Whole-genome circulating tumor DNA methylation landscape reveals sensitive biomarkers of breast cancer
Luo Hai
Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
Search for more papers by this authorLingyu Li
Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
Search for more papers by this authorZongzhi Liu
Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
University of Chinese Academy of Sciences, Beijing, China
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
Search for more papers by this authorCorresponding Author
Zhongsheng Tong
Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
Correspondence
Yingli Sun, Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China.
Email: [email protected]
Zhongsheng Tong, Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Yingli Sun
Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
University of Chinese Academy of Sciences, Beijing, China
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
Correspondence
Yingli Sun, Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China.
Email: [email protected]
Zhongsheng Tong, Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
Email: [email protected]
Search for more papers by this authorLuo Hai
Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
Search for more papers by this authorLingyu Li
Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
Search for more papers by this authorZongzhi Liu
Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
University of Chinese Academy of Sciences, Beijing, China
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
Search for more papers by this authorCorresponding Author
Zhongsheng Tong
Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
Correspondence
Yingli Sun, Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China.
Email: [email protected]
Zhongsheng Tong, Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Yingli Sun
Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
University of Chinese Academy of Sciences, Beijing, China
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
Correspondence
Yingli Sun, Central Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China.
Email: [email protected]
Zhongsheng Tong, Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
Email: [email protected]
Search for more papers by this authorLuo Hai, Lingyu Li, and Zongzhi Liu contributed equally to this work.
Abstract
The changes in circulating tumor DNA (ctDNA) methylation are believed to be early events in breast cancer initiation, which makes them suitable as promising biomarkers for early diagnosis. However, applying ctDNA in breast cancer early diagnosis remains highly challenging due to the contamination of background DNA from blood and low DNA methylation signals. Here, we report an improved way to extract ctDNA, reduce background contamination, and build a whole-genome bisulfite sequencing (WGBS) library from different stages of breast cancer. We first compared the DNA methylation data of 74 breast cancer patients with those of seven normal controls to screen candidate methylation CpG site biomarkers for breast cancer diagnosis. The obtained 26 candidate ctDNA methylation biomarkers produced high accuracy in breast cancer patients (area under the curve [AUC] = 0.889; sensitivity: 100%; specificity: 75%). Furthermore, we revealed potential ctDNA methylated CpG sites for detecting early-stage breast cancer (AUC = 0.783; sensitivity: 93.44%; specificity: 50%). In addition, different subtypes of breast cancer could be well distinguished by the ctDNA methylome, which was obtained through our improved ctDNA-WGBS method. Overall, we identified high specificity and sensitivity breast cancer-specific methylation CpG site biomarkers, and they will be expected to have the potential to be translated to clinical practice.
CONFLICT OF INTEREST
The authors declare no competing interests.
Open Research
DATA AVAILABILITY STATEMENT
The code and data that support the findings of this study are openly available in GitHub at https://github.com/zhq921/cfWGBS-bioinfo-pip. The raw sequencing data reported in this manuscript are publicly available at the Genome Sequence Archive under accession number CRA001142 (https://ngdc.cncb.ac.cn/gsa/browse/CRA001142). All the data and materials are available from the corresponding author upon reasonable request.
Supporting Information
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