EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD0000100081440EGA dataset EGAD00001000814EGADiffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations.Buczkowicz Pawel P, Hoeman Christine C, Rakopoulos Patricia P, Pajovic Sanja S, Letourneau Louis L, Dzamba Misko M, Morrison Andrew A, Lewis Peter P, Bouffet Eric E, Bartels Ute U, Zuccaro Jennifer J, Agnihotri Sameer S, Ryall Scott S, Barszczyk Mark M, Chornenkyy Yevgen Y, Bourgey Mathieu M, Bourque Guillaume G, Montpetit Alexandre A, Cordero Francisco F, Castelo-Branco Pedro P, Mangerel Joshua J, Tabori Uri U, Ho King Ching KC, Huang Annie A, Taylor Kathryn R KR, Mackay Alan A, Bendel Anne E AE, Nazarian Javad J, Fangusaro Jason R JR, Karajannis Matthias A MA, Zagzag David D, Foreman Nicholas K NK, Donson Andrew A, Hegert Julia V JV, Smith Amy A, Chan Jennifer J, Lafay-Cousin Lucy L, Dunn Sandra S, Hukin Juliette J, Dunham Chris C, Scheinemann Katrin K, Michaud Jean J, Zelcer Shayna S, Ramsay David D, Cain Jason J, Brennan Cameron C, Souweidane Mark M MM, Jones Chris C, Allis C David CD, Brudno Michael M, Becher Oren O, Hawkins Cynthia CVasp, fbw1a, DmelCG15112, ENHANCER OF ATNSI ACTIVITY, betaTrCP, BETA-TRCP, btrc-a, Data Set, E3RSIkappaB, b-TrCP, beta-TrCP, NDPP1, l(2)02029, FBXW1A, btrcp, btrcp1, enb, Beta-Trcp1, fbxw1, VASP, fbxw1a, Slimb, bTrCP, Fbw1a, E3RS-IkappaB, bTrCP1, HOS, fwd1, MENA, FBXW1, mKIAA4123, FBW1A, FWD1., Enb, ENA, Ena, CG15112, ENA/VASPtsri, fop, ActR-I, determination, diffuse, alk-2, actri, Acvrlk2, ACVR1A, scattered, xALK-2, SKR1, TSRI, acvrlk2, acvr1, ACVRLK2, ACTRI, acvr1a, Acvr, skr1, Alk-2, FOP, Alk8, sax, ALK2, ActRIA, chemical analysis, Tsk7L, Mutations., assay, alk8, D330013D15Rik, Intrinsic, alk2diffuse midline glioma, infiltrative brainstem glioma, Client., Patient, DIPG Brain Tumors, L-glutamic acid dipinacoline ester, Clients, Brain Tumor, whole genome, Diffuse Intrinsic Pontine Glioma, DIPG, DiPG, DIPG Brain TumorId-2, Brainstem, Materials, transforming growth factor beta ligand binding to type I receptor, BHLHB24, BHLHB26, selection process, adult stage, Brain Neoplasms, mycna, mycnb, acvr1, Tumor, Brain Metastases, phosphorylation, H3/c, acvr1a, Truncus Cerebri, Mutations, Histone H2b, C78922, Histone H2a, Readability, H3-f, "brain neoplasm" EXACT [CSP2005:2006-2736], diseases, L-glutamic acid dipinacoline ester, lamina pallidi incompleta, diseases and disorders, TGFbeta receptor binding, malignant primary brain tumour, AI255428, placement, adult, Id-1, treatment, increased, human disease, adult brain tumour, Genomes, DIPG Brain Tumors, ID125A, SKR1, Brain Malignant Neoplasms, Primary Brain Tumors, Brain Tumor, Nmyc1, N-myc, genetic, H3/d, Acvr, skr1, activin, TGF-beta receptor binding, neoplasm of brain, Brain Neoplasm, Primary Malignant Brain Tumors, XN-myc, Ac2-300, Recurrent Brain Tumor, disease management, inhibin, Therapies, Histone H5, Histone H4, Histone H7, Homo sapiens disease, Malignancies, Histone H1, Histone H3, single organism signaling, Tumors, Therapy, primary brain neoplasm, malignant tumour of adult brain, brain neoplasm, Intracranial Neoplasm, Malignant Brain Neoplasms, lamina medullaris accessoria, ID2A, Brain Benign Neoplasm, functional