Single-molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer

Nat Genet. 2023 Aug;55(8):1301-1310. doi: 10.1038/s41588-023-01446-3. Epub 2023 Jul 27.


Somatic mutations are a hallmark of tumorigenesis and may be useful for non-invasive diagnosis of cancer. We analyzed whole-genome sequencing data from 2,511 individuals in the Pan-Cancer Analysis of Whole Genomes (PCAWG) study as well as 489 individuals from four prospective cohorts and found distinct regional mutation type-specific frequencies in tissue and cell-free DNA from patients with cancer that were associated with replication timing and other chromatin features. A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected >90% of patients with lung cancer, including those with stage I and II disease. The fixed model was validated in an independent cohort, detected patients with cancer earlier than standard approaches and could be used to monitor response to therapy. This approach lays the groundwork for non-invasive cancer detection using genome-wide mutation features that may facilitate cancer screening and monitoring.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell-Free Nucleic Acids*
  • Humans
  • Lung Neoplasms* / diagnosis
  • Lung Neoplasms* / genetics
  • Mutation
  • Mutation Rate
  • Neoplasms* / diagnosis
  • Neoplasms* / genetics
  • Prospective Studies


  • Cell-Free Nucleic Acids