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

Tobias Rausch, Rene Snajder, Adrien Leger, Milena Simovic, Oliver Stegle, Ewan Birney, Marc Jan Bonder, Aurelie Ernst, Jan O. Korbel
2022 bioRxiv   pre-print
Cancer genomes harbor a broad spectrum of structural variants (SV) driving tumorigenesis, a relevant subset of which are likely to escape discovery in short reads. We employed Oxford Nanopore Technologies (ONT) sequencing in a paired diagnostic and post-therapy medulloblastoma to unravel the haplotype-resolved somatic genetic and epigenetic landscape. We assemble complex rearrangements and such associated with telomeric sequences, including a 1.55 Megabasepair chromothripsis event. We uncover a
more » ... complex SV pattern termed "templated insertion thread", characterized by short (mostly <1kb) insertions showing prevalent self-concatenation into highly amplified structures of up to 50kbp in size. Templated insertion threads occur in 3% of cancers, with a prevalence ranging 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 seven cancer-driver genes. Our study shows the potential of long-read sequencing in cancer.
doi:10.1101/2022.02.20.480758 fatcat:nok5elj5pbgizmal3hgqjeqt4i