failure, primary malignant neoplasm of brain, familial, Malignant Primary Brain Neoplasms, ID2H, malignant tumor of Brain, Primary Brain Neoplasm, results, Primary Brain Tumor, FOP, Benign, Brain Benign Neoplasms, Alk8, Idb1, Idb2, ALK2, Brain Malignant Neoplasm, adult brain tumor, Diseases, Malignant Primary Brain Tumors, Genetic Materials, relational spatial quality, alk8, brain stem, failure, malignant primary brain neoplasm, Adults, Genetic Material, Malignant Brain Neoplasm, alk2, tsri, Primary Malignant, xN-myc1, FSH-Releasing, infiltrative brainstem glioma, fop, H3FD, Drives, H3FC, Cancer of the Brain, alk-2, transforming growth factor beta receptor anchoring activity, TSRI, Benign Neoplasms, Cerebri, INSDC_feature:gene, XId2, tumor of the Brain, whole genome, Diffuse Intrinsic Pontine Glioma, primary brain tumor, FSH-Releasing Protein, ACVRLK2, Children, Treatments, "neoplasm of unspecified nature of brain" EXACT [ICD9CM_2006:239.6], Malignant Neoplasms, Intracranial, disease, Alk-2, Material, Cistron, malignant tumor of adult brain, inherited genetic, location, "neoplasm of unspecified nature of brain (disorder)" EXACT [SNOMEDCT_2005_07_31:189537005], accessory, Brain, Brain Tumors, other disease, Primary Malignant Brain Neoplasms, malignant neoplasm., Nmyc, Neoplasms, Primary Brain Neoplasms, Cancer of Brain, ODED, Benign Neoplasm, number, GIG8, Gene, disfunctional, Malignant, ID, DIPG, presence, supernumerary, lamina medullaris incompleta pallidi, mycn, Recurrent Brain Tumors, Recurrent, NMYC, disease or disorder, nmyc, Histone H3.3, Genetic, ActR-I, Malignancy, Acvrlk2, lamella pallidi incompleta, accessory medullary lamina of pallidum, Nmuc1, DIPG Brain Tumor, non-neoplastic, Neoplasias, MODED, disorder, "neoplasm of brain (disorder)" EXACT [SNOMEDCT_2005_07_31:126952004], Tsk7L, bHLHe37, adult malignant brain neoplasm, constitutitional genetic, Methylations, DiPG, malignant brain tumour, XNmyc, Activin, Cancer, Malignant Neoplasm, Benign Brain Neoplasms, disorders, Truncus, Phosphorylations, bHLHb24, bHLHb26, acvrlk2, Primary, defective, medical condition, brainstem, ACTRI, Cistrons, Histone, id2-A, truncus encephali, Brain Stems, count in organism, FSH Releasing Protein, "BT - Brain tumour" EXACT [SNOMEDCT_2005_07_31:254935002], Cerebrus, ActRIA, c-nmyc, Protein, Neoplasm, "tumor of the Brain" EXACT [NCI2004_11_17:C2907], Brain Cancers, condition, H3|d, transforming growth factor beta receptor ligand, H3|c, methylation, Brain Metastase, truncus encephalicus, Intracranial Neoplasms, malignant primary brain tumor, transforming growth factor beta, distinct, actri, ACVR1A, increased number, H3.1, xALK-2, Truncus Cerebrus, Cancers, Understanding, Brain Cancer, Brainstems, Histone H1(s), transforming growth factor beta ligand binding to type II receptor, Nmyc-1, present in greater numbers in organism, diffuse midline glioma, signalling process, Therapeutic, sax, cardinality, BT - Brain tumour, Benign Brain Neoplasm, Treatment, H3(any), hereditary, D330013D15Rik, Neoplasiafalseena-DATASET-BTRC-03-04-2014-18:00:02:250-43 - samplesWhole genome alignments of DIPG patients2017-07-26 15:39:25EGAD00001000814960624705254EGAC00001000149EGAS00001000575