapes of prostate cancer brain metastasis are shaped by early driver genetic alterations
| Autor: | John Gallon, Antonio Rodriguez-Calero, Andrej Benjak, Dilara Akhoundova, Sina Maletti, Ursula Amstutz, Ekkehard Hewer, Vera Genitsch, Achim Fleischmann, Elisabeth J. Rushing, Rainer Grobholz, Ingeborg Fischer, Wolfram Jochum, Gieri Cathomas, Adeboye O. Osunkoya, Lukas Bubendorf, Holger Moch, George Thalmann, Felix Y. Feng, Silke Gillessen, Charlotte K.Y. Ng, Mark A. Rubin, Salvatore Piscuoglio |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: |
Cancer Research
Oncology Humans Male DNA Methylation Prostatic Neoplasms/pathology CpG Islands/genetics Epigenomics Brain Neoplasms/genetics Nuclear Proteins/metabolism Repressor Proteins/genetics 570 Life sciences biology 610 Medicine & health 610 Medizin und Gesundheit 570 Biowissenschaften Biologie |
| Zdroj: | Gallon, John; Rodríguez-Calero, Antonio; Benjak, Andrej; Akhoundova, Dilara; Maletti, Sina; Amstutz, Ursula; Hewer, Ekkehard; Genitsch, Vera; Fleischmann, Achim; Rushing, Elisabeth J; Grobholz, Rainer; Fischer, Ingeborg; Jochum, Wolfram; Cathomas, Gieri; Osunkoya, Adeboye O; Bubendorf, Lukas; Moch, Holger; Thalmann, George; Feng, Felix Y; Gillessen, Silke; ... (2023). DNA methylation landscapes of prostate cancer brain metastasis are shaped by early driver genetic alterations. Cancer research, 83(8), pp. 1203-1213. American Association for Cancer Research AACR 10.1158/0008-5472.CAN-22-2236 Cancer research, vol. 83, no. 8, pp. 1203-1213 |
| DOI: | 10.1158/0008-5472.CAN-22-2236 |
| Popis: | 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 SPOP-mutant or TMPRSS2-ERG 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 sampling 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 SPOP-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. |
| Databáze: | OpenAIRE |
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