title: Profiling of somatic mutations in phaeochromocytoma and paraganglioma by targeted next generation sequencing analysis.
abstract: At least 12 genes (FH, HIF2A, MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL) have been implicated in inherited predisposition to phaeochromocytoma (PCC), paraganglioma (PGL), or head and neck paraganglioma (HNPGL) and a germline mutation may be detected in more than 30% of cases. Knowledge of somatic mutations contributing to PCC/PGL/HNPGL pathogenesis has received less attention though mutations in HRAS, HIF2A, NF1, RET, and VHL have been reported. To further elucidate the role of somatic mutation in PCC/PGL/HNPGL tumourigenesis, we employed a next generation sequencing strategy to analyse "mutation hotspots" in 50 human cancer genes. Mutations were identified for HRAS (c.37G>C; p.G13R and c.182A>G; p.Q61R) in 7.1% (6/85); for BRAF (c.1799T>A; p.V600E) in 1.2% (1/85) of tumours; and for TP53 (c.1010G>A; p.R337H) in 2.35% (2/85) of cases. Twenty-one tumours harboured mutations in inherited PCC/PGL/HNPGL genes and no HRAS, BRAF, or TP53 mutations occurred in this group. Combining our data with previous reports of HRAS mutations in PCC/PGL we find that the mean frequency of HRAS/BRAF mutations in sporadic PCC/PGL is 8.9% (24/269) and in PCC/PGL with an inherited gene mutation 0% (0/148) suggesting that HRAS/BRAF mutations and inherited PCC/PGL genes mutations might be mutually exclusive. We report the first evidence for BRAF mutations in the pathogenesis of PCC/PGL/HNPGL.
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK ; Cambridge NIHR Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Andrea
authors.identifier: 0000-0002-6770-4008
authors.initials: A
authors.lastname: Luchetti
authors.affiliation: Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Walsh
authors.affiliation: Cambridge NIHR Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Fay
authors.identifier: 0000-0002-0214-6287
authors.initials: F
authors.lastname: Rodger
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
authors.forename: Graeme
authors.identifier: 0000-0002-5543-2789
authors.initials: G
authors.lastname: Clark
authors.affiliation: Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham B15 2TH, UK.
authors.forename: Tom
authors.identifier: 0000-0001-7945-9786
authors.initials: T
authors.lastname: Martin
authors.affiliation: Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham B15 2TH, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Irving
authors.affiliation: Department of Otology & Skull Base Surgery, Gruppo Otologico, Via Antonio Emmanueli 42, 29121 Piacenza, Italy ; Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Via dei Vestini 1, 66100 Chieti, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Sanna
authors.affiliation: Department of Urology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa Ward, Yokohama, Kanagawa 236-0004, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yao
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain ; ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.affiliation: Section of Preventive Medicine, Department of Nephrology, Albert Ludwigs University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.
authors.forename: Hartmut P H
authors.initials: HP
authors.lastname: Neumann
authors.affiliation: Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Birmingham B15 2TT, UK ; Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
authors.forename: Emma R
authors.initials: ER
authors.lastname: Woodward
authors.affiliation: Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Farida
authors.initials: F
authors.lastname: Latif
authors.affiliation: Cambridge NIHR Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Abbs
authors.affiliation: Cambridge NIHR Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Howard
authors.identifier: 0000-0002-1618-7557
authors.initials: H
authors.lastname: Martin
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK ; Cambridge NIHR Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK ; Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher