DNA Methylation Landscapes of Prostate Cancer Brain Metastasis Are Shaped by Early Driver Genetic Alterations-Reference-Cited by-同舟云学术

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

Published:2023-02-07 Issue:8 Volume:83 Page:1203-1213
ISSN:0008-5472
Container-title:Cancer Research
language:en
Short-container-title:

Author:

Gallon John¹^ORCID,Rodriguez-Calero Antonio²³^ORCID,Benjak Andrej¹^ORCID,Akhoundova Dilara²⁴^ORCID,Maletti Sina²^ORCID,Amstutz Ursula⁵^ORCID,Hewer Ekkehard³^ORCID,Genitsch Vera³^ORCID,Fleischmann Achim³⁶^ORCID,Rushing Elisabeth J.⁷^ORCID,Grobholz Rainer⁸^ORCID,Fischer Ingeborg⁸^ORCID,Jochum Wolfram⁹^ORCID,Cathomas Gieri¹⁰^ORCID,Osunkoya Adeboye O.¹¹¹²^ORCID,Bubendorf Lukas¹³^ORCID,Moch Holger¹⁴^ORCID,Thalmann George¹⁵^ORCID,Feng Felix Y.¹⁶^ORCID,Gillessen Silke¹⁷¹⁸¹⁹^ORCID,Ng Charlotte K.Y.²²⁰²¹^ORCID,Rubin Mark A.²²¹^ORCID,Piscuoglio Salvatore¹¹³^ORCID

Affiliation:

1. 1Visceral Surgery and Precision Medicine Research Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.

2. 2Department for BioMedical Research, University of Bern, Bern, Switzerland.

3. 3Institute of Pathology, University of Bern, Bern, Switzerland.

4. 4Department of Medical Oncology, Inselspital, University Hospital of Bern, Bern, Switzerland.

5. 5Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

6. 6Institute of Pathology, Cantonal Hospital Thurgau, Münsterlingen, Switzerland.

7. 7Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.

8. 8Institute of Pathology, Cantonal Hospital Aarau, Aarau, Switzerland.

9. 9Institute of Pathology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.

10. 10Institute of Pathology, Cantonal Hospital Baselland, Liestal, Switzerland.

11. 11Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.

12. 12Department of Urology, Emory University School of Medicine, Atlanta, Georgia.

13. 13Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.

14. 14Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.

15. 15Department of Urology, Inselspital, Bern University Hospital, Bern, Switzerland.

16. 16UCSF Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco, California.

17. 17Faculty of Biomedical Sciences, USI, Lugano, Switzerland.

18. 18Department of Oncology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.

19. 19Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom.

20. 20SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.

21. 21Bern Center for Precision Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Abstract

AbstractMetastases 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.

Funder

National Cancer Institute

Swiss Personalized Health Network

Krebsliga Schweiz

Prof. Dr. Max Cloetta Foundation

Prostate Cancer Foundation

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Link

https://aacrjournals.org/cancerres/article-pdf/83/8/1203/3320663/1203.pdf