Rausch Tobias, Snajder Rene, Leger Adrien, Simovic Milena, Giurgiu Mădălina, Villacorta Laura, Henssen Anton G, Fröhling Stefan, Stegle Oliver, Birney Ewan, Bonder Marc Jan, Ernst Aurelie, Korbel Jan O
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
European Molecular Biology Laboratory (EMBL), GeneCore, Heidelberg, Germany.
Cell Genom. 2023 Mar 22;3(4):100281. doi: 10.1016/j.xgen.2023.100281. eCollection 2023 Apr 12.
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.
癌症基因组含有多种驱动肿瘤发生的结构变异（SVs），其中一部分相关变异通过短读长测序难以发现。我们在配对的诊断性和治疗后髓母细胞瘤中采用牛津纳米孔技术（ONT）长读长测序，以解析单倍型分辨的体细胞遗传和表观遗传图谱。我们组装了复杂重排，包括一个1.55兆碱基对的染色体碎裂事件，并且我们发现了一种称为模板插入（TI）链的复杂SV模式，其特征是短（大多<1千碱基）插入，这些插入普遍自连接形成大小高达50千碱基的高度扩增结构。TI链在3%的癌症中出现，在脂肪肉瘤中的发生率高达74%，并且经常与染色体碎裂共定位。我们还进行了基于长读长的甲基化组分析，发现了等位基因特异性甲基化（ASM）效应、表现出差异甲基化的复杂重排以及癌症驱动基因中的差异启动子甲基化。我们的研究显示了长读长测序在发现和表征复杂体细胞重排方面的优势。
