High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants
Menée à partir d'échantillons sanguins et d'échantillons tumoraux prélevés sur 124 patients atteints d'un cancer métastatique du sein, du poumon ou de la prostate et menée sur 47 témoins, cette étude analyse la possibilité technique d'un test de séquençage pour détecter des mutations dans l'ADN libre circulant et identifier leur source
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.
Nature Medicine , résumé, 2019