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Paul A. Northcott - One of the best experts on this subject based on the ideXlab platform.

  • abstract lb 203 structural variants shuffle chromatin to activate gfi1 family oncogenes in Medulloblastoma
    Cancer Research, 2014
    Co-Authors: Catherine Lee, Paul A. Northcott, Thomas Zichner, Peter Lichter, Jan O. Korbel, Stefan M. Pfister, Robert J Wechslerreya
    Abstract:

    Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Medulloblastoma is a highly malignant pediatric brain tumor currently treated with a combination of surgery, radiation, and non-specific chemotherapy, posing a significant threat to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of Medulloblastoma and identified four distinct molecular subgroups. Group 3 and Group 4 subgroup Medulloblastomas account for the majority of pediatric cases, yet, oncogenic drivers for these subtypes remain poorly understood. Here we report a series of prevalent, highly disparate genomic structural rearrangements, restricted to Groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto- oncogenes, GFI1 & GFI1B. Diverse mechanisms of structural variation activate GFI1/GFI1B expression through relocation of their coding sequences to genomic regions of transcriptionally active chromatin. Moreover, Gfi1 and Gfi1b each cooperate with Myc, an important oncogene in Group 3 Medulloblastomas, to drive tumor initiation in mice. These data reveal GFI1 and GFI1B as novel Medulloblastoma oncogenes, warranting their prioritization for molecularly targeted therapy of a marked proportion of Group 3 and Group 4 patients. Citation Format: Catherine Lee, Paul A. Northcott, Thomas Zichner, Peter Lichter, Jan O. Korbel, Stefan M. Pfister, Robert J. Wechsler-Reya. Structural variants shuffle chromatin to activate GFI1 family oncogenes in Medulloblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-203. doi:10.1158/1538-7445.AM2014-LB-203

  • enhancer hijacking activates gfi1 family oncogenes in Medulloblastoma
    Nature, 2014
    Co-Authors: Paul A. Northcott, Thomas Zichner, Adrian M Stutz, Serap Erkek, Daisuke Kawauchi, David Shih, Volker Hovestadt, Marc Zapatka, Dominik Sturm, David T W Jones
    Abstract:

    Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of Medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup Medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent Medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.

  • structural variants shuffle chromatin to activate gfi1 family oncogenes in Medulloblastoma
    Neuro-oncology, 2014
    Co-Authors: Paul A. Northcott, Catherine Lee, Thomas Zichner, Peter Lichter, Jan O. Korbel, Robert J Wechslerreya, Stefan M. Pfister
    Abstract:

    BACKGROUND: Genomics has illuminated the extensive intertumoural heterogeneity of Medulloblastoma and identified at least four distinct molecular subgroups of the disease. Group 3 and Group 4 subgroup Medulloblastomas account for the majority of pediatric cases, yet, oncogenic drivers for these subtypes remain poorly understood. Exome and genome sequencing studies have confirmed a paucity of recurrent gene-level mutations in Group 3 and Group 4, suggesting that alternative oncogenic mechanisms must account for the large fraction of cases that cannot currently be explained by single-nucleotide variants or insertions/deletions alone. METHODS: Analysis of whole-genome sequencing data consisting of 128 primary Group 3 and Group 4 Medulloblastoma samples facilitated a systematic, high-resolution screen for chromosomal breakpoints recurrently targeting novel Medulloblastoma drivers by structural variation. A non-overlapping set of 22 Medulloblastomas was sequenced by long-range paired-end mapping in order to validate structural variants observed in our discovery cohort. Select cases of interest were also investigated at the epigenome-level using a combination of whole-genome bisulphite sequencing and enhancer histone mark ChIP-sequencing. RESULTS: Our systematic analysis of structural variants identified highly disparate genomic structural rearrangements, restricted to Groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 & GFI1B. Diverse mechanisms of structural variation, including duplications, deletions, inversions, translocations, and other complex genomic variants were observed in nearly all GFI1/1B-activated cases. Comprehensive characterization of these structural variants established that GFI1/GFI1B expression becomes activated through relocation of their coding sequences to genomic regions of transcriptionally active chromatin. Functional analyses performed in mice confirmed the oncogenicity of Gfi1/Gfi1b in the context of Medulloblastoma and demonstrated apparent synergy between both of these candidates and the c-Myc oncogene. CONCLUSIONS: These studies establish GFI1 and GFI1B as novel, highly prevalent Medulloblastoma oncogenes specifically active in Group 3 and Group 4. Given their high frequencies of activation, GFI1 and GFI1B represent excellent candidates for prioritization of molecularly targeted therapy aimed at treatment of a significant proportion of Group 3 and Group 4 Medulloblastoma patients. SECONDARY CATEGORY: Pediatrics.

  • recurrence patterns across Medulloblastoma subgroups an integrated clinical and molecular analysis
    Lancet Oncology, 2013
    Co-Authors: Vijay Ramaswamy, Claudia C Faria, Adrian M Dubuc, Marc Remke, David Shih, Yoonjae Cho, Eric Bouffet, Sebastien Perreault, Betty Luu, Paul A. Northcott
    Abstract:

    Summary Background Recurrent Medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that Medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in Medulloblastoma recurrence patterns. Methods We retrospectively identified a discovery cohort of all recurrent Medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent Medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent Medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. Results Cohort 1 consisted of 30 patients with recurrent Medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent Medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p Interpretation Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main Medulloblastoma subgroups. Significant differences in the location and timing of recurrence across Medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases. Funding Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto.

  • oncogenic yap promotes radioresistance and genomic instability in Medulloblastoma through igf2 mediated akt activation
    Oncogene, 2012
    Co-Authors: Africa Fernandezl, Paul A. Northcott, Eric C Holland, Michael D Taylor, Massimo Squatrito, Aashir Awan, Zaher Nahle, Anna M Kenney
    Abstract:

    Radiation therapy remains the standard of care for many cancers, including the malignant pediatric brain tumor Medulloblastoma. Radiation leads to long-term side effects, whereas radioresistance contributes to tumor recurrence. Radio-resistant Medulloblastoma cells occupy the perivascular niche. They express Yes-associated protein (YAP), a Sonic hedgehog (Shh) target markedly elevated in Shh-driven Medulloblastomas. Here we report that YAP accelerates tumor growth and confers radioresistance, promoting ongoing proliferation after radiation. YAP activity enables cells to enter mitosis with un-repaired DNA through driving insulin-like growth factor 2 (IGF2) expression and Akt activation, resulting in ATM/Chk2 inactivation and abrogation of cell cycle checkpoints. Our results establish a central role for YAP in counteracting radiation-based therapies and driving genomic instability, and indicate the YAP/IGF2/Akt axis as a therapeutic target in Medulloblastoma.

David W. Ellison - One of the best experts on this subject based on the ideXlab platform.

  • pediatric posterior fossa Medulloblastoma the role of diffusion imaging in identifying molecular groups
    Journal of Neuroimaging, 2020
    Co-Authors: Nihaal Reddy, David W. Ellison, Bruno P Soares, Kathryn A Carson, Thierry A G M Huisman, Zoltan Patay
    Abstract:

    Background and purpose The molecular groups WNT activated (WNT), Sonic hedgehog activated (SHH), group 3, and group 4 are biologically and clinically distinct forms of Medulloblastoma. We evaluated apparent diffusion coefficient (ADC) values' utility in differentiating/predicting Medulloblastoma groups at the initial diagnostic imaging evaluation and prior to surgery. Methods We retrospectively measured the ADC values of the enhancing, solid portion of the tumor (EST) and of the whole tumor (WT) and performed Kruskal-Wallis testing to compare the absolute tumor ADC values and cerebellar and thalamic ratios of three Medulloblastoma groups (WNT, SHH, and group 3/group 4 combined). Results Ninety-three children (65 males) were included. Fifty-seven children had group 3/group 4, 27 had SHH, and 9 had WNT Medulloblastomas. The median absolute ADC values in the EST and WT were .719 × 10-3 and .864 × 10-3 mm2 /s for group 3/group 4; .660 × 10-3 and .965 × 10-3 mm2 /s for SHH; and .594 × 10-3 and .728 × 10-3 mm2 /s for WNT Medulloblastomas (P = .02 and .13). The median ratio of ADC values in the EST or the WT to normal cerebellar tissue was highest for group 3/group 4 and lowest for WNT Medulloblastomas (P = .03 and .09), with similar results in pairwise comparisons of the corresponding thalamic ADC values (P = .02 and .06). Conclusion ADC analysis of a tumor's contrast-enhancing solid portion may aid preoperative molecular classification/prediction of pediatric Medulloblastomas and may facilitate optimal surgical treatment planning, reducing surgery-induced morbidity.

