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

## TL;DR

This paper introduces a new method to estimate cancer DNA in the blood using patterns of DNA degradation, enabling non-invasive tracking of cancer progression.

## Contribution

A novel quantitative model using tissue-specific cfDNA degradation patterns to estimate ctDNA burden without relying on genomic mutations.

## Key findings

- Nucleosome-dependent cfDNA degradation at six regulatory regions accurately predicts ctDNA levels in colorectal cancer patients.
- A model using blood-specific regulatory regions can predict ctDNA levels across both colorectal and breast cancer patients.
- Targeted sequencing of predictive regions enables low-cost tracking of ctDNA dynamics.

## 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.

Circulating tumour DNA (ctDNA) represents a non-invasive option to monitor cancer progression. Here, the authors perform deep sequencing of plasma cell-free DNA, and find that nucleosome-dependent cfDNA degradation at 6 specific regulatory regions is predictive of ctDNA burden.