PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-6 (6)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma 
TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% ± 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% ± 2% vs. 57.4% ± 1.8% (p < 0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% ± 1.5% in lithium treated cells vs. 56.6 ± 3% (p < 0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% ± 8% for lithium treated cells vs. 27% ± 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-014-0174-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s40478-014-0174-y
PMCID: PMC4297452  PMID: 25539912
2.  Medulloblastomics: The End of the Beginning 
Nature reviews. Cancer  2012;12(12):818-834.
Subgrouping of medulloblastoma by microarray expression profiling has dramatically changed our perspective of this malignant childhood brain tumour. Now, the availability of next-generation sequencing and complementary high-density genomic technologies has unmasked novel driver mutations in each medulloblastoma subgroup. The implications of these findings for the management of patients are readily apparent, pinpointing previously unappreciated diagnostic and therapeutic targets. Here, we summarize the ’explosion’ of data emerging from the application of modern genomics to medulloblastoma, and in particular the recurrent targets of mutation in medulloblastoma subgroups. These data are making their way into contemporary clinical trials as we seek to integrate conventional and molecularly targeted therapies.
doi:10.1038/nrc3410
PMCID: PMC3889646  PMID: 23175120
3.  Subgroup specific structural variation across 1,000 medulloblastoma genomes 
Northcott, Paul A | Shih, David JH | Peacock, John | Garzia, Livia | Morrissy, Sorana | Zichner, Thomas | Stütz, Adrian M | Korshunov, Andrey | Reimand, Juri | Schumacher, Steven E | Beroukhim, Rameen | Ellison, David W | Marshall, Christian R | Lionel, Anath C | Mack, Stephen | Dubuc, Adrian | Yao, Yuan | Ramaswamy, Vijay | Luu, Betty | Rolider, Adi | Cavalli, Florence | Wang, Xin | Remke, Marc | Wu, Xiaochong | Chiu, Readman YB | Chu, Andy | Chuah, Eric | Corbett, Richard D | Hoad, Gemma R | Jackman, Shaun D | Li, Yisu | Lo, Allan | Mungall, Karen L | Nip, Ka Ming | Qian, Jenny Q | Raymond, Anthony GJ | Thiessen, Nina | Varhol, Richard J | Birol, Inanc | Moore, Richard A | Mungall, Andrew J | Holt, Robert | Kawauchi, Daisuke | Roussel, Martine F | Kool, Marcel | Jones, David TW | Witt, Hendrick | Fernandez-L, Africa | Kenney, Anna M | Wechsler-Reya, Robert J | Dirks, Peter | Aviv, Tzvi | Grajkowska, Wieslawa A | Perek-Polnik, Marta | Haberler, Christine C | Delattre, Olivier | Reynaud, Stéphanie S | Doz, François F | Pernet-Fattet, Sarah S | Cho, Byung-Kyu | Kim, Seung-Ki | Wang, Kyu-Chang | Scheurlen, Wolfram | Eberhart, Charles G | Fèvre-Montange, Michelle | Jouvet, Anne | Pollack, Ian F | Fan, Xing | Muraszko, Karin M | Gillespie, G. Yancey | Di Rocco, Concezio | Massimi, Luca | Michiels, Erna MC | Kloosterhof, Nanne K | French, Pim J | Kros, Johan M | Olson, James M | Ellenbogen, Richard G | Zitterbart, Karel | Kren, Leos | Thompson, Reid C | Cooper, Michael K | Lach, Boleslaw | McLendon, Roger E | Bigner, Darell D | Fontebasso, Adam | Albrecht, Steffen | Jabado, Nada | Lindsey, Janet C | Bailey, Simon | Gupta, Nalin | Weiss, William A | Bognár, László | Klekner, Almos | Van Meter, Timothy E | Kumabe, Toshihiro | Tominaga, Teiji | Elbabaa, Samer K | Leonard, Jeffrey R | Rubin, Joshua B | Liau, Linda M | Van Meir, Erwin G | Fouladi, Maryam | Nakamura, Hideo | Cinalli, Giuseppe | Garami, Miklós | Hauser, Peter | Saad, Ali G | Iolascon, Achille | Jung, Shin | Carlotti, Carlos G | Vibhakar, Rajeev | Ra, Young Shin | Robinson, Shenandoah | Zollo, Massimo | Faria, Claudia C | Chan, Jennifer A | Levy, Michael L | Sorensen, Poul HB | Meyerson, Matthew | Pomeroy, Scott L | Cho, Yoon-Jae | Bader, Gary D | Tabori, Uri | Hawkins, Cynthia E | Bouffet, Eric | Scherer, Stephen W | Rutka, James T | Malkin, David | Clifford, Steven C | Jones, Steven JM | Korbel, Jan O | Pfister, Stefan M | Marra, Marco A | Taylor, Michael D
Nature  2012;488(7409):49-56.
