EGAGenomicsDr. Cynthiahttps://ega-archive.org/dacs/EGAC00001000149EGAEGA DAC EGAC00001000149EGAcynthia.hawkins@sickkids.caDiffuse 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 Cfbxw1a, fbw1a, Slimb, bTrCP, betaTrCP, Fbw1a, BETA-TRCP, btrc-a, E3RS-IkappaB, E3RSIkappaB, b-TrCP, bTrCP1, beta-TrCP, HOS, fwd1, FBXW1, mKIAA4123, FBW1A, FWD1., FBXW1A, btrcp, btrcp1, Beta-Trcp1, fbxw1Glioma NOS, Glioma (except Nasal glioma, determination, glial tumors, malignant, obsolete_glioma, Mixed Glioma, acvrlk2, Malignant Glioma, Neuroglial Tumor, acvr1, Tumor, ACTRI, Malignant, acvr1a, FOP, Alk8, [M]Glioma NOS (morphologic abnormality), ALK2, ActRIA, chemical analysis, [M]Gliomas (morphologic abnormality), Mutations., Gliomas, Mixed, alk8, Glial Cell Tumor, [M]Glioma NOS, Mixed Gliomas, alk2, tsri, Glial Tumor, NOS (except Nasal glioma, fop, Neuroglial Neoplasm, ActR-I, glioma (morphologic abnormality), Neuroglial Neoplasms, Glioma NOS (morphologic abnormality), alk-2, 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tumour, Benign Brain Neoplasm, Treatment, Receptor, hereditary, D330013D15Rik, NeoplasiafalseBTRC Data Access CommitteeData Access Committee EGAC00001000149EGAC00001000149960624705254EGAS00001000575EGAD00001003305EGAD00001000814