Dynamics of the Cell-Free DNA Methylome of Metastatic Prostate Cancer During Androgen-Targeting Treatment

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::

• circulating cell free DNA
• DNA methylation
• epigenetic modifications
• genome-wide methylation analysis
• metastatic castration-resistant prostate cancer

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/full/10.2217/epi-2022-0173

Acknowledgments

The authors acknowledge the UHN Genitourinary clinic and Genitourinary Biobank for recruiting patients, collecting blood samples and for patient follow-up/data collection. All sequencing and initial data preprocessing was performed by the Princess Margaret Genomics Centre and the UHN Bioinformatics and HPC Core, Princess Margaret Cancer Centre, respectively. Differential methylation analysis was performed using the facilities provided by the Canada’s Michael Smith Genome Sciences Centre (British Columbia Cancer Agency). We also acknowledge Shivani Kamdar (SHS/LTRI) for assisting with sample processing and for helping to edit this manuscript.

Financial & competing interests disclosure

This study was supported by a Prostate Cancer Canada Movember Discovery Grant (D2014-10) and an Astellas Prostate Cancer Innovation Fund (2017) to B Bapat. DD De Carvalho and SY Shen are listed as inventors on patents related cfMeDIP-seq. DD De Carvalho is a co-founder of and provide consulting for DNAMx, Inc. DD De Carvalho shared the cfMeDIP-seq protocol with B Bapat. All experiments in this study were performed the laboratory of B Bapat and independently from the services provided by DNAMx. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

All patients in this study provided informed written consent in accordance with approved institutional Research Ethics Board protocols from University Health Network (UHN) and Sinai Health System (SHS). Progress updates were submitted and approved annually by respective Research Ethics Boards. The study was performed in accordance with the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. According to REB approvals, each patient was assigned unique study identifiers, which are not linked to personal health information.

Data sharing statement

All raw data files are available in the Gene Expression Omnibus (GEO) repository (accession no. GSE152631).

Additional information

Funding

This study was supported by a Prostate Cancer Canada Movember Discovery Grant (D2014-10) and an Astellas Prostate Cancer Innovation Fund (2017) to B Bapat. DD De Carvalho and SY Shen are listed as inventors on patents related cfMeDIP-seq. DD De Carvalho is a co-founder of and provide consulting for DNAMx, Inc. DD De Carvalho shared the cfMeDIP-seq protocol with B Bapat. All experiments in this study were performed the laboratory of B Bapat and independently from the services provided by DNAMx. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.