PMID- 22722829 OWN - NLM STAT- MEDLINE DCOM- 20120904 LR - 20220408 IS - 1476-4687 (Electronic) IS - 0028-0836 (Print) IS - 0028-0836 (Linking) VI - 488 IP - 7409 DP - 2012 Aug 2 TI - Novel mutations target distinct subgroups of medulloblastoma. PG - 43-8 LID - 10.1038/nature11213 [doi] AB - 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 machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development. FAU - Robinson, Giles AU - Robinson G AD - St Jude Children's Research Hospital, Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA. FAU - Parker, Matthew AU - Parker M FAU - Kranenburg, Tanya A AU - Kranenburg TA FAU - Lu, Charles AU - Lu C FAU - Chen, Xiang AU - Chen X FAU - Ding, Li AU - Ding L FAU - Phoenix, Timothy N AU - Phoenix TN FAU - Hedlund, Erin AU - Hedlund E FAU - Wei, Lei AU - Wei L FAU - Zhu, Xiaoyan AU - Zhu X FAU - Chalhoub, Nader AU - Chalhoub N FAU - Baker, Suzanne J AU - Baker SJ FAU - Huether, Robert AU - Huether R FAU - Kriwacki, Richard AU - Kriwacki R FAU - Curley, Natasha AU - Curley N FAU - Thiruvenkatam, Radhika AU - Thiruvenkatam R FAU - Wang, Jianmin AU - Wang J FAU - Wu, Gang AU - Wu G FAU - Rusch, Michael AU - Rusch M FAU - Hong, Xin AU - Hong X FAU - Becksfort, Jared AU - Becksfort J FAU - Gupta, Pankaj AU - Gupta P FAU - Ma, Jing AU - Ma J FAU - Easton, John AU - Easton J FAU - Vadodaria, Bhavin AU - Vadodaria B FAU - Onar-Thomas, Arzu AU - Onar-Thomas A FAU - Lin, Tong AU - Lin T FAU - Li, Shaoyi AU - Li S FAU - Pounds, Stanley AU - Pounds S FAU - Paugh, Steven AU - Paugh S FAU - Zhao, David AU - Zhao D FAU - Kawauchi, Daisuke AU - Kawauchi D FAU - Roussel, Martine F AU - Roussel MF FAU - Finkelstein, David AU - Finkelstein D FAU - Ellison, David W AU - Ellison DW FAU - Lau, Ching C AU - Lau CC FAU - Bouffet, Eric AU - Bouffet E FAU - Hassall, Tim AU - Hassall T FAU - Gururangan, Sridharan AU - Gururangan S FAU - Cohn, Richard AU - Cohn R FAU - Fulton, Robert S AU - Fulton RS FAU - Fulton, Lucinda L AU - Fulton LL FAU - Dooling, David J AU - Dooling DJ FAU - Ochoa, Kerri AU - Ochoa K FAU - Gajjar, Amar AU - Gajjar A FAU - Mardis, Elaine R AU - Mardis ER FAU - Wilson, Richard K AU - Wilson RK FAU - Downing, James R AU - Downing JR FAU - Zhang, Jinghui AU - Zhang J FAU - Gilbertson, Richard J AU - Gilbertson RJ LA - eng GR - R01 CA129541/CA/NCI NIH HHS/United States GR - R01CA129541/CA/NCI NIH HHS/United States GR - P01CA96832/CA/NCI NIH HHS/United States GR - P30CA021765/CA/NCI NIH HHS/United States GR - P30 CA021765/CA/NCI NIH HHS/United States GR - P01 CA096832/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Nature JT - Nature JID - 0410462 RN - 0 (Antigens, CD) RN - 0 (CDH1 protein, human) RN - 0 (CTNNB1 protein, human) RN - 0 (Cadherins) RN - 0 (Cdh1 Proteins) RN - 0 (Cell Cycle Proteins) RN - 0 (Fzr1 protein, mouse) RN - 0 (Hedgehog Proteins) RN - 0 (Histones) RN - 0 (Nuclear Proteins) RN - 0 (SHH protein, human) RN - 0 (Transcription Factors) RN - 0 (Wnt Proteins) RN - 0 (ZMYM3 protein, human) RN - 0 (beta Catenin) RN - EC 1.14.11.- (Histone Demethylases) RN - EC 1.14.11.- (KDM6A protein, human) RN - EC 2.3.1.48 (CREB-Binding Protein) RN - EC 2.3.1.48 (CREBBP protein, human) RN - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases) RN - EC 2.7.1.137 (PIK3CA protein, human) RN - EC 3.6.1.- (DDX3X protein, human) RN - EC 3.6.1.- (SMARCA4 protein, human) RN - EC 3.6.4.- (DNA Helicases) RN - EC 3.6.4.13 (DEAD-box RNA Helicases) SB - IM MH - Animals MH - Antigens, CD MH - CREB-Binding Protein/genetics MH - Cadherins/genetics MH - Cdh1 Proteins MH - Cell Cycle Proteins/deficiency/genetics MH - Cell Lineage MH - Cerebellar Neoplasms/*classification/*genetics/pathology MH - Child MH - Class I Phosphatidylinositol 3-Kinases MH - DEAD-box RNA Helicases/genetics MH - DNA Copy Number Variations MH - DNA Helicases/genetics MH - DNA Mutational Analysis MH - Disease Models, Animal MH - Genome, Human/genetics MH - Genomics MH - Hedgehog Proteins/metabolism MH - Histone Demethylases/genetics MH - Histones/metabolism MH - Humans MH - Medulloblastoma/*classification/*genetics/pathology MH - Methylation MH - Mice MH - Mutation/*genetics MH - Nuclear Proteins/genetics MH - Phosphatidylinositol 3-Kinases/genetics MH - Transcription Factors/genetics MH - Wnt Proteins/metabolism MH - beta Catenin/genetics PMC - PMC3412905 MID - NIHMS374717 EDAT- 2012/06/23 06:00 MHDA- 2012/09/05 06:00 PMCR- 2013/02/02 CRDT- 2012/06/23 06:00 PHST- 2012/01/13 00:00 [received] PHST- 2012/05/02 00:00 [accepted] PHST- 2012/06/23 06:00 [entrez] PHST- 2012/06/23 06:00 [pubmed] PHST- 2012/09/05 06:00 [medline] PHST- 2013/02/02 00:00 [pmc-release] AID - nature11213 [pii] AID - 10.1038/nature11213 [doi] PST - ppublish SO - Nature. 2012 Aug 2;488(7409):43-8. doi: 10.1038/nature11213.