High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants
By P. Razavi, Bob T. Li, David N. Brown, B. Jung, Earl Hubbell, Ronglai Shen, W. Abida, K. Juluru, Ino de Bruijn, C. Hou and 33 more. Nature Medicine, 2019
647 citations recorded by the source corpus.
Accurate identification of tumor-derived somatic variants in plasma circulating cell-free DNA (cfDNA) requires understanding of the various biological compartments contributing to the cfDNA pool. We sought to define the technical feasibility of a high-intensity sequencing assay of cfDNA and matched white blood cell DNA covering a large genomic region (508 genes; 2 megabases; >60,000× raw depth) in a prospective study of 124 patients with metastatic cancer, with contemporaneous matched tumor tissue biopsies, and 47 controls without cancer. The assay displayed high sensitivity and specificity, allowing for de novo detection of tumor-derived mutations and inference of tumor mutational burden, microsatellite instability, mutational signatures and sources of somatic mutations identified in cfDNA. The vast majority of cfDNA mutations (81.6% in controls and 53.2% in patients with cancer) had features consistent with clonal hematopoiesis. This cfDNA sequencing approach revealed that clonal hematopoiesis constitutes a pervasive biological phenomenon, emphasizing the importance of matched cfDNA–white blood cell sequencing for accurate variant interpretation. Ultra-sensitive cell-free DNA (cfDNA) sequencing uncovers clonal hematopoiesis as a major source of somatic cfDNA variants in healthy individuals and patients with cancer, and underscores the importance of matched white blood cell DNA sequencing in liquid biopsy procedures.
Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/2bfbaad4c6896aa9fd71afc7bad80485a00cc4de
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Citations in the corpus
- Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA (2020, neutral): “tumor types or treatment options(12) may be hampered by confounding signals from white blood cells (WBCs) or other tissue.(13,14) Similarly, approaches based on detecting somatic copy number alterations may be limited by smaller relative differences between cases and controls resulting in a need for”
- ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. (2022, background): “6,37 It is not possible to use allele fraction alone to differentiate CHIP from ctDNA, as true-positive tumour-derived variants are often of low allele fraction.”