Dynamics of the cell-free DNA methylome of metastatic prostate cancer during androgen-targeting treatment

Madonna R Peter; Misha Bilenky; Ruth Isserlin; Gary D Bader; Shu Yi Shen; Daniel D De Carvalho; Aaron R Hansen; Pingzhao Hu; Neil E Fleshner; Anthony M Joshua; Martin Hirst; Bharati Bapat

doi:10.2217/epi-2020-0173

Dynamics of the cell-free DNA methylome of metastatic prostate cancer during androgen-targeting treatment

Epigenomics. 2020 Aug;12(15):1317-1332. doi: 10.2217/epi-2020-0173. Epub 2020 Sep 1.

Authors

Madonna R Peter^{1

2}, Misha Bilenky³, Ruth Isserlin⁴, Gary D Bader⁴, Shu Yi Shen⁵, Daniel D De Carvalho^{5

6}, Aaron R Hansen⁷, Pingzhao Hu⁸, Neil E Fleshner⁹, Anthony M Joshua^{7

10}, Martin Hirst^{3

11}, Bharati Bapat^{1

2}

Affiliations

¹ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, M5G 1X5, Canada.
² Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
³ Canada's Michael Smith Genome Science Centre, BC Cancer Agency, Vancouver, BC, V5Z 4S6, Canada.
⁴ Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada.
⁵ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 2C1, Canada.
⁶ Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada.
⁷ Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON, M5G 2C1, Canada.
⁸ Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, MB, R3E 3N4, Canada.
⁹ Division of Urology, Department of Surgical Oncology, University Health Network, Toronto, ON, M5G 2C1, Canada.
¹⁰ Department of Medical Oncology, Kinghorn Cancer Centre, Darlinghurst, NSW 2010, Australia.
¹¹ Department of Microbiology & Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.

PMID: 32867540
DOI: 10.2217/epi-2020-0173

Abstract

Aim: We examined methylation changes in cell-free DNA (cfDNA) in metastatic castration-resistant prostate cancer (mCRPC) during treatment. Patients & methods: Genome-wide methylation analysis of sequentially collected cfDNA samples derived from mCRPC patients undergoing androgen-targeting therapy was performed. Results: Alterations in methylation states of genes previously implicated in prostate cancer progression were observed and patients that maintained methylation changes throughout therapy tended to have a longer time to clinical progression. Importantly, we also report that markers associated with a highly aggressive form of the disease, neuroendocrine-CRPC, were associated with a faster time to clinical progression. Conclusion: Our findings highlight the potential of monitoring the cfDNA methylome during therapy in mCRPC, which may serve as predictive markers of response to androgen-targeting agents.

Keywords: DNA methylation; circulating cell free DNA; epigenetic modifications; genome-wide methylation analysis; metastatic castration-resistant prostate cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Abiraterone Acetate / therapeutic use
Antineoplastic Agents / therapeutic use
Benzamides / therapeutic use
Cell-Free Nucleic Acids
Epigenome*
Humans
Male
Nitriles / therapeutic use
Phenylthiohydantoin / therapeutic use
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / genetics

Substances

Antineoplastic Agents
Benzamides
Cell-Free Nucleic Acids
Nitriles
Phenylthiohydantoin
enzalutamide
Abiraterone Acetate