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Nature. 2019 Oct 9. doi: 10.1038/s41586-019-1650-0. [Epub ahead of print]

Recurrent non-coding U1-snRNA mutations drive cryptic splicing in Shh medulloblastoma.

Author information

1
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
2
Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
3
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
4
Informatics and Biocomputing, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
5
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
6
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, 33006, Oviedo, Spain.
7
Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain.
8
Institut Curie, PSL Research University, CNRS UMR, INSERM, Orsay, France.
9
Universite´ Paris Sud, Universite´ Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France.
10
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States.
11
Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul, South Korea.
12
Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland.
13
Centre de Pathologie EST, Groupement Hospitalier EST, Université de Lyon, Bron, France.
14
INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences, Université de Lyon, Lyon, France.
15
Neuro-Oncology Unit, Istituto Giannina Gaslini, Genova, Italy.
16
Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, Minnesota, United States.
17
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States.
18
Department of Pathology, Erasmus University Medical Center, Rotterdam, Netherlands.
19
Department of Neurology, Erasmus University Medical Center, Rotterdam, Netherlands.
20
Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
21
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
22
Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
23
Departments of Pathology, Ophthalmology and Oncology, John Hopkins University School of Medicine, Baltimore, Maryland, United States.
24
Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.
25
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States.
26
Departments of Neurological Surgery, Pediatrics and Neurology, University of California San Francisco, San Francisco, California, United States.
27
Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
28
Division of Pediatric Hematology/Oncology, Hospital Pediatría Centro Médico Nacional Century XXI, Mexico City, Mexico.
29
Department of Pathology and Molecular Medicine, Division of Anatomical Pathology, McMaster University, Hamilton, Ontario, Canada.
30
Department of Pathology and Laboratory Medicine, Hamilton General Hospital, Hamilton, Ontario, Canada.
31
Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
32
Department of Neurosurgery and Hematology & Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia, United States.
33
Department of Neuroscience, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri, United States.
34
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States.
35
Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, Tennessee, United States.
36
Department of Neurosurgery, Osaka National Hospital, Osaka, Japan.
37
Department of Neurosurgery, University of Debrecen, Medical and Health Science Centre, Debrecen, Hungary.
38
Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.
39
Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal.
40
Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
41
McGill University and Genome Quebec Innovation Centre, Department of Human Genetics, McGill University, Montreal, Canada.
42
Department of Bioengineering, McGill University, Montreal, Canada.
43
Hopp Children´s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
44
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
45
Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
46
Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
47
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
48
Department of Pediatrics, University of California San Diego, San Diego, California, USA.
49
Department of Surgery, Division of Thoracic and Upper Gastrointestinal Surgery, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
50
Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
51
Department of Surgery, Division of Orthopedic Surgery, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
52
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
53
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
54
Division of Haematology / Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
55
Department of Cell and Systems Biology, University of Toronto, Toronto, Canada.
56
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. mdtaylor@sickkids.ca.
57
Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada. mdtaylor@sickkids.ca.
58
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. mdtaylor@sickkids.ca.
59
Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada. mdtaylor@sickkids.ca.

Abstract

Recurrent somatic single nucleotide variants (SNVs) in cancer are largely confined to protein-coding genes, and are rare in most paediatric cancers1-3. Here we report highly recurrent hotspot mutations of U1 spliceosomal small nuclear RNAs (snRNAs) in ~50% of Sonic hedgehog medulloblastomas (Shh-MB), which were not present across other medulloblastoma subgroups. This U1-snRNA hotspot mutation (r.3a>g), was identified in <0.1% of 2,442 cancers across 36 other tumour types. Largely absent from infant Shh-MB, the mutation occurs in 97% of adults (Shhδ), and 25% of adolescents (Shhα). The U1-snRNA mutation occurs in the 5' splice site binding region, and snRNA mutant tumours have significantly disrupted RNA splicing with an excess of 5' cryptic splicing events. Mutant U1-snRNA-mediated alternative splicing inactivates tumour suppressor genes (PTCH1), and activates oncogenes (GLI2, CCND2), represents a novel target for therapy, and constitutes a highly recurrent and tissue-specific mutation of a non-protein coding gene in cancer.

PMID:
31597162
DOI:
10.1038/s41586-019-1650-0

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