4.8 Article

Whole-genome bisulfite sequencing analysis of circulating tumour DNA for the detection and molecular classification of cancer

Journal

CLINICAL AND TRANSLATIONAL MEDICINE
Volume 12, Issue 8, Pages -

Publisher

JOHN WILEY & SONS LTD
DOI: 10.1002/ctm2.1014

Keywords

cancer early detection; circulating tumour DNA; DNA methylation; epigenetic biomarkers; liquid biopsy; whole-genome bisulfite sequencing

Funding

  1. National Key R&D Program of China [2019YFC1315701, 2019YFC1315700, 2020YFC2006400, 2021YFF1201300]
  2. National Natural Science Foundation of China [22005343, 31540033, 61871294, 82122053, 82188102, 81702796]
  3. Precision Medicine Research Program of the Chinese Academy of Sciences [KJZD-EW-L14]
  4. Strategic Priority Research Program of the Chinese Academy of Sciences [XDA12020343, XDA01040407]
  5. Sanming Project of Medicine in Shenzhen [SZSM201812062, SZSM201612097]
  6. National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital
  7. Chinese Academic of Medical Sciences
  8. Peking Union Medical College, Shenzhen Research Project [SZ2020ZD004]
  9. Key Task Project of Tianjin Health and Family Planning Commission [16KG128]
  10. Anticancer Key Technologies R&D Program of Tianjin [12ZCDZSY16200]
  11. Key-Area Research and Development Programof Guangdong Province [2021B0101420005]
  12. Beijing Municipal Science & Technology Commission [Z191100006619118]
  13. R&D Program of Beijing Municipal Education Commission [KJZD20191002302]
  14. Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences [2021-PT310-001]
  15. Aiyou Foundation [KY201701]
  16. Shenzhen Science and Technology Program [KCXFZ20201221173008022]
  17. CAMSInitiative for Innovative Medicine (CIFMS) [2021-1-I2M-012, 2021-1-I2M-067]

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This study provides a toolset for generating unbiased whole-genome ctDNA methylomes with a minimal amount of plasma, enabling the development of highly specific and sensitive biomarkers for early cancer diagnosis and molecular subtyping.
Background Cancer cell-specific variation and circulating tumour DNA (ctDNA) methylation are promising biomarkers for non-invasive cancer detection and molecular classification. Nevertheless, the applications of ctDNA to the early detection and screening of cancer remain highly challenging due to the scarcity of cancer cell-specific ctDNA, the low signal-to-noise ratio of DNA variation, and the lack of non-locus-specific DNA methylation technologies. Methods We enrolled three cohorts of breast cancer (BC) patients from two hospitals in China (BC: n = 123; healthy controls: n = 40). We developed a ctDNA whole-genome bisulfite sequencing technology employing robust trace ctDNA capture from up to 200 mu L plasma, mini-input (1 ng) library preparation, unbiased genome-wide coverage and comprehensive computational methods. Results A diagnostic signature comprising 15 ctDNA methylation markers exhibited high accuracy in the early (area under the curve [AUC] of 0.967) and advanced (AUC of 0.971) BC stages in multicentre patient cohorts. Furthermore, we revealed a ctDNA methylation signature that discriminates estrogen receptor status (Training set: AUC of 0.984 and Test set: AUC of 0.780). Different cancer types, including hepatocellular carcinoma and lung cancer, could also be well distinguished. Conclusions Our study provides a toolset to generate unbiased whole-genome ctDNA methylomes with a minimal amount of plasma to develop highly specific and sensitive biomarkers for the early diagnosis and molecular subtyping of cancer.

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