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Las mutaciones recurrentes no codificantes del ARN sn1 impulsan el empalme críptico en el meduloblastoma SHH

Hiromichi Suzuki ^1,2, Sachin A Kumar ^1,2,3, Shimin Shuai ^4,5

¹The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
²Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
³Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
⁴Informatics and Biocomputing, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
⁵Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
⁶Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
⁷Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain.
⁸CNRS UMR, INSERM, Institut Curie, PSL Research University, Orsay, France.
⁹CNRS UMR 3347, INSERM U1021, Université Paris Sud, Université Paris-Saclay, Orsay, France.
¹⁰Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
¹¹Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul, South Korea.
¹²Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland.
¹³Centre de Pathologie EST, Groupement Hospitalier EST, Université de Lyon, Bron, France.
¹⁴CNRS UMR5292, INSERM U1028, Centre de Recherche en Neurosciences, Université de Lyon, Lyon, France.
¹⁵Neuro-Oncology Unit, Istituto Giannina Gaslini, Genova, Italy.
¹⁶Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, USA.
¹⁷Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
¹⁸Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.
¹⁹Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
²⁰Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
²¹Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China.
²²Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
²³Department of Pathology, John Hopkins University School of Medicine, Baltimore, MD, USA.
²⁴Department of Opthalmology, John Hopkins University School of Medicine, Baltimore, MD, USA.
²⁵Department of Oncology, John Hopkins University School of Medicine, Baltimore, MD, USA.
²⁶Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
²⁷Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁸Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
²⁹Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
³⁰Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
³¹Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Japan.
³²Division of Pediatric Hematology/Oncology, Hospital Pediatría Centro Médico Nacional Century XXI, Mexico City, Mexico.
³³Department of Pathology and Molecular Medicine, Division of Anatomical Pathology, McMaster University, Hamilton, Ontario, Canada.
³⁴Department of Pathology and Laboratory Medicine, Hamilton General Hospital, Hamilton, Ontario, Canada.
³⁵Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
³⁶Winship Cancer Institute, Emory University, Atlanta, GA, USA.
³⁷Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, School of Medicine, Emory University, Atlanta, GA, USA.
³⁸Department of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, GA, USA.
³⁹Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, USA.
⁴⁰Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
⁴¹Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁴²Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN, USA.
⁴³Department of Neurosurgery, Osaka National Hospital, Osaka, Japan.
⁴⁴Department of Neurosurgery, Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary.
⁴⁵Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.
⁴⁶Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal.
⁴⁷Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
⁴⁸McGill University and Genome Quebec Innovation Centre, Department of Human Genetics, McGill University, Montreal, Canada.
⁴⁹Department of Bioengineering, McGill University, Montreal, Canada.
⁵⁰Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
⁵¹Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
⁵²Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
⁵³Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
⁵⁴Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵⁵Department of Pediatrics, University of California San Diego, San Diego, CA, USA.
⁵⁶Department of Surgery, Division of Thoracic and Upper Gastrointestinal Surgery, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
⁵⁷Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
⁵⁸Department of Surgery, Division of Orthopedic Surgery, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
⁵⁹Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
⁶⁰Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
⁶¹Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
⁶²Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁶³Department of Cell and Systems Biology, University of Toronto, Toronto, Canada.
⁶⁴The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. mdtaylor@sickkids.ca.
⁶⁵Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada. mdtaylor@sickkids.ca.
⁶⁶Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. mdtaylor@sickkids.ca.
⁶⁷Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada. mdtaylor@sickkids.ca.

⁰The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.

Nature +

|

31 de octubre de 2019

Ver abstracta en PubMed

Resumen

Las mutaciones altamente recurrentes de ARN nuclear pequeño espliceosomal U1 (ARNsn) impulsan los meduloblastomas de erizo sónico. Estas mutaciones de ARN no codificantes interrumpen el empalme, afectando a los oncogenes y los supresores de tumores, ofreciendo un objetivo terapéutico potencial.

Área De La Ciencia

En el campo de la oncología
La genética
Biología molecular

Sus Antecedentes

Las variantes somáticas recurrentes en el cáncer son típicamente raras en los cánceres pediátricos y afectan principalmente a los genes codificadores de proteínas.
Los pequeños ARN nucleares espliceosomales U1 (ARNsn) son componentes cruciales del espliceosoma, involucrados en el empalme del ARN.

Objetivo Del Estudio

Investigar el papel de las mutaciones en los genes no codificantes, específicamente en los snRNA U1, en los cánceres pediátricos.
Identificar las mutaciones recurrentes en los ARNn U1 dentro de subgrupos específicos de meduloblastoma.

Principales Métodos

Secuenciación de todo el exoma y análisis de variantes de muestras de meduloblastoma.
Secuenciación de ARN para evaluar patrones de empalme y identificar eventos de empalme crípticos.
Análisis de la frecuencia de mutación en diferentes tipos de cáncer y datos demográficos de los pacientes.

Principales Resultados

Descubrimiento de mutaciones de puntos calientes muy recurrentes (r.3A>G) en el snRNA U1 en aproximadamente el 50% de los medulloblastomas de Sonic hedgehog (SHH).
Estas mutaciones de U1 snRNA se encontraron en el 97% de los adultos y en el 25% de los adolescentes con meduloblastomas SHH, pero rara vez en los casos infantiles u otros tipos de cáncer (< 0,1%).
Las mutaciones en el snRNA U1 conducen a la interrupción del splicing de ARN, el aumento del splicing críptico 5', la inactivación de los supresores tumorales (PTCH1) y la activación de los oncogenes (GLI2, CCND2).

Conclusiones

Las mutaciones del snRNA U1 representan una nueva clase de mutaciones altamente recurrentes y específicas del tejido en un gen no codificante en el cáncer.
Estas mutaciones alteran significativamente la expresión génica a través del empalme aberrante, impulsando el desarrollo del meduloblastoma SHH.
Dirigirse al empalme alternativo mediado por el snRNA U1 mutante presenta una estrategia terapéutica potencial para los meduloblastomas de SHH.

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