Abstract

The diagnosed incidence of small intestine neuroendocrine tumors (SI-NETs) is increasing, and the underlying genomic mechanisms have not yet been defined. Using exome- and genome-sequence analysis of SI-NETs, we identified recurrent somatic mutations and deletions in CDKN1B, the cyclin-dependent kinase inhibitor gene, which encodes p27. We observed frameshift mutations of CDKN1B in 14 of 180 SI-NETs, and we detected hemizygous deletions encompassing CDKN1B in 7 out of 50 SI-NETs, nominating p27 as a tumor suppressor and implicating cell cycle dysregulation in the etiology of SI-NETs.

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Acknowledgements

This work was supported by grants from the Caring for Carcinoid Foundation (S.L.A. and M.M.), the Raymond and Beverly Sackler Foundation for the Arts and Sciences (C.T., A. Karpathakis, S.L.A. and M.M.) and Cancer Research UK (C.T. and A. Karpathakis).

Author information

Author notes

    • Alex H Ramos

    Present address: H3 Biomedicine, Cambridge, Massachusetts, USA.

    • Joshua M Francis
    • , Adam Kiezun
    •  & Alex H Ramos

    These authors contributed equally to this work.

Affiliations

  1. Broad Institute, Cambridge, Massachusetts, USA.

    • Joshua M Francis
    • , Adam Kiezun
    • , Alex H Ramos
    • , Chandra Sekhar Pedamallu
    • , Elizabeth Nickerson
    • , Nam Pho
    • , Michael S Lawrence
    • , Trevor Pugh
    • , Aaron McKenna
    • , Andrey Sivachenko
    • , Kristian Cibulskis
    • , Scott L Carter
    • , Akinyemi I Ojesina
    • , Douglas Voet
    • , Gordon Saksena
    • , Daniel Auclair
    • , Robert Onofrio
    • , Erica Shefler
    • , Carrie Sougnez
    • , Jonna Grimsby
    • , Lisa Green
    • , Niall Lennon
    • , Gad Getz
    •  & Matthew Meyerson
  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Joshua M Francis
    • , Alex H Ramos
    • , Chandra Sekhar Pedamallu
    • , Zhi Rong Qian
    • , Veronica Manzo
    • , Juliet Philips
    • , Susanne M Hooshmand
    • , Lauren K Brais
    • , Akinyemi I Ojesina
    • , Samuel Freeman
    • , Shuji Ogino
    • , Ramesh Shivdasani
    • , Matthew Kulke
    •  & Matthew Meyerson
  3. Department of Pathology, University Health Network, Toronto, Ontario, Canada.

    • Stefano Serra
    •  & Sylvia L Asa
  4. Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA.

    • Michaela S Banck
    • , Rahul Kanwar
    • , Amit A Kulkarni
    •  & Andreas S Beutler
  5. Mayo Clinic Cancer Center, Mayo Clinic, Rochester, Minnesota, USA.

    • Michaela S Banck
    •  & Andreas S Beutler
  6. University College London Cancer Institute, London, UK.

    • Anna Karpathakis
    • , Tim Meyer
    •  & Christina Thirlwell
  7. Royal Free Hospital NET Unit, London, UK.

    • Anna Karpathakis
    • , Tim Meyer
    • , Martyn Caplin
    •  & Christina Thirlwell
  8. Raymond and Beverly Sackler Foundation, New Brunswick, New Jersey, USA.

    • Tanupriya Contractor
    •  & Chris R Harris
  9. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Robert T Jones
    •  & Matthew Meyerson
  10. Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Daniel C Chung
  11. Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Daniel C Chung
  12. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Shuji Ogino
  13. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Shuji Ogino
  14. Ontario Cancer Institute, University of Toronto, Ontario, Canada.

    • Sylvia L Asa
  15. Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, USA.

    • Chris R Harris
  16. Department of Pediatrics, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, USA.

    • Chris R Harris

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Contributions

J.M.F., A. Kiezun, A.H.R., R.S., S.L.A., C.R.H., M.K. and M.M. conceived and designed the experiments. J.M.F., A. Kiezun, A.H.R., S.S., C.S.P., Z.R.Q., A. Karpathakis, S.O., C.T., R.S., S.L.A., C.R.H., G.G., M.K. and M.M. analyzed the data. C.S.P., Z.R.Q., M.S.B., R.K., A.A.K., A. Karpathakis, V.M., T.C., J.P., N.P., S.M.H., L.K.B., M.S.L., T.P., A.M., A.S., K.C., S.L.C., A.I.O., S.F., R.T.J., D.V., G.S., T.M., M.C., D.C.C., A.S.B., S.O., C.T., R.S., S.L.A., C.R.H., G.G., M.K., J.G., L.G. and N.L. contributed reagents, materials and tools. E.N., D.A., R.O., E.S. and C.S. provided project management support. J.M.F., A. Kiezun, A.H.R., S.L.A., M.K. and M.M. wrote the manuscript with contributions from all other authors.

Competing interests

M.M. is a paid consultant for and equity holder in Foundation Medicine, a genomics-based oncology diagnostics company.

Corresponding authors

Correspondence to Matthew Kulke or Matthew Meyerson.

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DOI

https://doi.org/10.1038/ng.2821

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