Ultra-Deep cfDNA Sequencing Reveals Clonal Haematopoiesis as the Dominant Source of Plasma Mutations
Using high-intensity sequencing at over 60,000x raw depth across 508 genes, this study found that 81.6% of cfDNA mutations in cancer-free controls and 53.2% in cancer patients were attributable to clonal haematopoiesis rather than tumour origin. The approach enabled de novo detection of tumour mutations and inference of tumour mutational burden, microsatellite instability and mutational signatures from plasma. The findings demonstrate that matched cfDNA-white blood cell sequencing is essential for accurate variant interpretation in clinical liquid biopsy.
The original study
High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants.
- Authors
- Razavi P, Li BT, Brown DN, Jung B, Hubbell E, Shen R, et al.
- Journal
- Nature medicine
- Type
- Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.
- PMID
- 31768066
Original abstract
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.