Refined detection and phasing of structural aberrations in pediatric acute lymphoblastic leukemia by linked-read whole genome sequencing
Refined detection and phasing of structural aberrations in pediatric acute lymphoblastic leukemia by linked-read whole genome sequencing
ABSTRACT Structural chromosomal rearrangements that may lead to in-frame gene-fusions represent a leading source of information for diagnosis, risk stratification, and prognosis in pediatric acute lymphoblastic leukemia (ALL). However, short-read whole genome sequencing (WGS) technologies struggle to accurately identify and phase such large-scale chromosomal aberrations in cancer genomes. We therefore evaluated linked-read WGS for detection of chromosomal rearrangements in an ALL cell line (REH) and primary samples of varying DNA quality from 12 patients diagnosed with ALL. We assessed the effect of input DNA quality on phased haplotype block size and the detectability of copy number aberrations (CNAs) and structural variants (SVs). Biobanked DNA isolated by standard column-based extraction methods was sufficient to detect chromosomal rearrangements even at low 10x sequencing coverage. Linked-read WGS enabled precise, allele-specific, digital karyotyping at a base-pair resolution for a wide range of structural variants including complex rearrangements and aneuploidy assessment. With use of haplotype information from the linked-reads, we also identified additional structural variants, such as a compound heterozygous deletion of ERG in a patient with the DUX4-IGH fusion gene. Thus, linked-read WGS allows detection of important pathogenic variants in ALL genomes at a resolution beyond that of traditional karyotyping or short-read WGS.
L?nnerholm Gudmar、Nordlund Jessica、Marincevic-Zuniga Yanara、Raine Amanda、Martin Tom、Lundmark Anders、Abrahamsson Jonas、Syv?nen Ann-Christine、Nor¨|n-Nystr?m Ulrika、Cavelier Lucia
Department of Women?ˉs and Children?ˉs Health, Pediatric Oncology, Uppsala UniversityDepartment of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala UniversityDepartment of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala UniversityDepartment of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala UniversityDepartment of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala UniversityDepartment of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala UniversityDepartment of Pediatrics, Institution for Clinical Sciences, Sahlgrenska Academy, Gothenburg UniversityDepartment of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala UniversityDepartment of Clinical Sciences and Pediatrics, University of Ume?Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University
医学研究方法肿瘤学遗传学
Childhood acute lymphoblastic leukemianext generation sequencinglinked-read WGSfusion genestructural variants
L?nnerholm Gudmar,Nordlund Jessica,Marincevic-Zuniga Yanara,Raine Amanda,Martin Tom,Lundmark Anders,Abrahamsson Jonas,Syv?nen Ann-Christine,Nor¨|n-Nystr?m Ulrika,Cavelier Lucia.Refined detection and phasing of structural aberrations in pediatric acute lymphoblastic leukemia by linked-read whole genome sequencing[EB/OL].(2025-03-28)[2025-05-01].https://www.biorxiv.org/content/10.1101/375659.点此复制
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