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Nat Genet. 2016 Feb;48(2):183-8. doi: 10.1038/ng.3473. Epub 2015 Dec 21.

Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma.

Author information

1
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
2
Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, USA.
3
Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
4
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
5
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
6
Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.
7
Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel and Christian Albrechts University Kiel, Kiel, Germany.
8
Transcriptome Bioinformatics, LIFE Research Center for Civilization Diseases, Leipzig, Germany.
9
Interdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, Germany.
10
Bioinformatics Group, Department of Computer Science, University of Leipzig, Leipzig, Germany.
11
MTA-SE Lendulet Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
12
Leibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
13
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
14
Haematological Malignancy Diagnostic Service, St. James's Institute of Oncology, Leeds, UK.
15
Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.
16
Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

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.

PMID:
26691987
PMCID:
PMC4731318
DOI:
10.1038/ng.3473
[Indexed for MEDLINE]
Free PMC Article

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