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  • A Corrigendum to this article was published on 27 May 2016

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Abstract

Follicular lymphoma is an incurable B cell malignancy1 characterized by the t(14;18) translocation and mutations affecting the epigenome2,3. Although frequent gene mutations in key signaling pathways, including JAK-STAT, NOTCH and NF-κB, have also been defined2,3,4,5,6,7, the spectrum of these mutations typically overlaps with that in the closely related diffuse large B cell lymphoma (DLBCL)6,7,8,9,10,11,12,13. 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.

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Change history

  • 12 January 2016

    In the version of this article initially published online, several funding sources were omitted from the Acknowledgments section. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We are indebted to the patients for donating tumor specimens as part of this study. We thank G. Clark at the Francis Crick Institute for automated DNA sequencing and the Queen Mary University of London Genome Centre for Illumina MiSeq sequencing. We acknowledge the support of Barts, Cambridge, Leeds and Southampton's Experimental Cancer Medicine and Cancer Research UK Centers. This work was supported by grants from the Kay Kendall Leukaemia Fund and Cancer Research UK (awarded to J.F.), grants from the US National Institutes of Health (NIH; R01 CA103866 and AI47389) and the US Department of Defense (W81XWH-07-0448) to D.M.S., and fellowship support from the US NIH to R.L.W. (T32 GM007753 and F30 CA189333). D.M.S. is an investigator of the Howard Hughes Medical Institute. J.O. is a recipient of the Kay Kendall Leukaemia Fund Junior Clinical Research Fellowship (KKL 557).

Author information

Author notes

    • Jessica Okosun
    •  & Rachel L Wolfson

    These authors contributed equally to this work.

    • David M Sabatini
    •  & Jude Fitzgibbon

    These authors jointly supervised this work.

Affiliations

  1. Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.

    • Jessica Okosun
    • , Shamzah Araf
    • , Lucy Wilkins
    • , Ahad Fahad Al Seraihi
    • , Sameena Iqbal
    • , Janet Matthews
    • , Andrew Clear
    • , Maria Calaminici
    • , T Andrew Lister
    • , Rebecca Auer
    • , Silvia Montoto
    • , John G Gribben
    •  & Jude Fitzgibbon
  2. Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts, USA.

    • Rachel L Wolfson
    • , Alejo Efeyan
    •  & David M Sabatini
  3. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Rachel L Wolfson
    • , Alejo Efeyan
    •  & David M Sabatini
  4. Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.

    • Jun Wang
    • , José Afonso Guerra-Assunção
    •  & Claude Chelala
  5. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.

    • Brian M Castellano
    •  & Roberto Zoncu
  6. Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK.

    • Leire Escudero-Ibarz
    •  & Ming-Qing Du
  7. Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel and Christian Albrechts University Kiel, Kiel, Germany.

    • Julia Richter
    •  & Reiner Siebert
  8. Transcriptome Bioinformatics, LIFE Research Center for Civilization Diseases, Leipzig, Germany.

    • Stephan H Bernhart
  9. Interdisciplinary Center for Bioinformatics, University of Leipzig, Leipzig, Germany.

    • Stephan H Bernhart
  10. Bioinformatics Group, Department of Computer Science, University of Leipzig, Leipzig, Germany.

    • Stephan H Bernhart
  11. MTA-SE Lendulet Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.

    • Csaba Bödör
  12. Leibniz Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.

    • Hilmar Quentmeier
  13. Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.

    • Christopher Mansbridge
    • , Peter Johnson
    • , Andrew Davies
    • , Jonathan C Strefford
    •  & Graham Packham
  14. Haematological Malignancy Diagnostic Service, St. James's Institute of Oncology, Leeds, UK.

    • Sharon Barrans
    •  & Andrew Jack
  15. Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts, USA.

    • David M Sabatini
  16. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • David M Sabatini

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Contributions

J.O. and J.F. conceived the study. J.O., D.M.S. and J.F. directed the study. C.M., G.P., P.J., A.D., J.C.S., M.-Q.D., S.B., A.J., T.A.L., R.A., S.M. and J.G.G. provided patient samples and clinical data. M.C., A.J. and M.-Q.D. conducted pathological review of specimens. J.M. collated clinical information. S.I. prepared and processed samples. H.Q. provided cell line DNA. J.O., R.L.W., S.A., L.W., B.M.C., L.E.-I., A.F.A.S., A.C., A.E., C.B. and R.Z. performed experiments. J.W., J.A.G.-A., S.H.B. and C.C. performed the bioinformatic analysis. J.R. and R.S. coordinated and verified the ICGC data set. J.O., R.L.W., J.W., D.M.S. and J.F. analyzed and interpreted the data. J.O., R.L.W., D.M.S. and J.F. wrote the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jessica Okosun or David M Sabatini.

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DOI

https://doi.org/10.1038/ng.3473

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