Dataset Information

Comprehensive molecular profiling identifies novel genetic drivers and subtypes underlying medulloblastoma

ABSTRACT: Current therapies for medulloblastoma (MB), a highly malignant childhood brain tumor, impose debilitating effects on the developing child, warranting the development of molecularly targeted treatments with reduced toxicities. Prior studies have failed to disclose the full spectrum of driver genes and molecular processes operative in MB or adequately explain heterogeneity among molecular subgroups. Herein, we detail the somatic landscape across 491 sequenced MBs and molecular heterogeneity amongst 1,256 epigenetically analyzed cases, identifying subgroup-specific mutational signatures, driver genes, and pathway alterations including previously unappreciated actionable therapeutic targets. Integrative approaches for assigning driver genes to subgroups explained >65-70% of Group 3 and Group 4, doubling previous knowledge. Novel subtypes underlying Group 3 and Group 4 were differentially enriched for specific driver events, including hotspot in-frame indels targeting KBTBD4 and ‘enhancer hijacking’ driving activation of PRDM6. Thus, application of integrative genomics to an unprecedented cohort of clinical samples derived from a single childhood cancer entity has disclosed a series of new cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for treating MB.

PROVIDER: EGAS00001001953 | EGA |

REPOSITORIES: EGA

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Publications

The whole-genome landscape of medulloblastoma subtypes.

Northcott Paul A PA Buchhalter Ivo I Morrissy A Sorana AS Hovestadt Volker V Weischenfeldt Joachim J Ehrenberger Tobias T Gröbner Susanne S Segura-Wang Maia M Zichner Thomas T Rudneva Vasilisa A VA Warnatz Hans-Jörg HJ Sidiropoulos Nikos N Phillips Aaron H AH Schumacher Steven S Kleinheinz Kortine K Waszak Sebastian M SM Erkek Serap S Jones David T W DTW Worst Barbara C BC Kool Marcel M Zapatka Marc M Jäger Natalie N Chavez Lukas L Hutter Barbara B Bieg Matthias M Paramasivam Nagarajan N Heinold Michael M Gu Zuguang Z Ishaque Naveed N Jäger-Schmidt Christina C Imbusch Charles D CD Jugold Alke A Hübschmann Daniel D Risch Thomas T Amstislavskiy Vyacheslav V Gonzalez Francisco German Rodriguez FGR Weber Ursula D UD Wolf Stephan S Robinson Giles W GW Zhou Xin X Wu Gang G Finkelstein David D Liu Yanling Y Cavalli Florence M G FMG Luu Betty B Ramaswamy Vijay V Wu Xiaochong X Koster Jan J Ryzhova Marina M Cho Yoon-Jae YJ Pomeroy Scott L SL Herold-Mende Christel C Schuhmann Martin M Ebinger Martin M Liau Linda M LM Mora Jaume J McLendon Roger E RE Jabado Nada N Kumabe Toshihiro T Chuah Eric E Ma Yussanne Y Moore Richard A RA Mungall Andrew J AJ Mungall Karen L KL Thiessen Nina N Tse Kane K Wong Tina T Jones Steven J M SJM Witt Olaf O Milde Till T Von Deimling Andreas A Capper David D Korshunov Andrey A Yaspo Marie-Laure ML Kriwacki Richard R Gajjar Amar A Zhang Jinghui J Beroukhim Rameen R Fraenkel Ernest E Korbel Jan O JO Brors Benedikt B Schlesner Matthias M Eils Roland R Marra Marco A MA Pfister Stefan M SM Taylor Michael D MD Lichter Peter P

Nature 20170701 7663

Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that operate in medulloblastoma subgroups. Here we analyse the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigeneti ...[more]

PMID: 28726821

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Project description:Medulloblastoma (MB) is the most common malignant brain tumor occurring in childhood and rarely found in adult. Based on transcriptome profile MB are currently classified into four major molecular groups reflecting a considerable biological heterogeneity: WNT-activated, SHH-activated, group 3 and group 4. Recently, DNA methylation profiling allowed the identification of additional subgroups within the four major molecular groups associated with different clinic-pathological and molecular features. Isocitrate Dehydrogenase-1 (IDH1) mutations have been described in several tumours, including gliomas, while in MB are exceptionally reported and not routinely investigated. By mean of magnetic resonance spectroscopy (MRS) we unequivocally assessed the presence the oncometabolite D-2-Hydroxyglutarate (2HG), a marker of IDH1 and IDH2 mutation, in a case of adult MB. Immunophenotypical work-up and methylation profiling assigned the diagnosis of MB, subclass SHH-A, and molecular testing revealed the presence of the non-canonical somatic IDH1(p.R132C) mutation and an additional GNAS mutation, also exceptionally described in MB. To our knowledge this is the first reported case of MB harboring both mutations together. Of note, tumour exhibited a heterogeneous phenotype with a tumour component displaying glial differentiation, with robust GFAP expression, and a component with conventional MB features and selective presence of GNAS mutation, suggesting coexistence of two different major tumour clones. These findings draw attention to the need of a deeper genetic characterization of MB in order to get insights into their biology and improve stratification and clinical management of the patients. Moreover, reported data underling the importance of performing MRS for the identification of IDH mutations in non-glial tumours. The use of throughput molecular profiling analysis and advanced medical imaging technology will certainly increase the frequency with which rare tumour entities will be identified. Whether they have any particular therapeutic implications or prognostic relevance requires further investigations.

Project description:Identification of novel molecular subgroups Background: International consensus recognises four medulloblastoma molecular subgroups - WNT, SHH, Group 3 and Group 4 - each defined by their characteristic genome-wide transcriptomic and DNA methylomic profiles. Subgroups harbor distinct clinico-pathological and molecular features, underpin current disease sub-classification and initial subgroup-directed therapies are underway in clinical trials (i.e. reduced risk-adapted treatments for favorable-risk WNT patients; SMO inhibitors for SHH patients). However, significant biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. Methods: We undertook comprehensive molecular profiling and unsupervised class discovery (non-negative matrix factorization, t-SNE) of test and validation cohorts to identify consensus primary molecular subgroups within childhood medulloblastoma (<16.0 years), and characterize their clinical and biological significance. Survival modeling was performed in clinically-annotated centrally-reviewed patients (>3.0 years). Findings: Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified, characterized by distinct biological/clinical features. For instance, SHH comprised two age-dependent subgroups, while Grp3 and Grp4 each split into two subgroups with significantly different survival rates. Survival analysis identified secondary features predictive of outcome. Cross-validated subgroup-dependent models incorporating these novel subgroups along with secondary features and established disease risk-factors, outperformed current disease risk-stratification schemes. These schema stratified patients into four clinical risk-groups - favorable-risk (91% 5-year survival, 25% of patients), standard-risk (81%, 23%), high-risk (42%, 38%) and very high-risk (28%, 13%) - to be considered for treatment reduction, intensification or novel therapies respectively. Interpretation: The discovery of seven novel, clinically-significant, subgroups significantly improves disease risk-stratification and provides a new foundation for future research and clinical investigations.

Dataset Information

Comprehensive molecular profiling identifies novel genetic drivers and subtypes underlying medulloblastoma

Publications

The whole-genome landscape of medulloblastoma subtypes.

Similar Datasets

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