Cost-effective methylome sequencing of cell-free DNA for accurately detecting and locating cancer.


Early cancer detection by cell-free DNA faces multiple challenges: low fraction of tumor cell-free DNA, molecular heterogeneity of cancer, and sample sizes that are not sufficient to reflect diverse patient populations. Here, we develop a cancer detection approach to address these challenges. It consists of an assay, cfMethyl-Seq, for cost-effective sequencing of the cell-free DNA methylome (with > 12-fold enrichment over whole genome bisulfite sequencing in CpG islands), and a computational method to extract methylation information and diagnose patients. Applying our approach to 408 colon, liver, lung, and stomach cancer patients and controls, at 97.9% specificity we achieve 80.7% and 74.5% sensitivity in detecting all-stage and early-stage cancer, and 89.1% and 85.0% accuracy for locating tissue-of-origin of all-stage and early-stage cancer, respectively. Our approach cost-effectively retains methylome profiles of cancer abnormalities, allowing us to learn new features and expand to other cancer types as training cohorts grow.

  • Aberle DR
  • Agopian V
  • Ahuja P
  • Alber F
  • Chen PJ
  • Choi G
  • Dry S
  • Dubinett SM
  • French S
  • Garon E
  • Geschwind D
  • Han SB
  • He S
  • Lajonchere C
  • Lee YT
  • Li PS
  • Li Q
  • Li S
  • Li W
  • Liu CC
  • Magyar CE
  • Ni X
  • Noor Z
  • Saab S
  • Stackpole ML
  • Sun F
  • Tomlinson JS
  • Tran B
  • Tseng HR
  • Wang Z
  • Winograd P
  • Wong WH
  • Yeh A
  • Yildirim A
  • Yokomizo M
  • Yuan Z
  • Zeng W
  • Zhou XJ
  • Zhou Y
  • Zhu Y
PubMed ID
Appears In
Nat Commun, 2022, 13 (1)