High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants

A prospective study of 124 patients with metastatic cancer and contemporaneous tumour biopsies, and 47 controls without cancer, sequenced plasma cell-free DNA and matched white blood cell DNA across 508 genes and 2 megabases at more than 60,000-fold raw depth. The assay allowed de novo detection of tumour mutations and inference of tumour mutational burden, microsatellite instability and mutational signatures from plasma.

The vast majority of cell-free DNA mutations, 81.6 per cent in controls and 53.2 per cent in patients with cancer, had features consistent with clonal haematopoiesis. The authors concluded that clonal haematopoiesis is pervasive and that matched plasma and white blood cell sequencing is important for accurate interpretation.