Clonal hematopoiesis: background player in plasma cell-free DNA variants

The presence of cell-free tumor-derived DNA (ctDNA) in plasma of cancer patients was first reported 30 years ago (1), which opens the door of blood-based analysis for cancer diagnosis and monitoring, or so-called cancer liquid biopsy. In recent years, with the development of high- throughput and high sensitive techniques, cancer liquid biopsy has gained much interest and is actively researched globally (2). As a genetic disease, one hallmark of cancer is acquired somatic mutations in the genome of tumor cells, which could be detected in plasma ctDNA. A variety of assays had been developed to screen and quantify the tumor-derived somatic mutations in plasma. For instance, assays that utilized high depth sequencing technology, either on the whole human genome or specific regions of interest using target capture approaches, had showed good sensitivity and accuracy in this task (3,4). However, parallel analysis of plasma DNA and matched tumor tissues had revealed that in cancer patients of various types, even though the somatic mutation profiles of these two materials showed remarkable concordance, they were not identical (4-6). Conventionally, the intratumor heterogeneity is proposed to be the major reason to this phenomenon (2,7). However, the tissue origin of the mysterious somatic mutations that are only found in the plasma still remains elusive.