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Abstract

Craniopharyngiomas are epithelial tumors that typically arise in the suprasellar region of the brain1. Patients experience substantial clinical sequelae from both extension of the tumors and therapeutic interventions that damage the optic chiasm, the pituitary stalk and the hypothalamic area2,3,4. Using whole-exome sequencing, we identified mutations in CTNNB1 (β-catenin) in nearly all adamantinomatous craniopharyngiomas examined (11/12, 92%) and recurrent mutations in BRAF (resulting in p.Val600Glu) in all papillary craniopharyngiomas (3/3, 100%). Targeted genotyping revealed BRAF p.Val600Glu in 95% of papillary craniopharyngiomas (36 of 39 tumors) and mutation of CTNNB1 in 96% of adamantinomatous craniopharyngiomas (51 of 53 tumors). The CTNNB1 and BRAF mutations were clonal in each tumor subtype, and we detected no other recurrent mutations or genomic aberrations in either subtype. Adamantinomatous and papillary craniopharyngiomas harbor mutations that are mutually exclusive and clonal. These findings have important implications for the diagnosis and treatment of these neoplasms.

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Acknowledgements

We thank M. Ducar for his assistance with genomic analyses; S. Chauvin for project management; L. Brown and H. Malkin for assisting with sample collection; T. Woo, B. Rich, R. Machaidze and D. Feldman for technical assistance; N. Stransky for the design of Figure 2a; and H. Taylor-Weiner and C.H. Brastianos for critical review of the manuscript. This work was supported by the Jared Branfman Sunflowers for Life Fund for Pediatric Brain and Spinal Cancer Research, the Pediatric Low-Grade Astrocytoma (PLGA) Program (S.S., W.C.H. and Charles D. Stiles), Pedals for Pediatrics and the Clark Family (P.E.M. and M.W.K.), the Stahl Family Charitable Foundation (P.E.M.), the Stop & Shop Pediatric Brain Tumor Program (P.E.M. and M.W.K.), the Pediatric Brain Tumor Clinical and Research Fund (P.E.M. and M.W.K.), the Children's Brain Tumor Foundation and the V Foundation (S.S.). S.S. is supported by grant K08 NS064168, and P.K.B. is supported by grant K12 CA090354-11, the Brain Science Foundation, Susan G. Komen for the Cure, the Terri Brodeur Breast Cancer Foundation, the Conquer Cancer Foundation and the American Brain Tumor Association.

Author information

Author notes

    • Priscilla K Brastianos
    • , Amaro Taylor-Weiner
    •  & Peter E Manley

    These authors contributed equally to this work.

    • Mark W Kieran
    • , Gad Getz
    •  & Sandro Santagata

    These authors jointly directed this work.

Affiliations

  1. Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Priscilla K Brastianos
  2. Division of Neuro-Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Priscilla K Brastianos
  3. Harvard Medical School, Boston, Massachusetts, USA.

    • Priscilla K Brastianos
    • , Dora Dias-Santagata
    • , Hart G W Lidov
    • , R Michael Scott
    • , Ian F Dunn
    • , Edward R Laws Jr
    • , Keith L Ligon
    • , Mai P Hoang
    • , William C Hahn
    • , David N Louis
    • , Mark W Kieran
    • , Gad Getz
    •  & Sandro Santagata
  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Priscilla K Brastianos
    • , Robert T Jones
    • , Aaron R Thorner
    • , Keith L Ligon
    • , Paul Van Hummelen
    •  & William C Hahn
  5. Broad Institute of MIT and Harvard, Boston, Massachusetts, USA.

    • Priscilla K Brastianos
    • , Amaro Taylor-Weiner
    • , Michael S Lawrence
    • , Chip Stewart
    • , William C Hahn
    •  & Gad Getz
  6. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Peter E Manley
    •  & Mark W Kieran
  7. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Robert T Jones
    • , Aaron R Thorner
    • , Laura Schubert
    • , Ashwini Sunkavalli
    • , Paul Van Hummelen
    •  & William C Hahn
  8. Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Dora Dias-Santagata
    • , Lindsay A Bernardo
    • , Mai P Hoang
    • , David N Louis
    •  & Gad Getz
  9. Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.

    • Fausto J Rodriguez
  10. Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Nick Shillingford
    • , Monica L Calicchio
    • , Hart G W Lidov
    • , Keith L Ligon
    •  & Sandro Santagata
  11. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Hart G W Lidov
    • , Keith L Ligon
    •  & Sandro Santagata
  12. Children's Cancer Hospital Egypt, Cairo, Egypt.

    • Hala Taha
  13. Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Maria Martinez-Lage
  14. Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Mariarita Santi
  15. Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Phillip B Storm
    • , John Y K Lee
    • , James N Palmer
    •  & Adam C Resnick
  16. Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Phillip B Storm
    •  & Adam C Resnick
  17. Department of Otorhinolaryngology–Head and Neck Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • James N Palmer
    •  & Nithin D Adappa
  18. Department of Neurosurgery, Boston Children's Hospital, Boston, Massachusetts, USA.

    • R Michael Scott
  19. Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Ian F Dunn
    •  & Edward R Laws Jr
  20. Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Mark W Kieran
  21. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Sandro Santagata

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Contributions

P.K.B., P.E.M., M.W.K., G.G. and S.S. designed the study. P.K.B., A.T.-W., C.S., G.G. and S.S. wrote the manuscript. A.T.-W., P.K.B., C.S., A.R.T. and G.G. performed computational analyses. P.V.H. supervised the sequencing. S.S. and D.N.L. reviewed the histopathology, and S.S., D.N.L. and M.P.H. coordinated and reviewed the immunohistochemistry. K.L.L. managed the tissue repository. R.T.J., L.A.B., A.S., N.S., L.S. and M.L.C. coordinated sample acquisition, processed samples and coordinated and performed exome and targeted sequencing. P.K.B., W.C.H., D.D.-S., D.N.L., A.C.R., M.W.K., G.G. and S.S. supervised the study. H.G.W.L., E.R.L., I.F.D., R.M.S., P.B.S., J.Y.K.L., J.N.P., N.D.A., H.T., M.M.-L., M.S., F.J.R., P.E.M., A.C.R., D.D.-S., D.N.L. and S.S. identified and provided materials for sequencing and validation, as well as clinical information. M.S.L. provided the code and the data to generate Figure 1. All authors discussed the results and implications and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Priscilla K Brastianos or Gad Getz or Sandro Santagata.

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DOI

https://doi.org/10.1038/ng.2868

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