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Severus detects somatic structural variation and complex rearrangements in cancer genomes using long-read sequencing

  1. Author:
    Keskus, Ayse G [ORCID]
    Bryant, Asher [ORCID]
    Ahmad, Tanveer
    Yoo, Byunggil
    Aganezov, Sergey
    Goretsky, Anton [ORCID]
    Donmez, Ataberk
    Lansdon, Lisa A
    Rodriguez, Isabel
    Park, Jimin
    Liu, Yuelin
    Cui, Xiwen
    Gardner, Joshua
    McNulty, Brandy
    Sacco, Samuel
    Shetty,Jyoti
    Zhao,Yongmei [ORCID]
    Tran,Bao
    Narzisi, Giuseppe [ORCID]
    Helland, Adrienne
    Cook, Daniel E
    Chang, Pi-Chuan [ORCID]
    Kolesnikov, Alexey
    Carroll, Andrew [ORCID]
    Molloy, Erin K
    Bi, Chengpeng
    Walter, Adam
    Gibson, Margaret
    Pushel, Irina [ORCID]
    Guest, Erin
    Pastinen, Tomi [ORCID]
    Shafin, Kishwar [ORCID]
    Miga, Karen H [ORCID]
    Malikic, Salem [ORCID]
    Day, Chi-Ping [ORCID]
    Robine, Nicolas [ORCID]
    Sahinalp, Cenk [ORCID]
    Dean, Michael
    Farooqi, Midhat S
    Paten, Benedict [ORCID]
    Kolmogorov, Mikhail [ORCID]

  2. Author Address

    Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA., Children 39;s Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA., Oxford Nanopore Technologies, New York, NY, USA., Department of Computer Science, University of Maryland, College Park, MD, USA., Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA., University of California, Santa Cruz, Genomics Institute, Santa Cruz, CA, USA., Sequencing Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Sequencing Facility Bioinformatics Group, Biomedical Informatics and Data Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., New York Genome Center, New York, NY, USA., Google, Inc., Mountain View, CA, USA., Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA. mikhail.kolmogorov@nih.gov.,
    1. Year: 2025
    2. Date: Apr 04
    3. Epub Date: 2025 04 04
  2. Journal: Nature Biotechnology
  4. Type of Article: Article
  1. Abstract:

    For the detection of somatic structural variation (SV) in cancer genomes, long-read sequencing is advantageous over short-read sequencing with respect to mappability and variant phasing. However, most current long-read SV detection methods are not developed for the analysis of tumor genomes characterized by complex rearrangements and heterogeneity. Here, we present Severus, a breakpoint graph-based algorithm for somatic SV calling from long-read cancer sequencing. Severus works with matching normal samples, supports unbalanced cancer karyotypes, can characterize complex multibreak SV patterns and produces haplotype-specific calls. On a comprehensive multitechnology cell line panel, Severus consistently outperforms other long-read and short-read methods in terms of SV detection F1 score (harmonic mean of the precision and recall). We also illustrate that compared to long-read methods, short-read sequencing systematically misses certain classes of somatic SVs, such as insertions or clustered rearrangements. We apply Severus to several clinical cases of pediatric leukemia/lymphoma, revealing clinically relevant cryptic rearrangements missed by standard genomic panels. © 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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External Sources

  1. View Full Text
  2. DOI: 10.1038/s41587-025-02618-8
  3. PMID: 40185952
  4. PII : 10.1038/s41587-025-02618-8

Library Notes

  1. Fiscal Year: FY2024-2025
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