Cell-free, methylated DNA in blood samples reveals tissue-specific, cellular damage from radiation treatment

Barefoot, M. E.; Loyfer, N.; Kiliti, A. J.; Schmidt, M. O.; Shabi-Porat, S.; Jain, S.; Roth, S. M.; McDeed, A. P.; Shahrour, N.; Ballew, E.; Lin, Y.-T.; Li, H.-H.; Mays, A. D.; Rudra, S.; Riegel, A. T.; Unger, K.; Kaplan, T.; Wellstein, A.

doi:10.1101/2022.04.12.487966

bioRxiv · 10.1101/2022.04.12.487966

Cell-free, methylated DNA in blood samples reveals tissue-specific, cellular damage from radiation treatment

Barefoot, M. E.·Loyfer, N.·Kiliti, A. J.·Schmidt, M. O.·Shabi-Porat, S.·Jain, S.·Roth, S. M.·McDeed, A. P.·Shahrour, N.·Ballew, E.·Lin, Y.-T.·Li, H.-H.·Mays, A. D.·Rudra, S.·Riegel, A. T.·Unger, K.·Kaplan, T.·Wellstein, A.

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Abstract

Radiation therapy is an effective cancer treatment although damage to healthy tissues is common. Here we characterize the methylomes of healthy human and mouse tissues to establish sequencing-based, cell-type specific reference DNA methylation atlases. Identified cell-type specific DNA blocks were mostly hypomethylated and located within genes intrinsic to cellular identity. Cell-free DNA fragments released from dying cells into the circulation were captured from serum samples by hybridization to CpG-rich DNA panels. The origins of the circulating DNA fragments were inferred from mapping to the established DNA methylation atlases. Thoracic radiation-induced tissue damages in a mouse model were reflected by dose-dependent increases in lung endothelial, cardiomyocyte and hepatocyte methylated DNA in serum. The analysis of serum samples from breast cancer patients undergoing radiation treatment revealed distinct 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 quantitative measure of the biologically effective radiation dose received by healthy tissues. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/487966v3_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@129f229org.highwire.dtl.DTLVardef@d999bcorg.highwire.dtl.DTLVardef@1fc3543org.highwire.dtl.DTLVardef@10cebc2_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Barefoot, M. E., Loyfer, N., Kiliti, A. J., Schmidt, M. O., Shabi-Porat, S., Jain, S., Roth, S. M., McDeed, A. P., Shahrour, N., Ballew, E., Lin, Y.-T., Li, H.-H., Mays, A. D., Rudra, S., Riegel, A. T., Unger, K., Kaplan, T., Wellstein, A.. 2022-04-13. Cell-free, methylated DNA in blood samples reveals tissue-specific, cellular damage from radiation treatment. https://doi.org/10.1101/2022.04.12.487966

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