  • yap1 is amplified and up regulated in hedgehog associated Medulloblastomas and mediates sonic hedgehog driven neural precursor proliferation
    Genes & Development, 2009
    Co-Authors: Africa Fernandezl, David W. Ellison, Paul A. Northcott, James T Dalton, Charles H Fraga, Stephane Angers, Michael D Taylor, Anna M Kenney
    Abstract:

    Medulloblastoma is the most common solid malignancy of childhood, with treatment side effects reducing survivors’ quality of life and lethality being associated with tumor recurrence. Activation of the Sonic hedgehog (Shh) signaling pathway is implicated in human Medulloblastomas. Cerebellar granule neuron precursors (CGNPs) depend on signaling by the morphogen Shh for expansion during development, and have been suggested as a cell of origin for certain Medulloblastomas. Mechanisms contributing to Shh pathway-mediated proliferation and transformation remain poorly understood. We investigated interactions between Shh signaling and the recently described tumor-suppressive Hippo pathway in the developing brain and Medulloblastomas. We report up-regulation of the oncogenic transcriptional coactivator yes-associated protein 1 (YAP1), which is negatively regulated by the Hippo pathway, in human Medulloblastomas with aberrant Shh signaling. Consistent with conserved mechanisms between brain tumorigenesis and development, Shh induces YAP1 expression in CGNPs. Shh also promotes YAP1 nuclear localization in CGNPs, and YAP1 can drive CGNP proliferation. Furthermore, YAP1 is found in cells of the perivascular niche, where proposed tumor-repopulating cells reside. Post-irradiation, YAP1 was found in newly growing tumor cells. These findings implicate YAP1 as a new Shh effector that may be targeted by Medulloblastoma therapies aimed at eliminating Medulloblastoma recurrence.

  • Dual and opposing roles of primary cilia in Medulloblastoma development.
    Nature Medicine, 2009
    Co-Authors: Young-goo Han, Hong Joo Kim, Andrzej A. Dlugosz, David W. Ellison, Richard J. Gilbertson, Arturo Alvarez-buylla
    Abstract:

    Recent work has shown that primary cilia are essential for Hedgehog (Hh) signaling during mammalian development. It is also known that aberrant Hh signaling can lead to cancer, but the role of primary cilia in oncogenesis is not known. Cerebellar granule neuron precursors (GNPs) can give rise to Medulloblastomas, the most common malignant brain tumor in children. The primary cilium and Hh signaling are required for GNP proliferation. We asked whether primary cilia in GNPs have a role in Medulloblastoma growth in mice. Genetic ablation of primary cilia blocked Medulloblastoma formation when this tumor was driven by a constitutively active Smoothened protein (Smo), an upstream activator of Hh signaling. In contrast, removal of cilia was required for Medulloblastoma growth by a constitutively active glioma-associated oncogene family zinc finger-2 (GLI2), a downstream transcription factor. Thus, primary cilia are either required for or inhibit Medulloblastoma formation, depending on the initiating oncogenic event. Remarkably, the presence or absence of cilia was associated with specific variants of human Medulloblastomas; primary cilia were found in Medulloblastomas with activation in HH or WNT signaling but not in most Medulloblastomas in other distinct molecular subgroups. Primary cilia could serve as a diagnostic tool and provide new insights into the mechanism of tumorigenesis.

  • the mir 17 92 polycistron is up regulated in sonic hedgehog driven Medulloblastomas and induced by n myc in sonic hedgehog treated cerebellar neural precursors
    Cancer Research, 2009
    Co-Authors: Paul A. Northcott, David W. Ellison, Africa Fernandezl, John P Hagan, Wesia Grajkowska, Yancey Gillespie, Richard Grundy, Timothy Van Meter, James T Rutka, Carlo M Croce
    Abstract:

