Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma

• Type of Material: Article
• Authors: Hiromichi Suzuki, Hospital for Sick Children; Sachin A. Kumar, Hospital for Sick Children; Shimin Shuai, University of Toronto; Ander Diaz-Navarro, University of Oviedo; Ana Gutierrez-Fernandez, University of Oviedo; Pasqualino De Antonellis, Hospital for Sick Children; Florence M. G. Cavalli, Hospital for Sick Children; K Juraschka, Hosp Sick Children; H Farooq, Hosp Sick Children; Erwin Van Meir, Emory University
• Language: English
• Date: 2019-10-31
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © The Author(s), under exclusive licence to Springer Nature Limited 2019.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41586-019-1650-0
• Title of Journal or Parent Work: Nature
• Volume: 574
• Issue: 7780
• Start Page: 707
• End Page: +
• Grant/Funding Information: X. S. P. is supported by Ministerio de Economía y Competitividad (MINECO) (SAF2013–45836-R). A.K. was supported by 2017–1.2.1-NKP-2017–00002 National Brain Research Program NAP 2.0. M. L. G. is supported by AIRC (Italian Association for Cancer Research) and by Fondazione Berlucchi.; SciNet is funded by the Canada Foundation for Innovation under the auspices of Compute Canada; the Government of Ontario; Ontario Research Fund - Research Excellence; and the University of Toronto.; Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is also supported by the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto. E.G.V.M. is supported by the NIH (R01-NS096236 and R01CA235162) and the CURE Childhood Cancer Foundation.; M.D.T. is also supported by a Canadian Cancer Society Research Institute Impact grant and by a Stand Up To Cancer (SU2C) St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113) and SU2C Canada Cancer Stem Cell Dream Team Research Funding (SU2C-AACR-DT-19–15) provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, with supplementary support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario.; Computations were partially performed on the NIG supercomputer at ROIS National Institute of Genetics and on the Niagara supercomputer at the SciNet HPC Consortium.; M.D.T. is supported by the NIH (R01CA148699 and R01CA159859), The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, The Canadian Institutes of Health Research, The Cure Search Foundation, b.r.a.i.n.child, Meagan’s Walk, Genome Canada, Genome BC, Genome Quebec, the Ontario Research Fund, Worldwide Cancer Research, V-Foundation for Cancer Research, and the Ontario Institute for Cancer Research through funding provided by the Government of Ontario.; H.S. is a recipient of a Research Fellowship (Astellas Foundation for Research on Metabolic Disorders). S.A.K. is a recipient of funding from the Restracomp Research Fellowship (SickKids Research Institute) and the MD/PhD Studentship Award (Canadian Institute of Health Research).; A. D-N is a recipient of the Department of Education of the Basque Government (PRE_2017_1_0100). J.R. is supported by Genome Canada Genome Technology Platform Grant 12505, Canada Foundation for Innovation Project 33408.
• Keywords: Cancer; Science & Technology - Other Topics; Multidisciplinary Sciences; Identification; Somatic point mutations; RNA; Copt number; Science & Technology
• Research Categories: Health Sciences, Human Development; Health Sciences, Oncology; Biology, Cell

Abstract

In cancer, recurrent somatic single-nucleotide variants—which are rare in most paediatric cancers—are confined largely to protein-coding genes1–3. 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 SHHδ) and 25% of adolescents (subtype SHHα) 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.