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Germline Elongator mutations in Sonic Hedgehog medulloblastoma.
Journal article

Germline Elongator mutations in Sonic Hedgehog medulloblastoma.

  • Waszak SM European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
  • Robinson GW Department of Oncology, Division of Neuro-Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Gudenas BL Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Smith KS Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Forget A Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France.
  • Kojic M Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
  • Garcia-Lopez J Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Hadley J Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Hamilton KV Department of Oncology, Division of Cancer Predisposition, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Indersie E Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France.
  • Buchhalter I Omics IT and Data Management Core Facility (W610), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Kerssemakers J Omics IT and Data Management Core Facility (W610), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Jäger N Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Sharma T Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Rausch T European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
  • Kool M Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Sturm D Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Jones DTW Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Vasilyeva A Cancer Center Administration, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Tatevossian RG Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Neale G Hartwell Center, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Lombard B Institut Curie, PSL Research University, Centre de Recherche, Laboratoire de Spectrométrie de Masse Protéomique, Paris, France.
  • Loew D Institut Curie, PSL Research University, Centre de Recherche, Laboratoire de Spectrométrie de Masse Protéomique, Paris, France.
  • Nakitandwe J Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Rusch M Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Bowers DC Division of Pediatric Hematology-Oncology, University of Texas Southwestern Medical School, Dallas, TX, USA.
  • Bendel A Department of Pediatric Hematology and Oncology, Children's Hospitals and Clinics of Minnesota, Minnesota, MN, USA.
  • Partap S Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
  • Chintagumpala M Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
  • Crawford J Department of Neurosciences, University of California San Diego and Rady Children's Hospital, San Diego, CA, USA.
  • Gottardo NG Department of Paediatric and Adolescent Oncology/Haematology, Perth Children's Hospital and Brain Tumour Research Programme, Telethon Kids Institute, Perth, Western Australia, Australia.
  • Smith A Arnold Palmer Hospital Center for Children's Cancer, Orlando, FL, USA.
  • Dufour C Gustave Roussy, Université Paris-Saclay, Department of Pediatric and Adolescent Oncology, Villejuif, France.
  • Rutkowski S Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Eggen T The Cancer Registry of Norway, Majorstuen, Oslo, Norway.
  • Wesenberg F Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.
  • Kjaerheim K Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.
  • Feychting M Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Lannering B Department of Pediatrics, University of Gothenburg, The Queen Silvia Children's Hospital, Gothenburg, Sweden.
  • Schüz J Section of Environment and Radiation, International Agency for Research on Cancer (IARC), Lyon, France.
  • Johansen C Oncology Clinic, Finsen Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
  • Andersen TV Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland.
  • Röösli M Swiss Childhood Cancer Registry, Institute of Social and Preventive Medicine University of Bern, Bern, Switzerland.
  • Kuehni CE Swiss Childhood Cancer Registry, Institute of Social and Preventive Medicine University of Bern, Bern, Switzerland.
  • Grotzer M University Children's Hospital of Zurich, Zurich, Switzerland.
  • Remke M Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
  • Puget S Department of Pediatric Neurosurgery, Necker Hospital, Université de Paris, Paris, France.
  • Pajtler KW Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Milde T Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Witt O Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Ryzhova M Department of Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia.
  • Korshunov A Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Orr BA Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Ellison DW Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Brugieres L Gustave Roussy, Université Paris-Saclay, Department of Pediatric and Adolescent Oncology, Villejuif, France.
  • Lichter P Division of Molecular Genetics, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany.
  • Nichols KE Department of Oncology, Division of Cancer Predisposition, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Gajjar A Department of Oncology, Division of Neuro-Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • Wainwright BJ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
  • Ayrault O Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France.
  • Korbel JO European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany. jan.korbel@embl.org.
  • Northcott PA Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA. paul.northcott@stjude.org.
  • Pfister SM Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. s.pfister@kitz-heidelberg.de.
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  • 2020-04-17
Published in:
  • Nature. - 2020
Cerebellar Neoplasms
Child
Female
Germ-Line Mutation
Humans
Male
Medulloblastoma
Pedigree
RNA, Transfer
Transcriptional Elongation Factors
English Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children1,2, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma3. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype4 and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U34) position5,6. Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems7-9. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.
Language
  • English
Open access status
green
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https://sonar.ch/global/documents/151801
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