Dataset Information

Proteomic analysis of human Medulloblastoma reveals distinct activated pathways between subgroups

ABSTRACT: Deregulations in fundamental signaling pathways are key events in pathogenesis of cancer. One intriguing illustration that still holds blind spots is the pediatric brain tumor arising from the developing cerebellum: medulloblastoma (MB). Extensive high-throughput sequencing led to the characterization of four MB subgroups (WNT, SHH, Group 3 and Group 4) delineated with distinct molecular signatures and clinical outcomes. However, up-to-date these analyses have not attained the global comprehension of their dynamic network complexity. Wishing to uncover a comprehensive view of all MB subgroups we employed a proteomic analysis to integrate accurate protein expression and activity that should ultimately give rise to a realistic picture of how MB cancer cells are regulated. In this study we present the first analysis regrouping methylation status, whole-transcriptome sequencing and quantitative proteomics (proteome and phosphoproteome) using a super SILAC / spiked in strategy across 38 flash frozen primary human MBs (5 WNT, 10 SHH, 10 Group 3 and 13 Group 4). First, our data pinpointed that proteomic analysis could reveal MB subgroup identity. Second, analysis of proteome and phosphoproteome highlighted disregulated signaling pathways that have not been predicted by transcriptomic analysis. Altogether, combined multi-scale analyses of MB have allowed us to identify unrevealed pathways involved in human MB genesis and progression.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Childhood Medulloblastoma

SUBMITTER: Guillaume Arras

LAB HEAD: Damarys Loew

PROVIDER: PXD006607 | Pride | 2020-07-23

REPOSITORIES: Pride

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Publications

Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling.

Forget Antoine A Martignetti Loredana L Puget Stéphanie S Calzone Laurence L Brabetz Sebastian S Picard Daniel D Montagud Arnau A Liva Stéphane S Sta Alexandre A Dingli Florent F Arras Guillaume G Rivera Jaime J Loew Damarys D Besnard Aurore A Lacombe Joëlle J Pagès Mélanie M Varlet Pascale P Dufour Christelle C Yu Hua H Mercier Audrey L AL Indersie Emilie E Chivet Anaïs A Leboucher Sophie S Sieber Laura L Beccaria Kevin K Gombert Michael M Meyer Frauke D FD Qin Nan N Bartl Jasmin J Chavez Lukas L Okonechnikov Konstantin K Sharma Tanvi T Thatikonda Venu V Bourdeaut Franck F Pouponnot Celio C Ramaswamy Vijay V Korshunov Andrey A Borkhardt Arndt A Reifenberger Guido G Poullet Patrick P Taylor Michael D MD Kool Marcel M Pfister Stefan M SM Kawauchi Daisuke D Barillot Emmanuel E Remke Marc M Ayrault Olivier O

Cancer cell 20180901 3

The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the (epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kina ...[more]

PMID: 30205043

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Project description:BACKGROUND Focal high-level amplifications of MYC define a subset of high-risk medulloblastoma patients. However, the prognostic role of MYCN oncogene amplification remains less clear. We aimed to evaluate the prognostic value of this alteration alone and in combination with biological modifiers in a large cohort of 67 pediatric medulloblastomas with MYCN amplification (MYCN-MB). METHODS Twenty-one MYCN-MB with MYCN amplication and 56 MYCN-MB were respectively examined using either gene expression profiling and array-CGH, or immunohistochemical analysis and FISH. All 67 tumors were further subject to mutational analyses. Semi non-negative matrix factorization–based and unsupervised hierarchical clustering methods were used to identify biological groups. We compared molecular, clinical, and prognostic characteristics both within biological MYCN-MB groups and with non-amplified tumors. RESULTS Transcriptomic analysis of this large cohort of MYCN-MBs demonstrated a significant enrichment of MYCN-MB in the SHH and group D variants. Further substantiating this biological dichotomy of MYCN-MB, respective group affiliations were also accompanied by variant-specific cytogenetic aberrations including deletion of 9q in the SHH variant, and gain of 7q and isochromosome 17q/17q gain in MYCN-MBs clustering with group D tumors. Among clinically relevant variables, SHH subtype and 10q loss for Non-SHH tumors comprised the most powerful markers of favorable prognosis in MYCN-MB. CONCLUSION We demonstrate considerable heterogeneity within MYCN-MB in terms of genetics, tumor biology, and clinical outcome. Thus, assessment of disease group and 10q copy-number status may improve risk stratification of this group and may delineate MYCN-MB with the same dismal prognosis as MYC amplified tumors. Furthermore, based on the enrichment of MYCN and GLI2 amplifications in SHH-driven medulloblastoma, amplification of these downstream signaling intermediates should be excluded before a patient is enrolled into a clinical trial using a Smoothened inhibitor.

Dataset Information

Proteomic analysis of human Medulloblastoma reveals distinct activated pathways between subgroups

Publications

Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling.

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