Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations

Abstract

Medulloblastomas are the most common malignant brain tumors in children1. 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 profiles2–5. Here, we utilized whole exome hybrid capture and deep 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, novel findings in medulloblastoma. 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 within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma.

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…Indeed, more than 50 different translocations or partial tandem duplications involving MLL on chromosome 11q23 have been described and are found to be associated with poor prognosis in acute lymphoblastic leukemia or normal-karyotype acute myeloid leukemia (AML) (reviewed in 94 ). Of interest, on the basis of genome-wide sequencing data, mutations of other MLLs, MLL2 (also called MLL4, KMT2D) and MLL3 (KMT2C), have been described in both GBM and medulloblastoma, 46,50,95,96,97,98,99 further increasing the interest for these MTs in cancer. Importantly, UTX (KDM6A) is part of the MLL3/4 complexes, while JMJD3 (KDM6B) associates with the common MLL complex proteins WDR5, ASH2L, and RBBP5.…”

“…Mutations have been reported in the genes encoding KDM5A (JARID1A); KDM5C (JARID1C), which affects H3K4 methylation; and KDM6A (UTX), which affects H3K27 methylation. 50,81,82,98,105,106 UTX (KDM6A) and JMJD3 (KDM6B) Besides EZH2 methyltransferase, H3K27 methylation is also determined by the activity of demethylases, including UTX/ KDM6A and JMJD3/KDM6B. Somatic loss-of-function mutations of UTX are found in multiple myeloma, esophageal squamous cell carcinomas, renal carcinomas, and occasionally in breast cancer, AML, T-ALL, GBM, and colorectal and bladder cancer (Table 1) (for review see.…”

Role of MYC in Medulloblastoma

“…Transcriptional profiling reveals a high expression of WNT pathway genes in these tumors compared with the other subgroups (Thompson et al 2006;Kool et al 2008;Northcott et al 2011). Next-generation sequencing studies show that 90% of these tumors harbor activating mutations in b-CATENIN (CTNNB1), the central orchestrator of the canonical WNT pathway Northcott et al 2012a;Pugh et al 2012;Robinson et al 2012). The only mouse model of this disease requires an activating mutation in Ctnnb1 and loss of Trp53 (Gibson et al 2010).…”

Les médulloblastomes et leurs cellules d’origine

“…Trois articles consacrés au séquençage de l'exome dans les médulloblastomes, publiés dans Nature après l'impression de cette Nouvelle [1][2][3], illustrent le faible taux de mutations ( 1 par mégabase) observé dans les médulloblastomes comparé au taux observé dans la majorité des cancers de l'adulte. Chacune des mutations rapportées est détectée dans moins de 10 % des médulloblastomes, démontrant une profonde hétérogénéité génétique dans ces cancers.…”

“…Les caractéristiques histologiques des GBM sont identiques quel que soit l'âge du patient ou la localisation de la tumeur, mais leurs caractéristiques génétiques diffèrent [1][2][3][4]. Par exemple, chez l'enfant, moins de 10 % des tumeurs ont des mutations/amplifications du récepteur à activité tyrosine kinase de l'EGF (epidermal growth factor) (EGFR), ou des mutations des enzymes isocitrate déshydroxygénase 1 ou 2 (IDH1/2), qui caractérisent respectivement la majorité …”