title: Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma.
abstract: Follicular lymphoma is an incurable B cell malignancy characterized by the t(14;18) translocation and mutations affecting the epigenome. Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined, the spectrum of these mutations typically overlaps with that in the closely related diffuse large B cell lymphoma (DLBCL). Using a combination of discovery exome and extended targeted sequencing, we identified recurrent somatic mutations in RRAGC uniquely enriched in patients with follicular lymphoma (17%). More than half of the mutations preferentially co-occurred with mutations in ATP6V1B2 and ATP6AP1, which encode components of the vacuolar H(+)-ATP ATPase (V-ATPase) known to be necessary for amino acid-induced activation of mTORC1. The RagC variants increased raptor binding while rendering mTORC1 signaling resistant to amino acid deprivation. The activating nature of the RRAGC mutations, their existence in the dominant clone and their stability during disease progression support their potential as an excellent candidate for therapeutic targeting.
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Okosun
authors.affiliation: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
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authors.initials: RL
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authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
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authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
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authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Lucy
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authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
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authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
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authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
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authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel and Christian Albrechts University Kiel, Kiel, Germany.
authors.forename: Julia
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authors.lastname: Richter
authors.affiliation: Transcriptome Bioinformatics, LIFE Research Center for Civilization Diseases, Leipzig, Germany.|Interdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, Germany.|Bioinformatics Group, Department of Computer Science, University of Leipzig, Leipzig, Germany.
authors.forename: Stephan H
authors.initials: SH
authors.lastname: Bernhart
authors.affiliation: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Alejo
authors.initials: A
authors.lastname: Efeyan
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Sameena
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authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Janet
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authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
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authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: José Afonso
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authors.affiliation: MTA-SE Lendulet Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Bödör
authors.affiliation: Leibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
authors.forename: Hilmar
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authors.lastname: Quentmeier
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Christopher
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authors.lastname: Mansbridge
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
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authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Andrew
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authors.lastname: Davies
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Jonathan C
authors.identifier: http://orcid.org/0000-0002-0972-2881
authors.initials: JC
authors.lastname: Strefford
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Graham
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authors.lastname: Packham
authors.affiliation: Haematological Malignancy Diagnostic Service, St. James's Institute of Oncology, Leeds, UK.
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authors.initials: S
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authors.affiliation: Haematological Malignancy Diagnostic Service, St. James's Institute of Oncology, Leeds, UK.
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authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
authors.forename: Ming-Qing
authors.initials: MQ
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authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Calaminici
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: T Andrew
authors.initials: TA
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authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Rebecca
authors.initials: R
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authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Silvia
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authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel and Christian Albrechts University Kiel, Kiel, Germany.
authors.forename: Reiner
authors.initials: R
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authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Claude
authors.initials: C
authors.lastname: Chelala
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Zoncu
authors.affiliation: Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Jude
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authors.lastname: Fitzgibbon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D017386:Sequence Homology, Amino Acid; D058570:TOR Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics*
chemical_list: D046912:Multiprotein Complexes; C430722:RRAGC protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins