Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures.
Nanopore methylation calling
cancer genomics
chromothripsis
complex rearrangements
epigenetic signatures
long read sequencing
templated insertions
Journal
Cell genomics
ISSN: 2666-979X
Titre abrégé: Cell Genom
Pays: United States
ID NLM: 9918284260106676
Informations de publication
Date de publication:
12 Apr 2023
12 Apr 2023
Historique:
received:
20
02
2022
revised:
14
06
2022
accepted:
22
02
2023
medline:
21
4
2023
pubmed:
21
4
2023
entrez:
21
04
2023
Statut:
epublish
Résumé
Cancer genomes harbor a broad spectrum of structural variants (SVs) driving tumorigenesis, a relevant subset of which escape discovery using short-read sequencing. We employed Oxford Nanopore Technologies (ONT) long-read sequencing in a paired diagnostic and post-therapy medulloblastoma to unravel the haplotype-resolved somatic genetic and epigenetic landscape. We assembled complex rearrangements, including a 1.55-Mbp chromothripsis event, and we uncover a complex SV pattern termed templated insertion (TI) thread, characterized by short (mostly <1 kb) insertions showing prevalent self-concatenation into highly amplified structures of up to 50 kbp in size. TI threads occur in 3% of cancers, with a prevalence up to 74% in liposarcoma, and frequent colocalization with chromothripsis. We also perform long-read-based methylome profiling and discover allele-specific methylation (ASM) effects, complex rearrangements exhibiting differential methylation, and differential promoter methylation in cancer-driver genes. Our study shows the advantage of long-read sequencing in the discovery and characterization of complex somatic rearrangements.
Identifiants
pubmed: 37082141
doi: 10.1016/j.xgen.2023.100281
pii: S2666-979X(23)00041-1
pmc: PMC10112291
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100281Informations de copyright
© 2023 The Authors.
Déclaration de conflit d'intérêts
E.B. is a paid consultant and shareholder of ONT. A.L. has received financial support from ONT for consumables during the course of the project and is currently an employee of ONT. O.S. is a paid consultant of Insitro, Inc.
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