Publication Date
1-1-2023
Journal
Frontiers in Oncology
DOI
10.3389/fonc.2023.1221611
PMID
37576901
PMCID
PMC10419201
PubMedCentral® Posted Date
7-28-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
medulloblastoma, linked-reads, enhancer hijacking, extrachromosomal DNA, whole-genome sequencing, RNA sequencing
Abstract
INTRODUCTION: Medulloblastoma is the most common type of malignant pediatric brain tumor with group 4 medulloblastomas (G4 MBs) accounting for 40% of cases. However, the molecular mechanisms that underlie this subgroup are still poorly understood. Point mutations are detected in a large number of genes at low incidence per gene while the detection of complex structural variants in recurrently affected genes typically requires the application of long-read technologies.
METHODS: Here, we applied linked-read sequencing, which combines the long-range genome information of long-read sequencing with the high base pair accuracy of short read sequencing and very low sample input requirements.
RESULTS: We demonstrate the detection of complex structural variants and point mutations in these tumors, and, for the first time, the detection of extrachromosomal DNA (ecDNA) with linked-reads. We provide further evidence for the high heterogeneity of somatic mutations in G4 MBs and add new complex events associated with it.
DISCUSSION: We detected several enhancer-hijacking events, an ecDNA containing the MYCN gene, and rare structural rearrangements, such a chromothripsis in a G4 medulloblastoma, chromoplexy involving 8 different chromosomes, a TERT gene rearrangement, and a PRDM6 duplication.
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