Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas.

Brastianos PK1, Taylor-Weiner A2, Manley PE3, Jones RT4, Dias-Santagata D5, Thorner AR4, Lawrence MS6, Rodriguez FJ7, Bernardo LA8, Schubert L9,Sunkavalli A9, Shillingford N10, Calicchio ML10, Lidov HG11, Taha H12, Martinez-Lage M13, Santi M14, Storm PB15, Lee JY16, Palmer JN17, Adappa ND18,Scott RM19, Dunn IF20, Laws ER Jr20, Stewart C6, Ligon KL21, Hoang MP5, Van Hummelen P4, Hahn WC22, Louis DN5, Resnick AC15, Kieran MW23, Getz G24, Santagata S25.

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Abstract

Craniopharyngiomas are epithelial tumors that typically arise in the suprasellar region of the brain. 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 area. 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.