Circulating cell-free methylated DNA reveals tissue-specific, cellular damage from radiation treatment
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 huma...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-07-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.156529 |
| _version_ | 1827767926749396992 |
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| author | Megan E. McNamara Netanel Loyfer Amber J. Kiliti Marcel O. Schmidt Sapir Shabi-Porat Sidharth S. Jain Sarah Martinez Roth A. Patrick McDeed IV Nesreen Shahrour Elizabeth Ballew Yun-Tien Lin Heng-Hong Li Anne Deslattes Mays Sonali Rudra Anna T. Riegel Keith Unger Tommy Kaplan Anton Wellstein |
| author_facet | Megan E. McNamara Netanel Loyfer Amber J. Kiliti Marcel O. Schmidt Sapir Shabi-Porat Sidharth S. Jain Sarah Martinez Roth A. Patrick McDeed IV Nesreen Shahrour Elizabeth Ballew Yun-Tien Lin Heng-Hong Li Anne Deslattes Mays Sonali Rudra Anna T. Riegel Keith Unger Tommy Kaplan Anton Wellstein |
| author_sort | Megan E. McNamara |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:05:18Z |
| format | Article |
| id | doaj.art-0eb9bcb8aa8b40a4ba4c47c4e39aa949 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:05:18Z |
| publishDate | 2023-07-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-0eb9bcb8aa8b40a4ba4c47c4e39aa9492023-11-07T16:25:54ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-07-01814Circulating cell-free methylated DNA reveals tissue-specific, cellular damage from radiation treatmentMegan E. McNamaraNetanel LoyferAmber J. KilitiMarcel O. SchmidtSapir Shabi-PoratSidharth S. JainSarah Martinez RothA. Patrick McDeed IVNesreen ShahrourElizabeth BallewYun-Tien LinHeng-Hong LiAnne Deslattes MaysSonali RudraAnna T. RiegelKeith UngerTommy KaplanAnton WellsteinRadiation 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.https://doi.org/10.1172/jci.insight.156529GeneticsOncology |
| spellingShingle | Megan E. McNamara Netanel Loyfer Amber J. Kiliti Marcel O. Schmidt Sapir Shabi-Porat Sidharth S. Jain Sarah Martinez Roth A. Patrick McDeed IV Nesreen Shahrour Elizabeth Ballew Yun-Tien Lin Heng-Hong Li Anne Deslattes Mays Sonali Rudra Anna T. Riegel Keith Unger Tommy Kaplan Anton Wellstein Circulating cell-free methylated DNA reveals tissue-specific, cellular damage from radiation treatment JCI Insight Genetics Oncology |
| title | Circulating cell-free methylated DNA reveals tissue-specific, cellular damage from radiation treatment |
| title_full | Circulating cell-free methylated DNA reveals tissue-specific, cellular damage from radiation treatment |
| title_fullStr | Circulating cell-free methylated DNA reveals tissue-specific, cellular damage from radiation treatment |
| title_full_unstemmed | Circulating cell-free methylated DNA reveals tissue-specific, cellular damage from radiation treatment |
| title_short | Circulating cell-free methylated DNA reveals tissue-specific, cellular damage from radiation treatment |
| title_sort | circulating cell free methylated dna reveals tissue specific cellular damage from radiation treatment |
| topic | Genetics Oncology |
| url | https://doi.org/10.1172/jci.insight.156529 |
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