Linked-read based analysis of the medulloblastoma genome

Melissa Zwaig; Michael J Johnston; John J Y Lee; Hamza Farooq; Marco Gallo; Nada Jabado; Michael D Taylor; Jiannis Ragoussis

doi:10.3389/fonc.2023.1221611

Linked-read based analysis of the medulloblastoma genome

Front Oncol. 2023 Jul 28:13:1221611. doi: 10.3389/fonc.2023.1221611. eCollection 2023.

Authors

Melissa Zwaig¹, Michael J Johnston², John J Y Lee^{3

4}, Hamza Farooq⁵, Marco Gallo², Nada Jabado^{6

7

8}, Michael D Taylor^{9

10}, Jiannis Ragoussis¹

Affiliations

¹ Victor Phillip Dahdaleh Institute of Genomic Medicine and Department of Human Genetics, McGill University, Montreal, QC, Canada.
² Alberta Children's Hospital Research Institute, Arnie Charbonneau Cancer Institute, and Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
³ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
⁴ Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA, United States.
⁵ BioBox Analytics Inc., Toronto, ON, Canada.
⁶ Department of Human Genetics, McGill University, Montreal, QC, Canada.
⁷ The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
⁸ Department of Pediatrics, McGill University, Montreal, QC, Canada.
⁹ Division of Neurosurgery, The Arthur and Sonia Labatt Brain Tumour Research Centre and the Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁰ Texas Children's Cancer Center , Hematology-Oncology Section and Department of Pediatrics - Hematology/Oncology and Neurosurgery, Baylor College of Medicine, Houston, TX, United States.

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.

Keywords: RNA sequencing; enhancer hijacking; extrachromosomal DNA; linked-reads; medulloblastoma; whole-genome sequencing.

Abstract

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