期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-21883-0
关键词
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资金
- NIH [R01CA148699, R01CA159859]
- Pediatric Brain Tumour Foundation
- Terry Fox Research Institute
- Canadian Institutes of Health Research
- Cure Search Foundation
- Brain Tumour Charity
- Genome Canada
- Genome BC
- Genome Quebec
- Ontario Research Fund
- Worldwide Cancer Research
- Ontario Institute for Cancer Research by the Government of Ontario
- Canadian Cancer Society Research Institute Impact grant
- Cancer Research UK' Brain Tumour Award
- Stand Up To Cancer (SU2C) St. Baldrick's Pediatric Dream Team Translational Research Grant by the Government of Canada through Genome Canada [SU2C-AACR-DT1113]
- SU2C Canada Cancer Stem Cell Dream Team Research Funding by the Government of Canada through Genome Canada [SU2C-AACR-DT-19-15]
- Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children
- University of Toronto
- Stephen Buttrum Brain Tumor Research Fellowship - Brain Tumor Foundation of Canada
- Cancer Research Society Scholarships for the Next Generation of Scientists
- Sickkids Restracomp Ph.D. scholarship
- Common Fund of the Office of the Director of the National Institutes of Health
- NCI
- NHGRI
- NHLBI
- NIDA
- NIMH
- NINDS
- NCI\Leidos Biomedical Research, Inc. [10XS170, 10XS171, X10S172]
- Leidos Biomedical Research, Inc. [10ST1035, HHSN261200800001E]
- NRNB (U.S. National Institutes of Health, National Center for Research Resources) [P41 GM103504]
- National Brain Research Program NAP 2.0 of Hungary [2017-1.2.1-NKP-2017-00002]
- Canada Foundation for Innovation under the Compute Canada
- Government of Ontario
- Ontario Research Fund-Research Excellence
- b.r.a.i.n.child
- Meagan's Walk
- SWIFTY Foundation
- V-Foundation for Cancer Research
- [HHSN268201000029C]
Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. The authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.
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. Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.
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