3D genome topology distinguishes molecular subgroups of medulloblastoma

John J Y Lee; Michael J Johnston; Hamza Farooq; Huey-Miin Chen; Subhi Talal Younes; Raul Suarez; Melissa Zwaig; Nikoleta Juretic; William A Weiss; Jiannis Ragoussis; Nada Jabado; Michael D Taylor; Marco Gallo

doi:10.1016/j.ajhg.2024.10.003

3D genome topology distinguishes molecular subgroups of medulloblastoma

Am J Hum Genet. 2024 Dec 5;111(12):2720-2734. doi: 10.1016/j.ajhg.2024.10.003. Epub 2024 Oct 30.

Authors

Affiliations

¹ The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada.
² Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
³ Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Cancer and Hematology Center, Texas Children's Hospital, Houston, TX 77030, USA.
⁴ Department of Human Genetics, McGill University, Montreal, QC H2A 1B1, Canada.
⁵ Department of Human Genetics, McGill University, Montreal, QC H2A 1B1, Canada; Department of Pediatrics, McGill University, The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC H3A 3J1, Canada.
⁶ Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurosurgery, University of California, San Francisco, San Francisco, CA 94143, USA; Brain Tumor Research Center, and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Department of Human Genetics, McGill University, Montreal, QC H2A 1B1, Canada; McGill Genome Centre, Montreal, QC H3A 0G1, Canada.
⁸ The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Cancer and Hematology Center, Texas Children's Hospital, Houston, TX 77030, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: michael.taylor@bcm.edu.
⁹ Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Cancer and Hematology Center, Texas Children's Hospital, Houston, TX 77030, USA; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: marco.gallo@bcm.edu.

Abstract

Four main medulloblastoma (MB) molecular subtypes have been identified based on transcriptional, DNA methylation, and genetic profiles. However, it is currently not known whether 3D genome architecture differs between MB subtypes. To address this question, we performed in situ Hi-C to reconstruct the 3D genome architecture of MB subtypes. In total, we generated Hi-C and matching transcriptome data for 28 surgical specimens and Hi-C data for one patient-derived xenograft. The average resolution of the Hi-C maps was 6,833 bp. Using these data, we found that insulation scores of topologically associating domains (TADs) were effective at distinguishing MB molecular subgroups. TAD insulation score differences between subtypes were globally not associated with differential gene expression, although we identified few exceptions near genes expressed in the lineages of origin of specific MB subtypes. Our study therefore supports the notion that TAD insulation scores can distinguish MB subtypes independently of their transcriptional differences.

Keywords: 3D genome; CNS tumor; Hi-C; cancer; medulloblastoma; transcriptome.

MeSH terms

Animals
Cerebellar Neoplasms / classification
Cerebellar Neoplasms / genetics
DNA Methylation
Female
Gene Expression Regulation, Neoplastic
Genome, Human
Humans
Male
Medulloblastoma* / classification
Medulloblastoma* / genetics
Medulloblastoma* / pathology
Mice
Transcriptome