    Medulloblastoma is the most common malignant pediatric brain tumour and mechanisms underlying its development are poorly understood. We identified recurrent amplification of the miR-17/92 polycistron proto-oncogene in 6% of pediatric Medulloblastomas by high-resolution SNP genotyping arrays and subsequent interphase FISH on a human Medulloblastoma tissue microarray. Profiling the expression of 427 mature microRNAs in a series of 90 primary human Medulloblastomas revealed that components of the miR-17/92 polycistron are the most highly up-regulated microRNAs in Medulloblastoma. Expression of miR-17/92 was highest in the subgroup of Medulloblastomas associated with activation of the Sonic Hedgehog (Shh) signaling pathway as compared to other subgroups of Medulloblastoma. Medulloblastomas in which miR-17/92 was up-regulated also had elevated levels of MYC/MYCN expression. Consistent with its regulation by Shh, we observed that Shh treatment of primary cerebellar granule neuron precursors (CGNPs), proposed cells-of-origin for the Shh-associated Medulloblastomas, resulted in increased miR-17/92 expression. In CGNPs, the Shh effector N-myc, but not Gli1, induced miR-17/92 expression. Ectopic miR-17/92 expression in CGNPs synergized with exogenous Shh to increase proliferation and also enabled them to proliferate in the absence of Shh. We conclude that miR-17/92 is a positive effector of Shh-mediated proliferation, and that aberrant expression/amplification of this miR confers a growth advantage to Medulloblastomas.

  • identification of cd15 as a marker for tumor propagating cells in a mouse model of Medulloblastoma
    Cancer Cell, 2009
    Co-Authors: David W. Ellison, Roger E Mclendon, Tracyann Read, Marie P Fogarty, Shirley L Markant, Zhengzheng Wei, Phillip G Febbo, Robert J Wechslerreya
    Abstract:

    Summary The growth of many cancers depends on self-renewing cells called cancer stem cells or tumor-propagating cells (TPCs). In human brain tumors, cells expressing the stem cell marker CD133 have been implicated as TPCs. Here we show that tumors from a model of Medulloblastoma, the Patched mutant mouse, are propagated not by CD133 + cells but by cells expressing the progenitor markers Math1 and CD15/SSEA-1. These cells have a distinct expression profile that suggests increased proliferative capacity and decreased tendency to undergo apoptosis and differentiation. CD15 is also found in a subset of human Medulloblastomas, and tumors expressing genes similar to those found in murine CD15 + cells have a poorer prognosis. Thus, CD15 may represent an important marker for TPCs in Medulloblastoma.

Marc Remke - One of the best experts on this subject based on the ideXlab platform.

  • foretinib is effective therapy for metastatic sonic hedgehog Medulloblastoma
    Cancer Research, 2015
    Co-Authors: Claudia C Faria, Adrian M Dubuc, Marc Remke, Brian Golbourn, Roberto J Diaz, Sameer Agnihotri, Amanda Luck, Nesrin Sabha, Samantha Olsen, Xiaochong Wu
    Abstract:

    Medulloblastoma is the most common malignant pediatric brain tumor, with metastases present at diagnosis conferring a poor prognosis. Mechanisms of dissemination are poorly understood and metastatic lesions are genetically divergent from the matched primary tumor. Effective and less toxic therapies that target both compartments have yet to be identified. Here, we report that the analysis of several large nonoverlapping cohorts of patients with Medulloblastoma reveals MET kinase as a marker of sonic hedgehog (SHH)–driven Medulloblastoma. Immunohistochemical analysis of phosphorylated, active MET kinase in an independent patient cohort confirmed its correlation with increased tumor relapse and poor survival, suggesting that patients with SHH Medulloblastoma may benefit from MET-targeted therapy. In support of this hypothesis, we found that the approved MET inhibitor foretinib could suppress MET activation, decrease tumor cell proliferation, and induce apoptosis in SHH Medulloblastomas in vitro and in vivo. Foretinib penetrated the blood–brain barrier and was effective in both the primary and metastatic tumor compartments. In established mouse xenograft or transgenic models of metastatic SHH Medulloblastoma, foretinib administration reduced the growth of the primary tumor, decreased the incidence of metastases, and increased host survival. Taken together, our results provide a strong rationale to clinically evaluate foretinib as an effective therapy for patients with SHH-driven Medulloblastoma. Cancer Res; 75(1); 134–46. ©2014 AACR.

  • wnt activation by lithium abrogates tp53 mutation associated radiation resistance in Medulloblastoma
    Acta neuropathologica communications, 2014
    Co-Authors: Nataliya Zhukova, Marc Remke, Vijay Ramaswamy, Dianna Martin, Pedro Castelobranco, Cindy H Zhang, Michael Fraser, Ken Tse, Raymond Poon, David Shih
    Abstract:

    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.

