Dataset Information

The transcriptional landscape of Shh medulloblastoma.

ABSTRACT: Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

SUBMITTER: Skowron P

PROVIDER: S-EPMC7979819 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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The transcriptional landscape of Shh medulloblastoma.

Skowron Patryk P Farooq Hamza H Cavalli Florence M G FMG Morrissy A Sorana AS Ly Michelle M Hendrikse Liam D LD Wang Evan Y EY Djambazian Haig H Zhu Helen H Mungall Karen L KL Trinh Quang M QM Zheng Tina T Dai Shizhong S Stucklin Ana S Guerreiro ASG Vladoiu Maria C MC Fong Vernon V Holgado Borja L BL Nor Carolina C Wu Xiaochong X Abd-Rabbo Diala D Bérubé Pierre P Wang Yu Chang YC Luu Betty B Suarez Raul A RA Rastan Avesta A Gillmor Aaron H AH Lee John J Y JJY Zhang Xiao Yun XY Daniels Craig C Dirks Peter P Malkin David D Bouffet Eric E Tabori Uri U Loukides James J Doz François P FP Bourdeaut Franck F Delattre Olivier O OO Masliah-Planchon Julien J Ayrault Olivier O Kim Seung-Ki SK Meyronet David D Grajkowska Wieslawa A WA Carlotti Carlos G CG de Torres Carmen C Mora Jaume J Eberhart Charles G CG Van Meir Erwin G EG Kumabe Toshihiro T French Pim J PJ Kros Johan M JM Jabado Nada N Lach Boleslaw B Pollack Ian F IF Hamilton Ronald L RL Rao Amulya A Nageswara AAN Giannini Caterina C Olson James M JM Bognár László L Klekner Almos A Zitterbart Karel K Phillips Joanna J JJ Thompson Reid C RC Cooper Michael K MK Rubin Joshua B JB Liau Linda M LM Garami Miklós M Hauser Peter P Li Kay Ka Wai KKW Ng Ho-Keung HK Poon Wai Sang WS Yancey Gillespie G G Chan Jennifer A JA Jung Shin S McLendon Roger E RE Thompson Eric M EM Zagzag David D Vibhakar Rajeev R Ra Young Shin YS Garre Maria Luisa ML Schüller Ulrich U Shofuda Tomoko T Faria Claudia C CC López-Aguilar Enrique E Zadeh Gelareh G Hui Chi-Chung CC Ramaswamy Vijay V Bailey Swneke D SD Jones Steven J SJ Mungall Andrew J AJ Moore Richard A RA Calarco John A JA Stein Lincoln D LD Bader Gary D GD Reimand Jüri J Ragoussis Jiannis J Weiss William A WA Marra Marco A MA Suzuki Hiromichi H Taylor Michael D MD

Nature communications 20210319 1

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 1 ...[more]

PMID: 33741928

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Project description:Medulloblastoma is heterogeneous, being characterized by molecular subgroups that demonstrate distinct gene expression profiles. Activation of the WNT or SHH signaling pathway characterizes two of these molecular subgroups, the former associated with low-risk disease and the latter potentially targeted by novel SHH pathway inhibitors. This manuscript reports the validation of a novel diagnostic immunohistochemical method to distinguish SHH, WNT, and non-SHH/WNT tumors and details their associations with clinical, pathological and cytogenetic variables. A cohort (n = 235) of medulloblastomas from patients aged 0.4-52 years was studied for expression of four immunohistochemical markers: GAB1, β-catenin, filamin A, and YAP1. Immunoreactivity (IR) for GAB1 characterizes only SHH tumors and nuclear IR for β-catenin only WNT tumors. IRs for filamin A and YAP1 identify SHH and WNT tumors. SHH, WNT, and non-SHH/WNT tumors contributed 31, 14, and 55% to the series. All desmoplastic/nodular (D/N) medulloblastomas were SHH tumors, while most WNT tumors (94%) had a classic phenotype. Monosomy 6 was strongly associated with WNT tumors, while PTCH1 loss occurred almost exclusively among SHH tumors. MYC or MYCN amplification and chromosome 17 imbalance occurred predominantly among non-SHH/WNT tumors. Among patients aged 3-16 years and entered onto the SIOP PNET3 trial, outcome was significantly better for children with WNT tumors, when compared to SHH or non-SHH/WNT tumors, which showed similar survival curves. However, high-risk factors (M+ disease, LC/A pathology, MYC amplification) significantly influenced survival in both SHH and non-SHH/WNT groups. We describe a robust method for detecting SHH, WNT, and non-SHH/WNT molecular subgroups in formalin-fixed medulloblastoma samples. In corroborating other studies that indicate the value of combining clinical, pathological, and molecular variables in therapeutic stratification schemes for medulloblastoma, we also provide the first outcome data based on a clinical trial cohort and novel data on how molecular subgroups are distributed across the range of disease.

Dataset Information

The transcriptional landscape of Shh medulloblastoma.

Publications

The transcriptional landscape of Shh medulloblastoma.

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