ID

45504

Description

Principal Investigator: Matthew Meyerson, Broad Institute, Cambridge MA, Dana Farber Cancer Institute, Boston, MA, USA MeSH: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000504 Medulloblastomas are the most common malignant brain tumors in children. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles. Here, we utilized whole exome hybrid capture and Illumina sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as *CTNNB1*, *PTCH1*, *MLL2*, *SMARCA4* and *TP53*. Recurrent somatic mutations were identified in an RNA helicase gene, *DDX3X*, often concurrent with *CTNNB1* mutations, and in the nuclear co-repressor (N-CoR) complex genes *GPS2*, *BCOR*, and *LDB1*, to our knowledge novel findings in medulloblastoma and all cancer. We show that mutant *DDX3X* potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now *N-CoR* pathways across medulloblastomas and nominates the RNA helicase *DDX3X* as a component of pathogenic beta-catenin signaling in medulloblastoma. "Reprinted from 'MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATION', with permission from Nature"

Link

dbGap study = phs000504

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Versions (2)

1. 11/2/22 11/2/22 - Tabea Kampen
2. 12/13/22 12/13/22 - Kristina Keller

Copyright Holder

Matthew Meyerson, Broad Institute, Cambridge MA, Dana Farber Cancer Institute, Boston, MA, USA

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December 13, 2022

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