Genome-wide mutational signatures in low-coverage whole genome sequencing of cell-free DNA Journal Article
| Authors: | Wan, J. C. M.; Stephens, D.; Luo, L.; White, J. R.; Stewart, C. M.; Rousseau, B.; Tsui, D. W. Y.; Diaz, L. A. Jr |
| Article Title: | Genome-wide mutational signatures in low-coverage whole genome sequencing of cell-free DNA |
| Abstract: | Mutational signatures accumulate in somatic cells as an admixture of endogenous and exogenous processes that occur during an individual’s lifetime. Since dividing cells release cell-free DNA (cfDNA) fragments into the circulation, we hypothesize that plasma cfDNA might reflect mutational signatures. Point mutations in plasma whole genome sequencing (WGS) are challenging to identify through conventional mutation calling due to low sequencing coverage and low mutant allele fractions. In this proof of concept study of plasma WGS at 0.3–1.5x coverage from 215 patients and 227 healthy individuals, we show that both pathological and physiological mutational signatures may be identified in plasma. By applying machine learning to mutation profiles, patients with stage I-IV cancer can be distinguished from healthy individuals with an Area Under the Curve of 0.96. Interrogating mutational processes in plasma may enable earlier cancer detection, and might enable the assessment of cancer risk and etiology. © 2022, The Author(s). |
| Keywords: | controlled study; gene mutation; major clinical study; single nucleotide polymorphism; genetics; mutation; area under the curve; cancer risk; cancer patient; pancreas cancer; cancer staging; neoplasm; neoplasms; colorectal cancer; allele; ovary cancer; breast cancer; cohort analysis; genome-wide association study; carcinogenesis; mismatch repair; microsatellite instability; gene identification; human genome; gene duplication; stomach cancer; cancer classification; point mutation; logistic regression analysis; multiple cancer; genome, human; machine learning; support vector machine; high throughput sequencing; high-throughput nucleotide sequencing; limit of quantitation; humans; human; article; whole genome sequencing; random forest; dna base composition; early cancer diagnosis; apolipoprotein b mrna editing enzyme catalytic polypeptide like; cell-free nucleic acids; tumor mutational burden; cell free nucleic acid; chloroplast dna; cross validation; circulating free dna |
| Journal Title: | Nature Communications |
| Volume: | 13 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-08-23 |
| Start Page: | 4953 |
| Language: | English |
| DOI: | 10.1038/s41467-022-32598-1 |
| PUBMED: | 35999207 |
| PROVIDER: | scopus |
| PMCID: | PMC9399180 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 October 2022 -- Source: Scopus |
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