title: Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas.
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.
authors.affiliation: 1] Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Division of Neuro-Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Harvard Medical School, Boston, Massachusetts, USA. [4] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [5] Broad Institute of MIT and Harvard, Boston, Massachusetts, USA. [6].
authors.forename: Priscilla K
authors.initials: PK
authors.lastname: Brastianos
authors.affiliation: 1] Broad Institute of MIT and Harvard, Boston, Massachusetts, USA. [2].
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2].
authors.forename: Peter E
authors.initials: PE
authors.lastname: Manley
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Jones
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Thorner
authors.affiliation: Broad Institute of MIT and Harvard, Boston, Massachusetts, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Fausto J
authors.initials: FJ
authors.lastname: Rodriguez
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Bernardo
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Schubert
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Sunkavalli
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Shillingford
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Monica L
authors.initials: ML
authors.lastname: Calicchio
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Hart G W
authors.initials: HG
authors.lastname: Lidov
authors.affiliation: Children's Cancer Hospital Egypt, Cairo, Egypt.
authors.forename: Hala
authors.initials: H
authors.lastname: Taha
authors.affiliation: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez-Lage
authors.affiliation: Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Mariarita
authors.initials: M
authors.lastname: Santi
authors.affiliation: 1] Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA. [2] Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Storm
authors.affiliation: Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: John Y K
authors.initials: JY
authors.lastname: Lee
authors.affiliation: 1] Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA. [2] Department of Otorhinolaryngology-Head and Neck Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: James N
authors.initials: JN
authors.lastname: Palmer
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Nithin D
authors.initials: ND
authors.lastname: Adappa
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Neurosurgery, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: R Michael
authors.initials: RM
authors.lastname: Scott
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Dunn
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Laws
authors.affiliation: Broad Institute of MIT and Harvard, Boston, Massachusetts, USA.
authors.forename: Chip
authors.initials: C
authors.lastname: Stewart
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA. [4] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Mai P
authors.initials: MP
authors.lastname: Hoang
authors.affiliation: 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Van Hummelen
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Broad Institute of MIT and Harvard, Boston, Massachusetts, USA. [4] Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
authors.affiliation: 1] Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA. [2] Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Resnick
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [3] Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA. [4].
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Boston, Massachusetts, USA. [3] Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA. [4].
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: 1] Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. [4] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [5].
authors.forename: Sandro
authors.initials: S
authors.lastname: Santagata
mesh_terms: D001483:Base Sequence; D001499:Bayes Theorem; D003397:Craniopharyngioma / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010911:Pituitary Neoplasms / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D017422:Sequence Analysis, DNA; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf