The cell-free DNA methylome captures distinctions between localized and metastatic prostate tumors

Sujun Chen; Jessica Petricca; Wenbin Ye; Jiansheng Guan; Yong Zeng; Nicholas Cheng; Linsey Gong; Shu Yi Shen; Junjie T Hua; Megan Crumbaker; Michael Fraser; Stanley Liu; Scott V Bratman; Theodorus van der Kwast; Trevor Pugh; Anthony M Joshua; Daniel D De Carvalho; Kim N Chi; Philip Awadalla; Guoli Ji; Felix Feng; Alexander W Wyatt; Housheng Hansen He

doi:10.1038/s41467-022-34012-2

The cell-free DNA methylome captures distinctions between localized and metastatic prostate tumors

Nat Commun. 2022 Oct 29;13(1):6467. doi: 10.1038/s41467-022-34012-2.

Authors

Sujun Chen^#^{1

2

3}, Jessica Petricca^#^{1

2}, Wenbin Ye^#^{1

4

5}, Jiansheng Guan^{1

6}, Yong Zeng¹, Nicholas Cheng², Linsey Gong^{1

2}, Shu Yi Shen¹, Junjie T Hua^{7

8}, Megan Crumbaker⁹, Michael Fraser¹, Stanley Liu^{2

10

11}, Scott V Bratman^{1

2}, Theodorus van der Kwast^{2

12}, Trevor Pugh^{1

2}, Anthony M Joshua¹², Daniel D De Carvalho^{1

2}, Kim N Chi¹³, Philip Awadalla¹⁴, Guoli Ji^{15

16}, Felix Feng^{17

18

19

20}, Alexander W Wyatt²¹, Housheng Hansen He^{22

23}

Affiliations

¹ Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
² Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
³ West China School of Public Health, West China Fourth Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China.
⁴ Department of Automation, Xiamen University, Xiamen, Fujian, China.
⁵ National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian, China.
⁶ College of Electrical Engineering and Automation, Xiamen University of Technology, Fujian, Xiamen, China.
⁷ Department of Radiation Oncology, University of California, San Francisco, CA, USA.
⁸ UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
⁹ Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia.
¹⁰ Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
¹¹ Department of Radiation Oncology, Sunnybrook Odette Cancer Centre, Toronto, ON, Canada.
¹² Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada.
¹³ British Columbia Cancer Agency, Vancouver Centre, Vancouver, BC, Canada.
¹⁴ Ontario Institute for Cancer Research, Toronto, ON, Canada.
¹⁵ Department of Automation, Xiamen University, Xiamen, Fujian, China. [email protected].
¹⁶ National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian, China. [email protected].
¹⁷ Department of Radiation Oncology, University of California, San Francisco, CA, USA. [email protected].
¹⁸ UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA. [email protected].
¹⁹ Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA. [email protected].
²⁰ Department of Urology, University of California San Francisco, San Francisco, CA, USA. [email protected].
²¹ Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. [email protected].
²² Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada. [email protected].
²³ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. [email protected].

^# Contributed equally.

Abstract

Metastatic prostate cancer remains a major clinical challenge and metastatic lesions are highly heterogeneous and difficult to biopsy. Liquid biopsy provides opportunities to gain insights into the underlying biology. Here, using the highly sensitive enrichment-based sequencing technology, we provide analysis of 60 and 175 plasma DNA methylomes from patients with localized and metastatic prostate cancer, respectively. We show that the cell-free DNA methylome can capture variations beyond the tumor. A global hypermethylation in metastatic samples is observed, coupled with hypomethylation in the pericentromeric regions. Hypermethylation at the promoter of a glucocorticoid receptor gene NR3C1 is associated with a decreased immune signature. The cell-free DNA methylome is reflective of clinical outcomes and can distinguish different disease types with 0.989 prediction accuracy. Finally, we show the ability of predicting copy number alterations from the data, providing opportunities for joint genetic and epigenetic analysis on limited biological samples.

Publication types

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

MeSH terms

Cell-Free Nucleic Acids* / genetics
DNA Methylation / genetics
Epigenome
Humans
Male
Prostate / pathology
Prostatic Neoplasms* / pathology

Substances

Cell-Free Nucleic Acids

Grants and funding

181755/CIHR/Canada