Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures

Rausch, T.; Snajder, R.; Leger, A.; Simovic, M.; Giurgiu, M.; Villacorta, L.; Henssen, A.G.; Fröhling, S.; Stegle, O.; Birney, E.; Bonder, M.J.; Ernst, A.; Korbel, J.O.

Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures

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Item Type:	Article
Title:	Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures
Creators Name:	Rausch, T., Snajder, R., Leger, A., Simovic, M., Giurgiu, M., Villacorta, L., Henssen, A.G., Fröhling, S., Stegle, O., Birney, E., Bonder, M.J., Ernst, A. and Korbel, J.O.
Abstract:	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.
Keywords:	Long Read Sequencing, Cancer Genomics, Templated Insertions, Complex Rearrangements, Epigenetic Signatures, Nanopore Methylation Calling, Chromothripsis
Source:	Cell Genomics
ISSN:	2666-979X
Publisher:	Cell Press
Volume:	3
Number:	4
Page Range:	100281
Date:	12 April 2023
Official Publication:	https://doi.org/10.1016/j.xgen.2023.100281
PubMed:	View item in PubMed

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