Tissue-specific cell-free DNA degradation quantifies circulating tumor DNA burden

Guanhua Zhu, Yu A. Guo, Danliang Ho, Polly Poon, Zhong Wee Poh, Pui Mun Wong, Anna Gan, Mei Mei Chang, Dimitrios Kleftogiannis, Yi Ting Lau, Brenda Tay, Wan Jun Lim, Clarinda Chua, Tira J. Tan, Si-Lin Koo, Dawn Q. Chong, Yoon Sim Yap, Iain Tan (), Sarah Ng () and Anders J. Skanderup ()
Additional contact information
Guanhua Zhu: Genome Institute of Singapore (GIS), A*STAR
Yu A. Guo: Genome Institute of Singapore (GIS), A*STAR
Danliang Ho: Genome Institute of Singapore (GIS), A*STAR
Polly Poon: Genome Institute of Singapore (GIS), A*STAR
Zhong Wee Poh: Genome Institute of Singapore (GIS), A*STAR
Pui Mun Wong: Genome Institute of Singapore (GIS), A*STAR
Anna Gan: Genome Institute of Singapore (GIS), A*STAR
Mei Mei Chang: Genome Institute of Singapore (GIS), A*STAR
Dimitrios Kleftogiannis: Genome Institute of Singapore (GIS), A*STAR
Yi Ting Lau: Genome Institute of Singapore (GIS), A*STAR
Brenda Tay: National Cancer Center Singapore
Wan Jun Lim: National Cancer Center Singapore
Clarinda Chua: National Cancer Center Singapore
Tira J. Tan: National Cancer Center Singapore
Si-Lin Koo: National Cancer Center Singapore
Dawn Q. Chong: National Cancer Center Singapore
Yoon Sim Yap: National Cancer Center Singapore
Iain Tan: Genome Institute of Singapore (GIS), A*STAR
Sarah Ng: Genome Institute of Singapore (GIS), A*STAR
Anders J. Skanderup: Genome Institute of Singapore (GIS), A*STAR

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Profiling of circulating tumor DNA (ctDNA) may offer a non-invasive approach to monitor disease progression. Here, we develop a quantitative method, exploiting local tissue-specific cell-free DNA (cfDNA) degradation patterns, that accurately estimates ctDNA burden independent of genomic aberrations. Nucleosome-dependent cfDNA degradation at promoters and first exon-intron junctions is strongly associated with differential transcriptional activity in tumors and blood. A quantitative model, based on just 6 regulatory regions, could accurately predict ctDNA levels in colorectal cancer patients. Strikingly, a model restricted to blood-specific regulatory regions could predict ctDNA levels across both colorectal and breast cancer patients. Using compact targeted sequencing (

Date: 2021
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DOI: 10.1038/s41467-021-22463-y

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