Circulating cell-free DNA fragmentation is a stepwise and conserved process linked to apoptosis

• Published in: BMC biology Vol. 21; no. 1; p. 253
• Main Authors: Zhu, Dandan, Wang, Haihong, Wu, Wei, Geng, Shuaipeng, Zhong, Guolin, Li, Yunfei, Guo, Han, Long, Guanghui, Ren, Qingqi, Luan, Yi, Duan, Chaohui, Wei, Bing, Ma, Jie, Li, Shiyong, Zhou, Jun, Mao, Mao
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 13.11.2023; BioMed Central; BMC
• Subjects: Analysis; Animals; Apoptosis; Cancer; Cell-Free Nucleic Acids; Cells; Circulating cell-free DNA; Deoxyribonucleic acid; Development and progression; Diagnosis; DNA; DNA Fragmentation; DNA sequencing; Dogs; End preference; Ethylenediaminetetraacetic acid; Fragmentation; Fragments; Gene sequencing; Genetic aspects; Genomes; Genomics; Health aspects; Hematopoietic stem cells; Humans; Leukemia; Mammals; Neoplasms; Nucleotide sequencing; Oncology, Experimental; Physiological aspects; Plasma; Shallow whole-genome sequencing; Size distribution; Size profiling of cfDNA; Whole genome sequencing; China; Germany; South Korea; Circulating cell-free DNA; End preference; Shallow whole-genome sequencing; Size profiling of cfDNA
• ISSN: 1741-7007; 1741-7007
• DOI: 10.1186/s12915-023-01752-6

Circulating cell-free DNA (cfDNA) is a pool of short DNA fragments mainly released from apoptotic hematopoietic cells. Nevertheless, the precise physiological process governing the DNA fragmentation and molecular profile of cfDNA remains obscure. To dissect the DNA fragmentation process, we use a human leukemia cell line HL60 undergoing apoptosis to analyze the size distribution of DNA fragments by shallow whole-genome sequencing (sWGS). Meanwhile, we also scrutinize the size profile of plasma cfDNA in 901 healthy human subjects and 38 dogs, as well as 438 patients with six common cancer types by sWGS. Distinct size distribution profiles were observed in the HL60 cell pellet and supernatant, suggesting fragmentation is a stepwise process. Meanwhile, C-end preference was seen in both intracellular and extracellular cfDNA fragments. Moreover, the cfDNA profiles are characteristic and conserved across mammals. Compared with healthy subjects, distinct cfDNA profiles with a higher proportion of short fragments and lower C-end preference were found in cancer patients. Our study provides new insight into fragmentomics of circulating cfDNA processing, which will be useful for early diagnosis of cancer and surveillance during cancer progression.