High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants. Academic Article uri icon

Overview

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.

authors

  • Razavi, Pedram
  • Li, Bob
  • Brown, David N
  • Jung, Byoungsok
  • Hubbell, Earl
  • Shen, Ronglai
  • Abida, Wassim
  • Juluru, Krishna
  • De Bruijn, Ino
  • Hou, Chenlu
  • Venn, Oliver
  • Lim, Raymond
  • Anand, Aseem
  • Maddala, Tara
  • Gnerre, Sante
  • Vijaya Satya, Ravi
  • Liu, Qinwen
  • Shen, Ling
  • Eattock, Nicholas
  • Yue, Jeanne
  • Blocker, Alexander W
  • Lee, Mark
  • Sehnert, Amy
  • Xu, Hui
  • Hall, Megan P
  • Santiago-Zayas, Angie
  • Novotny, William F
  • Isbell, James M
  • Rusch, Valerie W
  • Plitas, George
  • Heerdt, Alexandra S
  • Ladanyi, Marc
  • Hyman, David M
  • Jones, David
  • Morrow, Monica
  • Riely, Gregory J
  • Scher, Howard I
  • Rudin, Charles
  • Robson, Mark E
  • Diaz, Luis A
  • Solit, David B
  • Aravanis, Alexander M
  • Reis-Filho, Jorge S

publication date

  • November 25, 2019

Research

keywords

  • Cell-Free Nucleic Acids
  • Circulating Tumor DNA
  • Genomics
  • Neoplasms

Identity

PubMed Central ID

  • PMC7061455

Scopus Document Identifier

  • 85075478257

Digital Object Identifier (DOI)

  • 10.1038/s41591-019-0652-7

PubMed ID

  • 31768066

Additional Document Info

volume

  • 25

issue

  • 12