Circulating tumor-derived DNA is shorter than somatic DNA in plasma.

Circulating tumor DNA (ctDNA) is now widely investigated as a biomarker in translational and clinical research (1). However, despite the growing field of clinical applications, the biology of ctDNA remains unclear. In trying to learn about the origins of ctDNA, nature provides us with very few clues. One of the important accessible parameters is the size of those DNA fragments. In addition, a well-informed model of these sizes and biases can help design more efficient and accurate diagnostic methods. In PNAS, Jiang et al. take an important step in that direction (2). Previous efforts to characterize the size distribution of ctDNA were conducted with a variety of methods, and in different cancer types and stages, yielding contradictory evidence (3, 4). Such observations were hindered by technological limitations that only enabled assessment of limited fragment sizes and loci, or by methods that could not effectively differentiate germ-line DNA from DNA of tumor origin. Jiang et al.’s (2) work, directed by Dennis Lo, focuses on those limitations and proposes a novel design that makes use of next-generation sequencing and recurrent chromosomal aneuploidies frequently found in hepatocellular carcinoma (HCC) (2).