Tissue-specific cell-free DNA degradation quantifies circulating tumor DNA burden
Guanhua Zhu, Yu Amanda 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 Beehuat Tan, Sarah Ng, Anders J. Skanderup
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 (<25 kb) of predictive regions, we demonstrate how the approach could enable quantitative low-cost tracking of ctDNA dynamics and disease progression.