Analysis of error profiles of indels and structural variants in deep-sequencing data
Despite extensive studies of the error profiles of SNVs, those of insertions/deletions (indels)/structural variants (SVs) remain elusive. Using ultra-deep sequencing, we show that the error rates of indel/SVs are >100-fold lower than those of SNVs, although repeat indels have high error rates of 1%. We validated this pattern in a cohort of 103 patients with relapsed B cell acute lymphoblastic leukemia (B-ALL). We analyzed repeat indels in 339 cancer driver genes and demonstrated that the number of repeat units is highly predictive of the error rate. We then analyzed minimal residual disease samples from 72 patients with relapsed B-ALL and demonstrated that our approach had positive detections in 61% of cases, outperforming clinical flow cytometry (51% detection). Overall, we established indel and SV error profiles in deep next-generation sequencing (NGS) data, enabling superior tumor detection at very low burdens, which has a significant impact on the clinical diagnosis and monitoring of human cancers and other diseases.
Authors
- Patrick A. Brown
- Mignon L. Loh (ORCID: https://orcid.org/0000-0003-4099-4700)
- Lingyun Ji (ORCID: https://orcid.org/0000-0003-2500-1993)
- Quang Tran (ORCID: https://orcid.org/0000-0002-9263-0733)
- John Easton (ORCID: https://orcid.org/0000-0003-4503-6608)
- Jeffery M. Klco (ORCID: https://orcid.org/0000-0003-2961-6960)
- Heather L. Mulder (ORCID: https://orcid.org/0000-0003-2024-9498)
- Ying Shao (ORCID: https://orcid.org/0000-0002-0390-3315)
- Benjamin J. Huang (ORCID: https://orcid.org/0000-0001-6996-0833)
- Tyler R. Jones (ORCID: https://orcid.org/0000-0003-1871-2105)
- William L. Carroll (ORCID: https://orcid.org/0000-0003-1550-4167)
- Pandurang Kolekar (ORCID: https://orcid.org/0000-0003-0044-0076)
- Andrea McBride
- Soheil Meshinchi
- Yanling Liu (ORCID: https://orcid.org/0000-0002-2027-6464)
- Fan Li (ORCID: https://orcid.org/0000-0003-3084-5912)
- Zhikai Liang (ORCID: https://orcid.org/0000-0002-9963-8631)
- Yuan Feng
- Xiaotu Ma (ORCID: https://orcid.org/0000-0002-6233-2145)
- Jinghui Zhang (ORCID: https://orcid.org/0000-0003-1630-6250)
- Alexis Cameron
Institutions
- University of Southern California (US)
- St. Jude Children's Research Hospital (US)
- Nationwide Children's Hospital (US)
- Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA)
- University of California, San Francisco (US)
- Fred Hutch Cancer Center (US)
- Seattle Children's Hospital (US)
- Center for Cancer and Blood Disorders (US)
- Cambridge Collaborative (United States) (US)
Publication Details
- Journal
- Cell Genomics
- Published
- 2025-12-02
- DOI
- https://doi.org/10.1016/j.xgen.2025.101082
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Leukemia and Lymphoma Society
- American Lebanese Syrian Associated Charities
- National Institutes of Health
- National Cancer Institute