Severus: accurate detection and characterization of somatic structural variation in tumor genomes using long reads.
| Title: | Severus: accurate detection and characterization of somatic structural variation in tumor genomes using long reads. |
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| Authors: | Keskus A; Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.; Bryant A; Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.; Ahmad T; Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.; Yoo B; Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.; Aganezov S; Oxford Nanopore Technologies, NY, USA.; Goretsky A; Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.; Department of Computer Science, University of Maryland, College Park, MD, USA.; Donmez A; Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.; Department of Computer Science, University of Maryland, College Park, MD, USA.; Lansdon LA; Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.; Rodriguez I; Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA.; Park J; UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA.; Liu Y; Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.; Department of Computer Science, University of Maryland, College Park, MD, USA.; Cui X; Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.; Gardner J; UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA.; McNulty B; UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA.; Sacco S; UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA.; Shetty J; Sequencing Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.; Zhao Y; Sequencing Facility Bioinformatics Group, Biomedical Informatics and Data Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.; Tran B; Sequencing Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.; Narzisi G; New York Genome Center, NY, USA.; Helland A; New York Genome Center, NY, USA.; Cook DE; Google Inc, Mountain View, CA, USA.; Chang PC; Google Inc, Mountain View, CA, USA.; Kolesnikov A; Google Inc, Mountain View, CA, USA.; Carroll A; Google Inc, Mountain View, CA, USA.; Molloy EK; Department of Computer Science, University of Maryland, College Park, MD, USA.; Pushel I; Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.; Guest E; Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.; Pastinen T; Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.; Shafin K; Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA.; Miga KH; UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA.; Malikic S; Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.; Day CP; Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.; Robine N; New York Genome Center, NY, USA.; Sahinalp C; Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.; Dean M; Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA.; Farooqi MS; Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.; Paten B; UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA.; Kolmogorov M; Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA. |
| Source: | MedRxiv : the preprint server for health sciences [medRxiv] 2024 Mar 26. Date of Electronic Publication: 2024 Mar 26. |
| Publication Type: | Preprint; Journal Article |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101767986 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: medRxiv Subsets: PubMed not MEDLINE |
| Abstract: | Most current studies rely on short-read sequencing to detect somatic structural variation (SV) in cancer genomes. Long-read sequencing offers the advantage of better mappability and long-range phasing, which results in substantial improvements in germline SV detection. However, current long-read SV detection methods do not generalize well to the analysis of somatic SVs in tumor genomes with complex rearrangements, heterogeneity, and aneuploidy. Here, we present Severus: a method for the accurate detection of different types of somatic SVs using a phased breakpoint graph approach. To benchmark various short- and long-read SV detection methods, we sequenced five tumor/normal cell line pairs with Illumina, Nanopore, and PacBio sequencing platforms; on this benchmark Severus showed the highest F1 scores (harmonic mean of the precision and recall) as compared to long-read and short-read methods. We then applied Severus to three clinical cases of pediatric cancer, demonstrating concordance with known genetic findings as well as revealing clinically relevant cryptic rearrangements missed by standard genomic panels. |
| Competing Interests: | Competing interests. S.A. is an employee and stockholder of Oxford Nanopore Technologies. A.K., P.C., K.S., D.C., A.C. are employees of Google LLC and own Alphabet stock as part of the standard compensation package. E.G. served on advisory boards for Jazz Pharmaceuticals and Syndax Pharmaceuticals. M.S.F. is part of the speakers bureau for Bayer and PacBio. The remaining authors declare no competing interests. |
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| Grant Information: | U41 HG010972 United States HG NHGRI NIH HHS; U01 CA253405 United States CA NCI NIH HHS; OT2 OD033761 United States OD NIH HHS; U24 HG010262 United States HG NHGRI NIH HHS; R01 HG010485 United States HG NHGRI NIH HHS; U24 HG011853 United States HG NHGRI NIH HHS; U01 HG013748 United States HG NHGRI NIH HHS |
| Entry Date(s): | Date Created: 20240408 Latest Revision: 20241207 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10996739 |
| DOI: | 10.1101/2024.03.22.24304756 |
| PMID: | 38585974 |
| Database: | MEDLINE |
Preprint; Journal Article