The analysis of cfDNA in childhood cancers has focused primarily on tumor-specific genetic aberrations, including chromosomal translocations (fusion genes) and copy-number alternations (CNAs), using assays such as droplet digital PCR (ddPCR), targeted NGS panels, exome sequencing, and low-coverage whole-genome sequencing 17, 19, 20, 21, 22, 23, 24, 25, 26, 27. In pediatric tumors, high levels of tumor-derived DNA in blood have been linked to poor clinical outcome 17, and initial studies illustrate the value of liquid biopsy analysis for disease monitoring 18, 19. As a consequence, cfDNA analysis holds great promise for precision oncology and personalized therapies, and is currently evaluated in a broad range of clinical studies 15, 16. In cancer patients, cfDNA consists in part of cancer-derived circulating tumor DNA (ctDNA), and it has been shown that tumor-related genetic and epigenetic alterations can be detected by analyzing cfDNA in cancer patients 6, 7, 8, 9, 10, 11, 12, 13, 14. Sample collection is quick and minimally invasive, thus allowing longitudinal analysis with high temporal resolution. Liquid biopsy analysis of circulating cell-free DNA (cfDNA) from peripheral blood has emerged as a valuable diagnostic tool in oncology 1, 2, 3, 4, 5. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates.
Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations.
To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. Nature Communications volume 12, Article number: 3230 ( 2021) Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden
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