  • the g protein α subunit gαs is a tumor suppressor in sonic hedgehog driven Medulloblastoma
    Nature Medicine, 2014
    Co-Authors: Liguo Zhang, Marc Remke, David Shih, Vijay Ramaswamy, Ying Chen, Haibo Wang, Yaqi Deng, Yong Xia, Fan Wang, Wenhao Zhou
    Abstract:

    Medulloblastoma, the most common malignant childhood brain tumor, exhibits distinct molecular subtypes and cellular origins. Genetic alterations driving Medulloblastoma initiation and progression remain poorly understood. Herein, we identify GNAS, encoding the G protein Gαs, as a potent tumor suppressor gene that, when expressed at low levels, defines a subset of aggressive Sonic hedgehog (SHH)-driven human Medulloblastomas. Ablation of the single Gnas gene in anatomically distinct progenitors in mice is sufficient to induce Shh-associated Medulloblastomas, which recapitulate their human counterparts. Gαs is highly enriched at the primary cilium of granule neuron precursors and suppresses Shh signaling by regulating both the cAMP-dependent pathway and ciliary trafficking of Hedgehog pathway components. Elevation in levels of a Gαs effector, cAMP, effectively inhibits tumor cell proliferation and progression in Gnas-ablated mice. Thus, our gain- and loss-of-function studies identify a previously unrecognized tumor suppressor function for Gαs that can be found consistently across Shh-group Medulloblastomas of disparate cellular and anatomical origins, highlighting G protein modulation as a potential therapeutic avenue.

  • foretinib is effective therapy for metastatic sonic hedgehog Medulloblastoma
    Neuro-oncology, 2014
    Co-Authors: Christian A Smith, Claudia C Faria, Adrian M Dubuc, Marc Remke, Brian Golbourn, Roberto J Diaz, Sameer Agnihotri, Amanda Luck, Nesrin Sabha, Samantha Olsen
    Abstract:

    BACKGROUND: (blind field). METHODS: Expression profiling, molecular subgrouping and analysis of somatic copy number alterations were conducted on multiple independent cohorts of patient tumour samples to examine intermediates of the MET signaling pathway in Medulloblastoma. To examine the in vitro and in vivo effects of foretinib treatment; MET signalling biochemical analysis; migration and invasion assays; and foretinib pharmacokinetic studies were performed. Medulloblastoma xenografts and transgenic mouse models were used to evaluate foretinib treatment in vivo. RESULTS: We analyzed three large non-overlapping cohorts of Medulloblastoma patients (discovery cohort, n = 199; validation cohort 1, n = 439; validation cohort 2, n = 285) and demonstrated that cMET, known to be involved in tumor progression and dissemination, is a marker of sonic hedgehog (SHH) Medulloblastoma. Importantly, immunohistochemical analysis of activated cMET (phosphorylated cMET) in another independent patient cohort (n = 385) revealed that cMET activation correlates with increased tumor relapse and a poor survival in pediatric patients with SHH Medulloblastomas, thus defining a subset of patients that may benefit from cMET targeted therapy. We show that foretinib, an FDA approved inhibitor of cMET, suppresses cMET activation, decreases proliferation and induces apoptosis, both in Medulloblastoma cell lines and in SHH Medulloblastoma xenografts. Furthermore foretinib penetrates the blood-brain barrier and is effective both in the primary and in the metastatic compartments. Treatment of mouse xenografts and of an aggressive transgenic model of metastatic SHH Medulloblastoma with foretinib reduced primary Medulloblastoma growth, decreased the incidence of metastases by 36% and increased survival by 45%. CONCLUSIONS: Our results provide strong rationale for advancing foretinib into clinical trials for SHH-driven Medulloblastomas. SECONDARY CATEGORY: Tumor Biology.

  • recurrence patterns across Medulloblastoma subgroups an integrated clinical and molecular analysis
    Lancet Oncology, 2013
    Co-Authors: Vijay Ramaswamy, Claudia C Faria, Adrian M Dubuc, Marc Remke, David Shih, Yoonjae Cho, Eric Bouffet, Sebastien Perreault, Betty Luu, Paul A. Northcott
    Abstract:

    Summary Background Recurrent Medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that Medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in Medulloblastoma recurrence patterns. Methods We retrospectively identified a discovery cohort of all recurrent Medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent Medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent Medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. Results Cohort 1 consisted of 30 patients with recurrent Medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent Medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p Interpretation Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main Medulloblastoma subgroups. Significant differences in the location and timing of recurrence across Medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases. Funding Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto.

Stefan M. Pfister - One of the best experts on this subject based on the ideXlab platform.

