期刊
NATURE
卷 574, 期 7780, 页码 707-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-019-1650-0
关键词
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资金
- NIH [R01-NS096236, R01CA235162]
- Pediatric Brain Tumour Foundation
- Terry Fox Research Institute
- Canadian Institutes of Health Research
- Cure Search Foundation, b.r.a.i.n.child, Meagan's Walk, Genome Canada
- Genome BC
- Genome Quebec
- Ontario Research Fund
- Worldwide Cancer Research, V-Foundation
- Ontario Institute for Cancer Research
- Government of Ontario
- Canadian Cancer Society Research Institute Impact grant
- Stand Up To Cancer (SU2C) St. Baldrick's Pediatric Dream Team Translational Research Grant [SU2C-AACR-DT1113]
- SU2C Canada Cancer Stem Cell Dream Team Research Funding [SU2C-AACR-DT-19-15]
- Government of Canada through Genome Canada
- Entertainment Industry Foundation
- Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children
- University of Toronto
- CURE Childhood Cancer Foundation
- Ministerio de Economia y Competitividad (MINECO) [SAF2013-45836-R, 2017-1.2.1-NKP-2017-00002]
- National Brain Research Program NAP 2.0
- AIRC (Italian Association for Cancer Research)
- Fondazione Berlucchi
- (Astellas Foundation for Research on Metabolic Disorders)
- Restracomp Research Fellowship (SickKids Research Institute)
- MD/PhD Studentship Award (Canadian Institute of Health Research)
- Department of Education of the Basque Government [PRE_2017_1_0100]
- Genome Canada Genome Technology Platform Grant [12505]
- Canada Foundation for Innovation Project [33408]
- Canada Foundation for Innovation under the auspices of Compute Canada
- Ontario Research Fund -Research Excellence
- Labatt Brain Tumour Research Centre
In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes(1-3). Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHH delta) and 25% of adolescents (subtype SHH alpha) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.
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