A comprehensive characterization of the cell-free transcriptome reveals tissue- and subtype-specific biomarkers for cancer detection

Nat Commun. 2021 Apr 21;12(1):2357. doi: 10.1038/s41467-021-22444-1.


Cell-free RNA (cfRNA) is a promising analyte for cancer detection. However, a comprehensive assessment of cfRNA in individuals with and without cancer has not been conducted. We perform the first transcriptome-wide characterization of cfRNA in cancer (stage III breast [n = 46], lung [n = 30]) and non-cancer (n = 89) participants from the Circulating Cell-free Genome Atlas (NCT02889978). Of 57,820 annotated genes, 39,564 (68%) are not detected in cfRNA from non-cancer individuals. Within these low-noise regions, we identify tissue- and cancer-specific genes, defined as "dark channel biomarker" (DCB) genes, that are recurrently detected in individuals with cancer. DCB levels in plasma correlate with tumor shedding rate and RNA expression in matched tissue, suggesting that DCBs with high expression in tumor tissue could enhance cancer detection in patients with low levels of circulating tumor DNA. Overall, cfRNA provides a unique opportunity to detect cancer, predict the tumor tissue of origin, and determine the cancer subtype.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / genetics*
  • Breast Neoplasms / blood
  • Breast Neoplasms / genetics*
  • Cell-Free Nucleic Acids / blood
  • Cell-Free Nucleic Acids / genetics*
  • Cohort Studies
  • Databases, Nucleic Acid
  • Female
  • Gene Expression Profiling
  • Humans
  • Lung Neoplasms / blood
  • Lung Neoplasms / genetics*
  • Molecular Sequence Annotation
  • Organ Specificity / genetics
  • RNA, Messenger / blood
  • RNA, Messenger / genetics
  • Transcriptome*


  • Biomarkers, Tumor
  • Cell-Free Nucleic Acids
  • RNA, Messenger

Associated data

  • ClinicalTrials.gov/NCT02889978