Summary
Medulloblastoma, the most common malignant pediatric brain tumour, is currently treated with non-specific cytotoxic therapies including surgery, whole brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, prior attempts to identify targets for therapy have been underpowered due to small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup enriched. The most common region of focal copy number gain is a tandem duplication of the Parkinson’s disease gene SNCAIP, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1 that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGFβ signaling in Group 3, and NF-κB signaling in Group 4 suggest future avenues for rational, targeted therapy.
doi:10.1038/nature11327
PMCID: PMC3683624  PMID: 22832581
4.  ICGC PedBrain: Dissecting the genomic complexity underlying medulloblastoma 
Jones, David TW | Jäger, Natalie | Kool, Marcel | Zichner, Thomas | Hutter, Barbara | Sultan, Marc | Cho, Yoon-Jae | Pugh, Trevor J | Hovestadt, Volker | Stütz, Adrian M | Rausch, Tobias | Warnatz, Hans-Jörg | Ryzhova, Marina | Bender, Sebastian | Sturm, Dominik | Pleier, Sabrina | Cin, Huriye | Pfaff, Elke | Sieber, Laura | Wittmann, Andrea | Remke, Marc | Witt, Hendrik | Hutter, Sonja | Tzaridis, Theophilos | Weischenfeldt, Joachim | Raeder, Benjamin | Avci, Meryem | Amstislavskiy, Vyacheslav | Zapatka, Marc | Weber, Ursula D | Wang, Qi | Lasitschka, Bärbel | Bartholomae, Cynthia C | Schmidt, Manfred | von Kalle, Christof | Ast, Volker | Lawerenz, Chris | Eils, Jürgen | Kabbe, Rolf | Benes, Vladimir | van Sluis, Peter | Koster, Jan | Volckmann, Richard | Shih, David | Betts, Matthew J | Russell, Robert B | Coco, Simona | Tonini, Gian Paolo | Schüller, Ulrich | Hans, Volkmar | Graf, Norbert | Kim, Yoo-Jin | Monoranu, Camelia | Roggendorf, Wolfgang | Unterberg, Andreas | Herold-Mende, Christel | Milde, Till | Kulozik, Andreas E | von Deimling, Andreas | Witt, Olaf | Maass, Eberhard | Rössler, Jochen | Ebinger, Martin | Schuhmann, Martin U | Frühwald, Michael C | Hasselblatt, Martin | Jabado, Nada | Rutkowski, Stefan | von Bueren, André O | Williamson, Dan | Clifford, Steven C | McCabe, Martin G | Collins, V. Peter | Wolf, Stephan | Wiemann, Stefan | Lehrach, Hans | Brors, Benedikt | Scheurlen, Wolfram | Felsberg, Jörg | Reifenberger, Guido | Northcott, Paul A | Taylor, Michael D | Meyerson, Matthew | Pomeroy, Scott L | Yaspo, Marie-Laure | Korbel, Jan O | Korshunov, Andrey | Eils, Roland | Pfister, Stefan M | Lichter, Peter
Nature  2012;488(7409):100-105.
Summary
Medulloblastoma is an aggressively-growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and displays tremendous biological and clinical heterogeneity1. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life.
Four tumour subgroups with distinct clinical, biological and genetic profiles are currently discriminated2,3. WNT tumours, displaying activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens4. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis2. Group 3 & 4 tumours are molecularly less well-characterised, and also present the greatest clinical challenges2,3,5. The full repertoire of genetic events driving this distinction, however, remains unclear.
Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs. Tetraploidy was identified as a frequent early event in Group 3 & 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA-sequencing confirmed these alterations, and revealed the expression of the first medulloblastoma fusion genes. Chromatin modifiers were frequently altered across all subgroups.
These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 & 4 patients.
doi:10.1038/nature11284
PMCID: PMC3662966  PMID: 22832583
6.  Genome-Wide Analysis of Subependymomas Shows Underlying Chromosomal Copy Number Changes Involving Chromosomes 6, 7, 8 and 14 in a Proportion of Cases 
Subependymomas (SE) are slow-growing brain tumors that tend to occur within the ventricles of middle-aged and elderly adults. The World Health Organization classifies these tumors within the ependymoma group. Previous limited analysis of this tumor type had not revealed significant underlying cytogenetic abnormalities.
We have used microarray comparative genomic hybridization to study a series of SE (n = 12). A whole-genome array at 0.97-Mb resolution showed copy number abnormalities in five of 12 cases (42%). Two cases (17%) showed regions of loss on chromosome 6. More detailed analysis of all cases using a chromosome 6 tile-path array confirmed the presence of overlapping regions of loss in only these two cases. One of these cases also showed trisomy chromosome 7. Monosomy of chromosome 8 was seen in a further two cases (17%), and a partial loss on chromosome 14 was observed in one additional case.
This is the first array-based, genome-wide study of SE. The observation that five of 12 cases examined (42%) at 0.97-Mb resolution showed chromosomal copy number abnormalities is a novel finding in this tumor type.
doi:10.1111/j.1750-3639.2008.00148.x
PMCID: PMC2659379  PMID: 18397339
aCGH; array comparative genomic hybridization; ependymoma; microarray; subependymoma; whole genome

Results 1-6 (6)