MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATIONS

By Trevor J Pugh, S. D. Weeraratne, Tenley C. Archer, D. P. Pomeranz Krummel, D. Auclair, James Bochicchio, Mauricio O. Carneiro, Scott L. Carter, Kristian Cibulskis, R. Erlich and 33 more. Nature, 2012

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Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, 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 newly 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. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, β-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic β-catenin signalling in medulloblastoma.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/df287fe035d1160cb9927e1b09932bf79ecbdb9e

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Citations in the corpus

The whole-genome landscape of medulloblastoma subtypes (2017, positive): “Re-analysis of NGS data derived from previous studies ( n = 173) 5,9,14 indicated that less than one-third of Group 3 (32”
Neuroblastoma and MYCN (2013, background): “The low mutation rate in neuroblastoma resembles other pediatric tumors, including medulloblastoma (Pugh et al. 2012), and stands in contrast to changes in chromosomal copy number, which are quite frequent and robust.”
Oncotator: cancer variant annotation tool (2015, neutral): “…2011; Banerji et al., 2012; Barbieri et al., 2012; Barretina et al., 2012; Berger et al., 2012; Hodis et al., 2012; Imielinski et al., 2012; Lee et al., 2012; Lohr et al., 2012; Pugh et al., 2012, 2013, 2014; Ciriello et al., 2013; Francis et al., 2013; Lawrence et al., 2013; Ojesina et al., 2013).”
Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas (2014, background): “MLL genes encode histone lysine methyltransferases that are involved in chromatin remodeling and recurrently mutated in several cancer types (43-46).”
New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs (2016, positive): “High expression of altered BCOR transcripts in CNS HGNET-BCOR tumors suggests a mechanism different from BCOR loss-of-function mutations reported in other malignancies, such as medulloblastoma (Jones et al., 2012; Pugh et al., 2012).”
Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition (2014, methodology): “Interestingly, mutations affecting the SWI-SNF complex, also mainly found in the WNT-MBs in children (Jones et al., 2012; Northcott et al., 2012a; Pugh et al., 2012; Robinson et al., 2012), were also frequently seen in adult SHH-MBs.”
The integrated landscape of driver genomic alterations in glioblastoma (2013, background): “BCOR mutations have recently been described in retinoblastoma and medulloblastoma 14,15 .”