  • imaging characteristics of wingless pathway subgroup Medulloblastomas results from the german hit siop trial cohort
    American Journal of Neuroradiology, 2019
    Co-Authors: Annika Stock, Stefan M. Pfister, Dominik Sturm, Torsten Pietsch, Steven C Clifford, Martin Mynarek, Tobias Goschzik, Edward C Schwalbe
    Abstract:

    BACKGROUND AND PURPOSE: In addition to the 4 histopathologically defined entities of Medulloblastoma, 4 distinct genetically defined subgroups have been included in the World Health Organization classification of 2016. The smallest subgroup is the Medulloblastoma with activated wingless pathway. The goal of this study was to identify a typical MR imaging morphology in a larger number of pediatric patients with wingless pathway Medulloblastoma. MATERIALS AND METHODS: From January 2001 to October 2017, of 75 patients with histologically confirmed and molecularly subgrouped wingless pathway Medulloblastomas recruited to the German Pediatric Brain Tumor (HIT) trials, 38 patients (median age, 12.8 ± 4.6 years at diagnosis; 24 [63.2%] female) had preoperative imaging that passed the entry criteria for this study. Images were rated by the local standardized imaging criteria of the National Reference Center of Neuroradiology. Additionally, a modified laterality score was used to determine tumor localization and extension. RESULTS: Twenty-eight of 38 (73.7%) were primary midline tumors but with a lateral tendency in 39.3%. One extensively eccentric midline tumor was rated by the laterality score as in an off-midline position. Five tumors were found in the cerebellopontine angle; 3, in the deep white matter; and 2, in a cerebellar hemisphere. Leptomeningeal dissemination was rare (11.5%). In 60.5%, intratumoral blood-degradation products were found, and 26.3% showed cysts with blood contents. CONCLUSIONS: According to our observations, wingless pathway Medulloblastomas are not preferentially off-midline tumors as postulated in previous studies with smaller wingless pathway Medulloblastoma cohorts. Dense intratumoral blood-degradation products and cysts with blood contents are frequently found and might help to differentiate wingless pathway Medulloblastoma from other Medulloblastoma subtypes.

  • abstract lb 203 structural variants shuffle chromatin to activate gfi1 family oncogenes in Medulloblastoma
    Cancer Research, 2014
    Co-Authors: Catherine Lee, Paul A. Northcott, Thomas Zichner, Peter Lichter, Jan O. Korbel, Stefan M. Pfister, Robert J Wechslerreya
    Abstract:

    Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Medulloblastoma is a highly malignant pediatric brain tumor currently treated with a combination of surgery, radiation, and non-specific chemotherapy, posing a significant threat to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of Medulloblastoma and identified four distinct molecular subgroups. Group 3 and Group 4 subgroup Medulloblastomas account for the majority of pediatric cases, yet, oncogenic drivers for these subtypes remain poorly understood. Here we report a series of prevalent, highly disparate genomic structural rearrangements, restricted to Groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto- oncogenes, GFI1 & GFI1B. Diverse mechanisms of structural variation activate GFI1/GFI1B expression through relocation of their coding sequences to genomic regions of transcriptionally active chromatin. Moreover, Gfi1 and Gfi1b each cooperate with Myc, an important oncogene in Group 3 Medulloblastomas, to drive tumor initiation in mice. These data reveal GFI1 and GFI1B as novel Medulloblastoma oncogenes, warranting their prioritization for molecularly targeted therapy of a marked proportion of Group 3 and Group 4 patients. Citation Format: Catherine Lee, Paul A. Northcott, Thomas Zichner, Peter Lichter, Jan O. Korbel, Stefan M. Pfister, Robert J. Wechsler-Reya. Structural variants shuffle chromatin to activate GFI1 family oncogenes in Medulloblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-203. doi:10.1158/1538-7445.AM2014-LB-203

  • structural variants shuffle chromatin to activate gfi1 family oncogenes in Medulloblastoma
    Neuro-oncology, 2014
    Co-Authors: Paul A. Northcott, Catherine Lee, Thomas Zichner, Peter Lichter, Jan O. Korbel, Robert J Wechslerreya, Stefan M. Pfister
    Abstract:

