Circulating cell-free methylated DNA reveals tissue-specific, cellular damage from radiation treatment

Megan E. McNamara, Netanel Loyfer, Amber J. Kiliti, Marcel O. Schmidt, Sapir Shabi-Porat, Sidharth S. Jain, Sarah Martinez Roth, A. Patrick McDeed, Nesreen Shahrour, Elizabeth Ballew, Yun Tien Lin, Heng Hong Li, Anne Deslattes Mays, Sonali Rudra, Anna T. Riegel, Keith Unger, Tommy Kaplan, Anton Wellstein

Research output: Contribution to journalArticlepeer-review


Radiation therapy is an effective cancer treatment, although damage to healthy tissues is common. Here we analyzed cell-free, methylated DNA released from dying cells into the circulation to evaluate radiation-induced cellular damage in different tissues. To map the circulating DNA fragments to human and mouse tissues, we established sequencing-based, cell-type-specific reference DNA methylation atlases. We found that cell-type-specific DNA blocks were mostly hypomethylated and located within signature genes of cellular identity. Cell-free DNA fragments were captured from serum samples by hybridization to CpG-rich DNA panels and mapped to the DNA methylation atlases. In a mouse model, thoracic radiation-induced tissue damage was reflected by dose-dependent increases in lung endothelial and cardiomyocyte methylated DNA in serum. The analysis of serum samples from patients with breast cancer undergoing radiation treatment revealed distinct dose-dependent and tissue-specific epithelial and endothelial responses to radiation across multiple organs. Strikingly, patients treated for right-sided breast cancers also showed increased hepatocyte and liver endothelial DNA in the circulation, indicating the impact on liver tissues. Thus, changes in cell-free methylated DNA can uncover cell-type-specific effects of radiation and provide a readout of the biologically effective radiation dose received by healthy tissues.

Original languageAmerican English
JournalJCI insight
Issue number14
StatePublished - 24 Jul 2023


  • Breast cancer
  • Epigenetics
  • Genetics
  • Oncology
  • Radiation therapy


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