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