2. Academic Validation
  3. Germline Elongator mutations in Sonic Hedgehog medulloblastoma

Germline Elongator mutations in Sonic Hedgehog medulloblastoma

  • Nature. 2020 Apr;580(7803):396-401. doi: 10.1038/s41586-020-2164-5.
Sebastian M Waszak # 1,  Giles W Robinson # 2,  Brian L Gudenas 3,  Kyle S Smith 3,  Antoine Forget 4,  Marija Kojic 5,  Jesus Garcia-Lopez 3,  Jennifer Hadley 3,  Kayla V Hamilton 6,  Emilie Indersie 4,  Ivo Buchhalter 7,  Jules Kerssemakers 7,  Natalie Jäger 8 9,  Tanvi Sharma 8 9,  Tobias Rausch 1,  Marcel Kool 8 9 10,  Dominik Sturm 8 11,  David T W Jones 8 11,  Aksana Vasilyeva 12,  Ruth G Tatevossian 13,  Geoffrey Neale 14,  Bérangère Lombard 15,  Damarys Loew 15,  Joy Nakitandwe 13,  Michael Rusch 16,  Daniel C Bowers 17,  Anne Bendel 18,  Sonia Partap 19,  Murali Chintagumpala 20,  John Crawford 21 22,  Nicholas G Gottardo 23,  Amy Smith 24,  Christelle Dufour 25,  Stefan Rutkowski 26,  Tone Eggen 27,  Finn Wesenberg 28,  Kristina Kjaerheim 28,  Maria Feychting 29,  Birgitta Lannering 30,  Joachim Schüz 31,  Christoffer Johansen 32 33,  Tina V Andersen 34,  Martin Röösli 35,  Claudia E Kuehni 35 36,  Michael Grotzer 37,  Marc Remke 38,  Stéphanie Puget 39,  Kristian W Pajtler 8 9 40,  Till Milde 8 40 41,  Olaf Witt 8 40 41,  Marina Ryzhova 42,  Andrey Korshunov 43 44,  Brent A Orr 13,  David W Ellison 13,  Laurence Brugieres 25,  Peter Lichter 45,  Kim E Nichols 6,  Amar Gajjar 2,  Brandon J Wainwright 5,  Olivier Ayrault 4,  Jan O Korbel 46,  Paul A Northcott 47,  Stefan M Pfister 48 49 50
Affiliations

Affiliations

  • 1 European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
  • 2 Department of Oncology, Division of Neuro-Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 3 Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 4 Université Paris Sud, Université Paris-Saclay, CNRS UMR 3347, INSERM U1021, Orsay, France.
  • 5 Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
  • 6 Department of Oncology, Division of Cancer Predisposition, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 7 Omics IT and Data Management Core Facility (W610), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 8 Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • 9 Division of Pediatric Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 10 Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
  • 11 Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 12 Cancer Center Administration, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 13 Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 14 Hartwell Center, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 15 Institut Curie, PSL Research University, Centre de Recherche, Laboratoire de Spectrométrie de Masse Protéomique, Paris, France.
  • 16 Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 17 Division of Pediatric Hematology-Oncology, University of Texas Southwestern Medical School, Dallas, TX, USA.
  • 18 Department of Pediatric Hematology and Oncology, Children's Hospitals and Clinics of Minnesota, Minnesota, MN, USA.
  • 19 Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
  • 20 Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
  • 21 Department of Neurosciences, University of California San Diego and Rady Children's Hospital, San Diego, CA, USA.
  • 22 Department of Pediatrics, University of California San Diego and Rady Children's Hospital, San Diego, CA, USA.
  • 23 Department of Paediatric and Adolescent Oncology/Haematology, Perth Children's Hospital and Brain Tumour Research Programme, Telethon Kids Institute, Perth, Western Australia, Australia.
  • 24 Arnold Palmer Hospital Center for Children's Cancer, Orlando, FL, USA.
  • 25 Gustave Roussy, Université Paris-Saclay, Department of Pediatric and Adolescent Oncology, Villejuif, France.
  • 26 Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 27 The Cancer Registry of Norway, Majorstuen, Oslo, Norway.
  • 28 Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.
  • 29 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • 30 Department of Pediatrics, University of Gothenburg, The Queen Silvia Children's Hospital, Gothenburg, Sweden.
  • 31 Section of Environment and Radiation, International Agency for Research on Cancer (IARC), Lyon, France.
  • 32 Oncology Clinic, Finsen Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
  • 33 Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.
  • 34 Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland.
  • 35 Swiss Childhood Cancer Registry, Institute of Social and Preventive Medicine University of Bern, Bern, Switzerland.
  • 36 Department of Paediatric Haematology and Oncology, University Children's Hospital, Bern, Switzerland.
  • 37 University Children's Hospital of Zurich, Zurich, Switzerland.
  • 38 Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.
  • 39 Department of Pediatric Neurosurgery, Necker Hospital, Université de Paris, Paris, France.
  • 40 Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
  • 41 Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 42 Department of Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia.
  • 43 Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 44 Department of Neuropathology, University Hospital, Heidelberg, Germany.
  • 45 Division of Molecular Genetics, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany.
  • 46 European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany. jan.korbel@embl.org.
  • 47 Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA. paul.northcott@stjude.org.
  • 48 Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany. s.pfister@kitz-heidelberg.de.
  • 49 Division of Pediatric Neurooncology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. s.pfister@kitz-heidelberg.de.
  • 50 Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany. s.pfister@kitz-heidelberg.de.
  • # Contributed equally.
PMID: 32296180 DOI: 10.1038/s41586-020-2164-5
Abstract

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.

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