The Genetic Landscape of Childhood Brain Tumors Scott
The Genetic Landscape of Childhood Brain Tumors Scott L. Pomeroy, M. D. , Ph. D. Bronson Crothers Professor of Neurology Harvard Medical School Broad Institute of MIT and Harvard Chair, Department of Neurology Neurologist-in-Chief Boston Children’s Hospital Boston, Massachusetts Society of Neurological Surgeons Boston June 2013
Childhood Brain Tumors ~5 per 100, 000 person-years
Embryonal Tumor Histology Medulloblastoma Classic PNET Desmoplastic AT/RT Glioblastoma
Transcriptome Analysis Reveals Tumor Specific Gene Expression Profiles MD MGlio Rhab NC PNET Pomeroy et al. Nature 2002
Clustering of Embryonal Tumors by Principal Component Analysis Medulloblastoma Malignant Glioma Rhabdoid Renal/Extrarenal AT/RT CNS Normal Cerebellum PNET Pomeroy et al. Nature 2002
AT/RT HAVE GENOMIC STABILITY and LOSS OF SNF 5/INI 1 with EPIGENETIC INSTABILITY Mc. Kenna ES et al. MCB 2008
Subtypes defined by Non-negative Matrix Factorization (NMF) of Transcriptome The 25 top upregulated marker genes for each NMF subtype c 2 c 4 NEURONAL/ GLUTAMATERGIC c 5 c 1 PHOTORECEPTOR/ GABAergic _____ “mixed” neuronal/ photoreceptor signature _______ MYC activation signature c 6 ____ WNT c 3 ________ nl cbl SHH Cho et al. J Clin Oncol 2011
SNP PROFILES REVEAL UNIQUE DNA COPY ALTERATIONS IN EACH SUBTYPE c 2 CN lesion c 4 p-value* c 5 c 1 WNT SHH CN lesion p-value* CN lesion p-value* c-MYC gain 0. 0001 ch 6+ <0. 0001 GLI 2 gain 0. 0019 0. 0348 i 17 q 0. 0065 ch 12 q+ 0. 0072 ch 14+ <0. 0001 i 17 q alone <0. 0001 MYCN gain 0. 05 ch 10 - 0. 004 ch 1 q+ 0. 0099 ch 9 q- ch 4+ 0. 0302 ch 16 - 0. 0131 ch 8 + <0. 0001 ch 3 q+ <0. 0001 ch 11 - 0. 0386 ch 20 p- 0. 009 ch 13 - 0. 0534 ch 2+ 0. 0793 ch 17+ 0. 0008 ch 8 - 0. 0156 ch 1 q+ 0. 0421 *Fisher's exact test (two-sided) of GISTIC lesion in subgroup tumors versus all other tumors Cho et al. J Clin Oncol 2011
Taylor et al. , Acta Neuropath 2012
Low Mutation Rate in Medulloblastoma (MED) Medulloblastoma
Genes with Significant Frequency of Mutation across 92 Medulloblastomas Pugh et al. , Nature 2012
Mutations DNA Copy Number Subtype-Specific DNA Copy Number and Somatic Mutations Black: Missense Orange: Nonsense/splice site/indel Green: Germline Gray: Silent Red: Copy number gain Blue: Copy number loss Pugh et al. Nature 2012
Point mutations DDX 3 X ATP-Dependent RNA Helicase Mutation RNA Mg-ATP analog aa 166 -405 aa 406 -582 R 276 K D 354 H R 376 C D 506 Y R 528 H R 534 H P 568 L
DDX 3 X Point Mutations Potentiate β-Catenin Pugh et al. Nature 2012
Mutations DNA Copy Number SUBTYPE-SPECIFIC BIOLOGY HAS IMPLICATIONS FOR THE DEVELOPMENT OF TARGETED THERAPIES Black: Missense Orange: Nonsense/splice site/indel Green: Germline Gray: Silent Red: Copy number gain Blue: Copy number loss
Histone Mutations in Diffuse Intrinsic Pontine Gliomas and High Grade Astrocytomas associated with ATRX mutations Schwartzentruber et al. , Nature 2012 Wu et al. , Nature Genet 2012
TARGETS OF THE EPIGENOME Me ARID 1 A ARID 1 B ATRX BRG 1 BRD 2 BRD 3 BRD 4 Me Remodelers Readers H 3. 3 MYCN Me Transcription Factors Writers DNMT EZH 2 MLL 3 Erasers UTX JMJD 3 HDAC
Our current understanding of epigenetics offers therapeutic opportunities
Next-Gen Sequencing of Pilocytic Astrocytomas • Whole-genome sequencing complete for 96 tumor-normal pairs (average 36 x coverage), with matched RNAseq data for 73 samples • Extremely low mutation rate (<0. 1/Mb); < 2 non-synonymous SNVs per case (range 0 -9) Pilocytic Astrocytoma Jones et al. Nature Genetics 2013 Medulloblastoma
Pilocytic astrocytoma: a single-pathway disease Jones et al. Nature Genetics 2013 • This study has expanded the spectrum of MAPK pathway alterations in PA, from ligand to RTKs to downstream molecules • 100% cases displayed an alteration in this pathway, with almost perfect exclusivity – PA is a prototypic single -pathway disease • Novel potential therapeutic targets identified for clinically challenging subsets of PA Exclusivity p < 0. 0001, coverage = 100%
Children’s Hospital Boston Department of Neurology Tenley Archer Jessica Pierre Francois Natalia Teider Nicole Ullrich Dilhan Weeraratne Dept of Neurosurgery Al Cohen Liliana Goumnerova Joe Madsen Mark Proctor Dody Robinson Michael Scott Ed Smith Dana-Farber Cancer Institute Charlie Roberts Tom Roberts Chuck Stiles Stanford University School of Medicine Yoon-Jae Cho Jerry Crabtree DKFZ German Cancer Research Center Natalie Jaeger Peter Lichter Marcel Kool Stefan Pfister Children’s Oncology Group Mary Mc. Nulty (CHTN) Roger Packer Ian Pollack Allen Buxton Tianni Zhou Broad Institute Rameen Beroukhim Stacey Gabriel www. broad. mit. edu/cancer Gady Getz Todd Golub Heidi Greulich Eric Lander MIT Ernest Fraenkel Jill Mesirov Matthew Meyerson Nurcan Tuncbag Trevor Pugh The Hospital for Sick Children Aravind Subramanian Paul A. Northcott Pablo Tamayo Michael D. Taylor Aviad Tshemiak St. Jude Curie Institute, France Richard Gilbertson Olivier Delattre Amar Gajjar Christine Haberler The Johns Hopkins University Francois Doz Charles Eberhart Sarah Fattet Brandeis University Daniel A. Pomeranz Krummel University of Washington Jim Olson Funding/Support:
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