Multimodal analysis of cell-free DNA whole-methylome sequencing for cancer detection and localization

Fenglong Bie, Zhijie Wang, Yulong Li, Wei Guo, Yuanyuan Hong, Tiancheng Han, Fang Lv, Shunli Yang, Suxing Li, Xi Li, Peiyao Nie, Shun Xu, Ruochuan Zang, Moyan Zhang, Peng Song, Feiyue Feng, Jianchun Duan, Guangyu Bai, Yuan Li, Qilin Huai, Bolun Zhou, Yu S. Huang, Weizhi Chen, Fengwei Tan () and Shugeng Gao ()
Additional contact information
Fenglong Bie: Chinese Academy of Medical Sciences and Peking Union Medical College
Zhijie Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Yulong Li: Genecast Biotechnology Co., Ltd.
Wei Guo: Chinese Academy of Medical Sciences and Peking Union Medical College
Yuanyuan Hong: Genecast Biotechnology Co., Ltd.
Tiancheng Han: Genecast Biotechnology Co., Ltd.
Fang Lv: Genecast Biotechnology Co., Ltd.
Shunli Yang: Genecast Biotechnology Co., Ltd.
Suxing Li: Genecast Biotechnology Co., Ltd.
Xi Li: Genecast Biotechnology Co., Ltd.
Peiyao Nie: Genecast Biotechnology Co., Ltd.
Shun Xu: The First Hospital of China Medical University
Ruochuan Zang: Chinese Academy of Medical Sciences and Peking Union Medical College
Moyan Zhang: Chinese Academy of Medical Sciences and Peking Union Medical College
Peng Song: Chinese Academy of Medical Sciences and Peking Union Medical College
Feiyue Feng: Chinese Academy of Medical Sciences and Peking Union Medical College
Jianchun Duan: Chinese Academy of Medical Sciences and Peking Union Medical College
Guangyu Bai: Chinese Academy of Medical Sciences and Peking Union Medical College
Yuan Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Qilin Huai: Chinese Academy of Medical Sciences and Peking Union Medical College
Bolun Zhou: Chinese Academy of Medical Sciences and Peking Union Medical College
Yu S. Huang: Genecast Biotechnology Co., Ltd.
Weizhi Chen: Genecast Biotechnology Co., Ltd.
Fengwei Tan: Chinese Academy of Medical Sciences and Peking Union Medical College
Shugeng Gao: Chinese Academy of Medical Sciences and Peking Union Medical College

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Multimodal epigenetic characterization of cell-free DNA (cfDNA) could improve the performance of blood-based early cancer detection. However, integrative profiling of cfDNA methylome and fragmentome has been technologically challenging. Here, we adapt an enzyme-mediated methylation sequencing method for comprehensive analysis of genome-wide cfDNA methylation, fragmentation, and copy number alteration (CNA) characteristics for enhanced cancer detection. We apply this method to plasma samples of 497 healthy controls and 780 patients of seven cancer types and develop an ensemble classifier by incorporating methylation, fragmentation, and CNA features. In the test cohort, our approach achieves an area under the curve value of 0.966 for overall cancer detection. Detection sensitivity for early-stage patients achieves 73% at 99% specificity. Finally, we demonstrate the feasibility to accurately localize the origin of cancer signals with combined methylation and fragmentation profiling of tissue-specific accessible chromatin regions. Overall, this proof-of-concept study provides a technical platform to utilize multimodal cfDNA features for improved cancer detection.

Date: 2023
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DOI: 10.1038/s41467-023-41774-w

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