Error-corrected flow-based sequencing at whole-genome scale and its application to circulating cell-free DNA profiling Journal Article
| Authors: | Cheng, A. P.; Widman, A. J.; Arora, A.; Rusinek, I.; Sossin, A.; Rajagopalan, S.; Midler, N.; Hooper, W. F.; Murray, R. M.; Halmos, D.; Langanay, T.; Chu, H.; Inghirami, G.; Potenski, C.; Germer, S.; Marton, M.; Manaa, D.; Helland, A.; Furatero, R.; McClintock, J.; Winterkorn, L.; Steinsnyder, Z.; Wang, Y.; Alimohamed, A. I.; Malbari, M. S.; Saxena, A.; Callahan, M. K.; Frederick, D. T.; Spain, L.; Sigouros, M.; Manohar, J.; King, A.; Wilkes, D.; Otilano, J.; Elemento, O.; Mosquera, J. M.; Jaimovich, A.; Lipson, D.; Turajlic, S.; Zody, M. C.; Altorki, N. K.; Wolchok, J. D.; Postow, M. A.; Robine, N.; Faltas, B. M.; Boland, G.; Landau, D. A. |
| Article Title: | Error-corrected flow-based sequencing at whole-genome scale and its application to circulating cell-free DNA profiling |
| Abstract: | Differentiating sequencing errors from true variants is a central genomics challenge, calling for error suppression strategies that balance costs and sensitivity. For example, circulating cell-free DNA (ccfDNA) sequencing for cancer monitoring is limited by sparsity of circulating tumor DNA, abundance of genomic material in samples and preanalytical error rates. Whole-genome sequencing (WGS) can overcome the low abundance of ccfDNA by integrating signals across the mutation landscape, but higher costs limit its wide adoption. Here, we applied deep (~120×) lower-cost WGS (Ultima Genomics) for tumor-informed circulating tumor DNA detection within the part-per-million range. We further leveraged lower-cost sequencing by developing duplex error-corrected WGS of ccfDNA, achieving 7.7 × 10−7 error rates, allowing us to assess disease burden in individuals with melanoma and urothelial cancer without matched tumor sequencing. This error-corrected WGS approach will have broad applicability across genomics, allowing for accurate calling of low-abundance variants at efficient cost and enabling deeper mapping of somatic mosaicism as an emerging central aspect of aging and disease. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025. |
| Keywords: | genetics; mutation; melanoma; blood; genomics; sequence analysis, dna; procedures; high throughput sequencing; high-throughput nucleotide sequencing; dna sequencing; humans; human; whole genome sequencing; circulating tumor dna; cell-free nucleic acids; cell free nucleic acid |
| Journal Title: | Nature Methods |
| Volume: | 22 |
| Issue: | 5 |
| ISSN: | 1548-7091 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-05-01 |
| Start Page: | 973 |
| End Page: | 981 |
| Language: | English |
| DOI: | 10.1038/s41592-025-02648-9 |
| PUBMED: | 40217113 |
| PROVIDER: | scopus |
| PMCID: | PMC12077166 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF -- Source: Scopus |
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