DNA Methylation Landscapes of Prostate Cancer Brain Metastasis Are Shaped by Early Driver Genetic Alterations.

Publication

DNA Methylation Landscapes of Prostate Cancer Brain Metastasis Are Shaped by Early Driver Genetic Alterations.

Journal Paper/Review - Apr 14, 2023

Gallon John, Rodriguez-Calero Antonio, Benjak Andrej, Akhoundova Dilara, Maletti Sina, Amstutz Ursula, Hewer Ekkehard, Genitsch Vera, Fleischmann Achim, Rushing Elisabeth Jane, Grobholz Rainer, Fischer Ingeborg, Jochum Wolfram, Cathomas Gieri, Osunkoya Adeboye O, Bubendorf Lukas, Moch Holger, Thalmann George N, Feng Felix Y, Gillessen Silke, Chiang Charleston W K, Rubin Monika Afzali, Piscuoglio Salvatore

Citation

Gallon J, Rodriguez-Calero A, Benjak A, Akhoundova D, Maletti S, Amstutz U, Hewer E, Genitsch V, Fleischmann A, Rushing E, Grobholz R, Fischer I, Jochum W, Cathomas G, Osunkoya A, Bubendorf L, Moch H, Thalmann G, Feng F, Gillessen S, Chiang C, Rubin M, Piscuoglio S. DNA Methylation Landscapes of Prostate Cancer Brain Metastasis Are Shaped by Early Driver Genetic Alterations. Cancer Res 2023; 83:1203-1213.

Type

Journal Paper/Review (English)

Journal

Cancer Res 2023; 83

Publication Date

Apr 14, 2023

Issn Electronic

1538-7445

Pages

1203-1213

Brief description/objective

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.