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

Area of Science:

• Molecular Biology
• Genomics
• Cancer Research

Background:

• Circulating tumor DNA (ctDNA) profiling offers a non-invasive method for monitoring cancer progression.
• Accurate quantification of ctDNA is crucial for effective disease management.
• Current methods often rely on detecting specific genomic alterations, limiting their applicability.

Purpose of the Study:

• To develop a novel quantitative method for estimating ctDNA burden.
• To achieve ctDNA quantification independent of specific genomic aberrations.
• To enable low-cost, non-invasive monitoring of cancer progression.

Main Methods:

• Developed a quantitative model based on local, tissue-specific cell-free DNA (cfDNA) degradation patterns.
• Exploited nucleosome-dependent cfDNA degradation at promoter and exon-intron regions.
• Utilized compact targeted sequencing (<25 kb) of 6 predictive regulatory regions.

Main Results:

• The model accurately predicted ctDNA levels in colorectal cancer patients using only 6 regulatory regions.
• A model restricted to blood-specific regulatory regions accurately predicted ctDNA levels in both colorectal and breast cancer patients.
• Demonstrated the potential for quantitative, low-cost tracking of ctDNA dynamics.

Conclusions:

• Tissue-specific cfDNA degradation patterns provide a robust basis for ctDNA quantification.
• This approach enables accurate, aberration-independent ctDNA monitoring across different cancer types.
• The method facilitates cost-effective, non-invasive tracking of ctDNA dynamics and disease progression.