    BACKGROUND: Genomics has illuminated the extensive intertumoural heterogeneity of Medulloblastoma and identified at least four distinct molecular subgroups of the disease. Group 3 and Group 4 subgroup Medulloblastomas account for the majority of pediatric cases, yet, oncogenic drivers for these subtypes remain poorly understood. Exome and genome sequencing studies have confirmed a paucity of recurrent gene-level mutations in Group 3 and Group 4, suggesting that alternative oncogenic mechanisms must account for the large fraction of cases that cannot currently be explained by single-nucleotide variants or insertions/deletions alone. METHODS: Analysis of whole-genome sequencing data consisting of 128 primary Group 3 and Group 4 Medulloblastoma samples facilitated a systematic, high-resolution screen for chromosomal breakpoints recurrently targeting novel Medulloblastoma drivers by structural variation. A non-overlapping set of 22 Medulloblastomas was sequenced by long-range paired-end mapping in order to validate structural variants observed in our discovery cohort. Select cases of interest were also investigated at the epigenome-level using a combination of whole-genome bisulphite sequencing and enhancer histone mark ChIP-sequencing. RESULTS: Our systematic analysis of structural variants identified highly disparate genomic structural rearrangements, restricted to Groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 & GFI1B. Diverse mechanisms of structural variation, including duplications, deletions, inversions, translocations, and other complex genomic variants were observed in nearly all GFI1/1B-activated cases. Comprehensive characterization of these structural variants established that GFI1/GFI1B expression becomes activated through relocation of their coding sequences to genomic regions of transcriptionally active chromatin. Functional analyses performed in mice confirmed the oncogenicity of Gfi1/Gfi1b in the context of Medulloblastoma and demonstrated apparent synergy between both of these candidates and the c-Myc oncogene. CONCLUSIONS: These studies establish GFI1 and GFI1B as novel, highly prevalent Medulloblastoma oncogenes specifically active in Group 3 and Group 4. Given their high frequencies of activation, GFI1 and GFI1B represent excellent candidates for prioritization of molecularly targeted therapy aimed at treatment of a significant proportion of Group 3 and Group 4 Medulloblastoma patients. SECONDARY CATEGORY: Pediatrics.

  • the histone acetyltransferase hmof is frequently downregulated in primary breast carcinoma and Medulloblastoma and constitutes a biomarker for clinical outcome in Medulloblastoma
    International Journal of Cancer, 2008
    Co-Authors: Stefan M. Pfister, Stephen Rea, Mikko Taipale, Frank Mendrzyk, Beate K Straub, Carina Ittrich, Olaf Thuerigen, Hanspeter Sinn, Asifa Akhtar
    Abstract:

    Loss of H4 lysine 16 (H4K16) acetylation was shown to be a common feature in human cancer. However, it remained unclear which enzyme is responsible for the loss of this modification. Having recently identified the histone acetyltransferase human MOF (hMOF) to be required for bulk H4K16 acetylation, here we examined the involvement of hMOF expression and H4K16 acetylation in breast cancer and Medulloblastoma. Analysis of a recent mRNA expression profiling study in breast cancer (n = 100 cases) and an array-CGH screen in Medulloblastomas (n = 102 cases), revealed downregulation in 40% and genomic loss in 11% of cases, respectively. We investigated hMOF protein expression as well as H4K16 acetylation in large series of primary breast carcinomas (n = 298) and primary Medulloblastomas (n = 180) by immunohistochemistry. In contrast to nontransformed control tissues, significant fractions of both primary breast carcinomas and Medulloblastomas showed markedly reduced hMOF mRNA and protein expression. In addition, hMOF protein expression tightly correlated with acetylation of H4K16 in all tested samples. For Medulloblastoma, downregulation of hMOF protein expression was associated with lower survival rates identifying hMOF as an independent prognostic marker for clinical outcome in univariate as well as multivariate analyses.

Robert J Wechslerreya - One of the best experts on this subject based on the ideXlab platform.

  • abstract lb 203 structural variants shuffle chromatin to activate gfi1 family oncogenes in Medulloblastoma
    Cancer Research, 2014
    Co-Authors: Catherine Lee, Paul A. Northcott, Thomas Zichner, Peter Lichter, Jan O. Korbel, Stefan M. Pfister, Robert J Wechslerreya
    Abstract:

    Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Medulloblastoma is a highly malignant pediatric brain tumor currently treated with a combination of surgery, radiation, and non-specific chemotherapy, posing a significant threat to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of Medulloblastoma and identified four distinct molecular subgroups. Group 3 and Group 4 subgroup Medulloblastomas account for the majority of pediatric cases, yet, oncogenic drivers for these subtypes remain poorly understood. Here we report a series of prevalent, highly disparate genomic structural rearrangements, restricted to Groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto- oncogenes, GFI1 & GFI1B. Diverse mechanisms of structural variation activate GFI1/GFI1B expression through relocation of their coding sequences to genomic regions of transcriptionally active chromatin. Moreover, Gfi1 and Gfi1b each cooperate with Myc, an important oncogene in Group 3 Medulloblastomas, to drive tumor initiation in mice. These data reveal GFI1 and GFI1B as novel Medulloblastoma oncogenes, warranting their prioritization for molecularly targeted therapy of a marked proportion of Group 3 and Group 4 patients. Citation Format: Catherine Lee, Paul A. Northcott, Thomas Zichner, Peter Lichter, Jan O. Korbel, Stefan M. Pfister, Robert J. Wechsler-Reya. Structural variants shuffle chromatin to activate GFI1 family oncogenes in Medulloblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-203. doi:10.1158/1538-7445.AM2014-LB-203

  • structural variants shuffle chromatin to activate gfi1 family oncogenes in Medulloblastoma
    Neuro-oncology, 2014
    Co-Authors: Paul A. Northcott, Catherine Lee, Thomas Zichner, Peter Lichter, Jan O. Korbel, Robert J Wechslerreya, Stefan M. Pfister
    Abstract:

    BACKGROUND: Genomics has illuminated the extensive intertumoural heterogeneity of Medulloblastoma and identified at least four distinct molecular subgroups of the disease. Group 3 and Group 4 subgroup Medulloblastomas account for the majority of pediatric cases, yet, oncogenic drivers for these subtypes remain poorly understood. Exome and genome sequencing studies have confirmed a paucity of recurrent gene-level mutations in Group 3 and Group 4, suggesting that alternative oncogenic mechanisms must account for the large fraction of cases that cannot currently be explained by single-nucleotide variants or insertions/deletions alone. METHODS: Analysis of whole-genome sequencing data consisting of 128 primary Group 3 and Group 4 Medulloblastoma samples facilitated a systematic, high-resolution screen for chromosomal breakpoints recurrently targeting novel Medulloblastoma drivers by structural variation. A non-overlapping set of 22 Medulloblastomas was sequenced by long-range paired-end mapping in order to validate structural variants observed in our discovery cohort. Select cases of interest were also investigated at the epigenome-level using a combination of whole-genome bisulphite sequencing and enhancer histone mark ChIP-sequencing. RESULTS: Our systematic analysis of structural variants identified highly disparate genomic structural rearrangements, restricted to Groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 & GFI1B. Diverse mechanisms of structural variation, including duplications, deletions, inversions, translocations, and other complex genomic variants were observed in nearly all GFI1/1B-activated cases. Comprehensive characterization of these structural variants established that GFI1/GFI1B expression becomes activated through relocation of their coding sequences to genomic regions of transcriptionally active chromatin. Functional analyses performed in mice confirmed the oncogenicity of Gfi1/Gfi1b in the context of Medulloblastoma and demonstrated apparent synergy between both of these candidates and the c-Myc oncogene. CONCLUSIONS: These studies establish GFI1 and GFI1B as novel, highly prevalent Medulloblastoma oncogenes specifically active in Group 3 and Group 4. Given their high frequencies of activation, GFI1 and GFI1B represent excellent candidates for prioritization of molecularly targeted therapy aimed at treatment of a significant proportion of Group 3 and Group 4 Medulloblastoma patients. SECONDARY CATEGORY: Pediatrics.

  • identification of cd15 as a marker for tumor propagating cells in a mouse model of Medulloblastoma
    Cancer Cell, 2009
    Co-Authors: David W. Ellison, Roger E Mclendon, Tracyann Read, Marie P Fogarty, Shirley L Markant, Zhengzheng Wei, Phillip G Febbo, Robert J Wechslerreya
    Abstract:

    Summary The growth of many cancers depends on self-renewing cells called cancer stem cells or tumor-propagating cells (TPCs). In human brain tumors, cells expressing the stem cell marker CD133 have been implicated as TPCs. Here we show that tumors from a model of Medulloblastoma, the Patched mutant mouse, are propagated not by CD133 + cells but by cells expressing the progenitor markers Math1 and CD15/SSEA-1. These cells have a distinct expression profile that suggests increased proliferative capacity and decreased tendency to undergo apoptosis and differentiation. CD15 is also found in a subset of human Medulloblastomas, and tumors expressing genes similar to those found in murine CD15 + cells have a poorer prognosis. Thus, CD15 may represent an important marker for TPCs in Medulloblastoma.