Dataset Information

The Genomic Analysis of Medulloblastoma

ABSTRACT:

Medulloblastoma is a heterogenous disease made up of at least four distinct subtypes of disease which appear to exploit and disrupt naturally occurring developmental pathways of cellular growth and hindbrain development. To better understand the driver mutations of this disease, we performed whole genome sequencing of 37 medulloblastomas and the corresponding normal DNA of the 37 affected children treated at St. Jude Children's Research Hospital. We have found several novel mutations which appear subtype specific. These mutations were checked for frequency in a separate tumor cohort of 56 children with medulloblastoma, also treated on the St. Jude Medulloblastoma 2003 trial, and were tested in several animal models of medulloblastoma for proof of oncogenic potential.

OTHER RELATED OMICS DATASETS IN: PRJNA159949

PROVIDER: phs000409.v1.p1 | EGA |

REPOSITORIES: EGA

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Publications

Novel mutations target distinct subgroups of medulloblastoma.

Robinson Giles G Parker Matthew M Kranenburg Tanya A TA Lu Charles C Chen Xiang X Ding Li L Phoenix Timothy N TN Hedlund Erin E Wei Lei L Zhu Xiaoyan X Chalhoub Nader N Baker Suzanne J SJ Huether Robert R Kriwacki Richard R Curley Natasha N Thiruvenkatam Radhika R Wang Jianmin J Wu Gang G Rusch Michael M Hong Xin X Becksfort Jared J Gupta Pankaj P Ma Jing J Easton John J Vadodaria Bhavin B Onar-Thomas Arzu A Lin Tong T Li Shaoyi S Pounds Stanley S Paugh Steven S Zhao David D Kawauchi Daisuke D Roussel Martine F MF Finkelstein David D Ellison David W DW Lau Ching C CC Bouffet Eric E Hassall Tim T Gururangan Sridharan S Cohn Richard R Fulton Robert S RS Fulton Lucinda L LL Dooling David J DJ Ochoa Kerri K Gajjar Amar A Mardis Elaine R ER Wilson Richard K RK Downing James R JR Zhang Jinghui J Gilbertson Richard J RJ

Nature 20120801 7409

Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machine ...[more]

PMID: 22722829

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Project description:Primitive neuro-ectodermal tumours (PNET) of the supratentorial region are rare, highly malignant embryonal brain tumours affecting young children. Although supratentorial PNET (sPNET) are histologically similar to infratentorial PNET/medulloblastoma, sPNET have more aggressive clinical phenotypes, which suggest sPNET represents distinct biological entities. In contrast to considerable progress in understanding the signalling pathways involved in medulloblastoma, little is known about sPNET pathogenesis. Prior low resolution CGH (comparative genomic hybridization) studies indicate sPNET have frequent genomic imbalances and copy number aberrations (CNAs). To define genes involved in sPNET pathogenesis, we utilized the Affymetrix 250K Nsp SNP (single nucleotide polymorphism) analysis to identify genes targeted by recurrent CNAs in primary human sPNET samples. Copy number analysis was conducted on 39 primary PNET samples. Select target genes were validated by genomic and/or RT-PCR. Our analysis revealed frequent CNA across the sPNET genome, encompassing large and focal chromosome segments, and corroborated previous reports that isochromosome 17q, an abnormality found in ~ 30% of medulloblastoma, is rare in sPNET. Keywords: single nucleotide polymorphism array, disease state analysis A total of 56 primary sPNET samples were collected for this study from The Hospital for Sick Children, John Hopkins University, St. Jude Research Hospital, University of Cambridge, Children’s Hospital Boston, Virginia Commonwealth University, Instituto nazionale per lo studio e la cura dei tumori, and Texas Children’s Hospital, with local Institutional Research Ethics Board approval. Pineoblastoma and rhaboid tumours were specifically excluded, leaving 52 samples, 39 of which had good quality DNA available. These samples, in addition to 28 diploid reference samples (a gift from Dr. S. Scherer, University of Toronto), were analyzed on the Affymetrix GeneChip Mapping 250K Nsp SNP array. Due to sample availability at the time the arrays were run, the diploid reference samples analyzed on the Sty arrays are different from reference samples analyzed on the Nsp arrays.

Project description:We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC gene family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this molecular group died of rapidly progressive disease post-relapse. To study this genetic interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of Trp53 function in this model produced aggressive tumors that mimicked the characteristics of relapsed human tumors with combined P53–MYC dysfunction. Restoration of p53 activity, genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53–MYC interactions which emerge at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically. There are currently no effective therapies for children with relapsed medulloblastoma. While clinical and biological features of the disease at diagnosis are increasingly well understood, biopsy is rarely performed at relapse and few biological data are available to guide more effective treatments. Here, we show that medulloblastomas develop altered biology at relapse which is predictive of disease course and cannot be detected at diagnosis. We have discovered the emergence of P53–MYC interactions at relapse, as biomarkers of clinically aggressive relapsed disease, which can be modelled and targeted therapeutically in genetically-engineered mice. These data provide clear precedent for the incorporation of biopsy at relapse into routine clinical practice, to direct palliative care and the development of improved treatment strategies. mouse model expression profiles from various mouse Medulloblastoma models MYCN/MYC overexpressing with/without p53 Mutations were compared to human MB expression profiles using Non-negative Matrix Factorization projection in order to sub-type the mouse models

Project description:Mutations in Hedgehog (Hh) pathway genes, leading to constitutive activation of Smoothened (Smo), occur in sporadic medulloblastoma, the most common brain cancer in children. Antagonists of Smo induce tumor regression in mouse models of medulloblastoma and hold great promise for targeted therapy for this tumor. However, acquired resistance has emerged as one of the major challenges of targeted cancer therapy. Here, we describe novel mechanisms of acquired resistance to Smo antagonists in medulloblastoma. NVP-LDE225, a potent and selective Smo antagonist, inhibits Hh signaling and induces tumor regressions in allograft models of medulloblastoma that are driven by mutations of Patched (Ptch), a tumor suppressor in the Hh pathway. However, after long-term treatment, evidence of acquired resistance was observed. Genome-wide profiling of resistant tumors revealed distinct mechanisms to evade the inhibitory effects of Smo antagonists. Chromosomal amplification of Gli2, a downstream effector of Hh signaling, reactivated Hh signaling and restored tumor growth. Analysis of pathway gene-expression signatures selectively deregulated in resistant tumors identified increased phosphoinosite-3-kinase (PI3K) signaling as another potential resistance mechanism. Probing the functional relevance of increased PI3K signaling, we showed that the combination of NVP-LDE225 with the dual PI3K/mTOR inhibitor NVP-BEZ235 markedly delayed the development of resistance. Our findings have important clinical implications for future treatment strategies in medulloblastoma. mRNA profiling: RNA was prepared from tumours from vehicle or NVP-LDE225 treated nude mice allografted with medulloblastoma tumors derived from Ptch+/-p53-/- transgenic mouse and hybridized on Affymetrix Mouse Genome 430 2.0 RNA expression array. The dosage terminology (BID & QD) reflects the dosing schedule, where BID = twice a day, QD = once a day. aCGH: DNA was prepared from tumors from vehicle or NVP-LDE225 treated nude mice allografted with medulloblastoma tumors derived from Ptch+/-p53-/- transgenic mouse and hybridized on Agilent mouse CGH 244K Array.

Dataset Information

The Genomic Analysis of Medulloblastoma

Publications

Novel mutations target distinct subgroups of medulloblastoma.

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