EGAGenomicsIllumina HiSeq 2000, Illumina Genome Analyzer IIxWhole Genome Sequencinghttps://ega-archive.org/studies/EGAS00001000085EGAEGA study EGAS00001000085Whole Genome DNA Sequencing of matched brain tumor-normal pairs (ICGC)ICGC Germany PedBrain Medulloblastoma Pilot_2_LMrestrictedEGAGenomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations.Rausch Tobias T, Jones David T W DT, Zapatka Marc M, Stütz Adrian M AM, Zichner Thomas T, Weischenfeldt Joachim J, Jäger Natalie N, Remke Marc M, Shih David D, Northcott Paul A PA, Pfaff Elke E, Tica Jelena J, Wang Qi Q, Massimi Luca L, Witt Hendrik H, Bender Sebastian S, Pleier Sabrina S, Cin Huriye H, Hawkins Cynthia C, Beck Christian C, von Deimling Andreas A, Hans Volkmar V, Brors Benedikt B, Eils Roland R, Scheurlen Wolfram W, Blake Jonathon J, Benes Vladimir V, Kulozik Andreas E AE, Witt Olaf O, Martin Dianna D, Zhang Cindy C, Porat Rinnat R, Merino Diana M DM, Wasserman Jonathan J, Jabado Nada N, Fontebasso Adam A, Bullinger Lars L, Rücker Frank G FG, Döhner Konstanze K, Döhner Hartmut H, Koster Jan J, Molenaar Jan J JJ, Versteeg Rogier R, Kool Marcel M, Tabori Uri U, Malkin David D, Korshunov Andrey A, Taylor Michael D MD, Lichter Peter P, Pfister Stefan M SM, Korbel Jan O JOMaterials, localized primitive neuroectodermal tumor, MDB, Arachnoidal Cerebellar Sarcoma, cerebellar medulloblastoma, Gene, Genome Stability, desmoplastic, Genomic Stability, medulloblastoma with extensive nodularity, CNS PNET, Cistrons, Melanocytic, Stabilities, Stability, medulloblastoma, CPNET, Instabilities, Genomic Instabilities, Circumscribed Arachnoidal, Medullomyoblastomas, Genetic Materials, Medulloblastoma, Cerebellar, infratentorial primitive neuroectodermal tumour, Desmoplastic Medulloblastomas, Genome Stabilities, Genetic Material, Genome Instabilities, Medulloblastomas, Genetic, Circumscribed, Desmoplastic, Childhood, Adult Medulloblastomas, Adult Medulloblastoma, Adult, Melanocytic Medulloblastomas, localised primitive neuroectodermal tumour, Genomic, Sarcoma, childhood, Genome Instability, infratentorial 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TAF1falseLinking genes, genomic instability and molecular subgroups in medulloblastomaBrain tumors are the second most common pediatric cancer and carry the highest mortality rates in this age group. Medulloblastoma is the most frequent malignant brain tumor of childhood. Recent studies indicate that medulloblastoma comprises at least four sub-entities (SHH-signaling, WNT-signaling, Group-C, Group-D) that differ in molecular alterations, cell of origin, clinicopathological features and outcome. Further characterization of the entire spectrum of genomic alterations underlying the formation of these distinct groups is urgently needed to identify diagnostic and prognostic biomarkers for clinical management and uncover novel therapeutic targets.2019-10-31 12:52:10EGAS00001000085960622265402EGAD00001000697EGAD00001000027EGAC00001000010