Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas



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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Figure 1: Plot of the number of nonsynonymous mutations per megabase in craniopharyngiomas (n = 15) in comparison to a broad range of pediatric and adult tumors n = 3,083).
Figure 2: Mutations in adamantinomatous and papillary craniopharyngiomas.
Figure 3: β-catenin localization is different in adamantinomatous and papillary craniopharyngiomas.
Figure 4: BRAF and CTNNB1 mutations are clonal in craniopharyngiomas.


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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




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.

Corresponding authors

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

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The authors declare no competing financial interests.

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Brastianos, P., Taylor-Weiner, A., Manley, P. et al. Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nat Genet 46, 161–165 (2014). https://doi.org/10.1038/ng.2868

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