A Novel Tissue-Free Method to Estimate Tumor-Derived Cell-Free DNA Quantity Using Tumor Methylation Patterns

Estimating the abundance of cell-free DNA (cfDNA) fragments shed from a tumor (i.e., circulating tumor DNA (ctDNA)) can approximate tumor burden, which has numerous clinical applications. We derived a novel, broadly applicable statistical method to quantify cancer-indicative methylation patterns wit...

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Bibliographic Details
Published in:Cancers 2023-12, Vol.16 (1), p.82
Main Authors: Melton, Collin A, Freese, Peter, Zhou, Yifan, Shenoy, Archana, Bagaria, Siddhartha, Chang, Christopher, Kuo, Chih-Chung, Scott, Eric, Srinivasan, Subashini, Cann, Gordon, Roychowdhury-Saha, Manami, Chang, Pei-Yun, Singh, Amoolya H
Format: Article
Language:English
Subjects:
Alleles
Biopsy
Biotechnology industry
Blood
Cancer
Cancer screening
Cancer therapies
Care and treatment
Data processing
Diagnosis
DNA
DNA methylation
Genetic aspects
Genetic research
Genomes
Invasiveness
Leukemia
Lymphoma
Metabolism
Methods
Methylation
Oncology, Experimental
Plasma
Prognosis
Statistical analysis
Tumor cells
Tumors
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Summary:Estimating the abundance of cell-free DNA (cfDNA) fragments shed from a tumor (i.e., circulating tumor DNA (ctDNA)) can approximate tumor burden, which has numerous clinical applications. We derived a novel, broadly applicable statistical method to quantify cancer-indicative methylation patterns within cfDNA to estimate ctDNA abundance, even at low levels. Our algorithm identified differentially methylated regions (DMRs) between a reference database of cancer tissue biopsy samples and cfDNA from individuals without cancer. Then, without utilizing matched tissue biopsy, counts of fragments matching the cancer-indicative hyper/hypo-methylated patterns within DMRs were used to determine a tumor methylated fraction (TMeF; a methylation-based quantification of the circulating tumor allele fraction and estimate of ctDNA abundance) for plasma samples. TMeF and small variant allele fraction (SVAF) estimates of the same cancer plasma samples were correlated (Spearman's correlation coefficient: 0.73), and synthetic dilutions to expected TMeF of 10 and 10 had estimated TMeF within two-fold for 95% and 77% of samples, respectively. TMeF increased with cancer stage and tumor size and inversely correlated with survival probability. Therefore, tumor-derived fragments in the cfDNA of patients with cancer can be leveraged to estimate ctDNA abundance without the need for a tumor biopsy, which may provide non-invasive clinical approximations of tumor burden.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers16010082