title: Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4.
abstract: Next generation sequencing of uveal melanoma (UM) samples has identified a number of recurrent oncogenic or loss-of-function mutations in key driver genes including: GNAQ, GNA11, EIF1AX, SF3B1 and BAP1. To search for additional driver mutations in this tumor type we carried out whole-genome or whole-exome sequencing of 28 tumors or primary cell lines. These samples have a low mutation burden, with a mean of 10.6 protein changing mutations per sample (range 0 to 53). As expected for these sun-shielded melanomas the mutation spectrum was not consistent with an ultraviolet radiation signature, instead, a BRCA mutation signature predominated. In addition to mutations in the known UM driver genes, we found a recurrent mutation in PLCB4 (c.G1888T, p.D630Y, NM_000933), which was validated using Sanger sequencing. The identical mutation was also found in published UM sequence data (1 of 56 tumors), supporting its role as a novel driver mutation in UM. PLCB4 p.D630Y mutations are mutually exclusive with mutations in GNA11 and GNAQ, consistent with PLCB4 being the canonical downstream target of the former gene products. Taken together these data suggest that the PLCB4 hotspot mutation is similarly a gain-of-function mutation leading to activation of the same signaling pathway, promoting UM tumorigenesis.
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Johansson
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Lauren G
authors.initials: LG
authors.lastname: Aoude
authors.affiliation: Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Karin
authors.initials: K
authors.lastname: Wadt
authors.affiliation: The Terrace Eye Centre, Brisbane, QLD, Australia.
authors.forename: William J
authors.initials: WJ
authors.lastname: Glasson
authors.affiliation: The Terrace Eye Centre, Brisbane, QLD, Australia.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Warrier
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.|Lions Eye Institute, University of Western Australia, Perth, WA, Australia.
authors.forename: Alex W
authors.initials: AW
authors.lastname: Hewitt
authors.affiliation: Department of Ophthalmology, Rigshospitalet-Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens Folke
authors.initials: JF
authors.lastname: Kiilgaard
authors.affiliation: Department of Ophthalmology, Rigshospitalet-Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.|Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Heegaard
authors.affiliation: Lions Eye Institute, University of Western Australia, Perth, WA, Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Isaacs
authors.affiliation: Lions Eye Institute, University of Western Australia, Perth, WA, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Franchina
authors.affiliation: Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: Ingvar
authors.affiliation: The Royal Perth Hospital, Perth, WA, Australia.
authors.forename: Tersia
authors.initials: T
authors.lastname: Vermeulen
authors.affiliation: Sullivan Nicolaides Pathology, Brisbane, QLD, Australia.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Whitehead
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Schmidt
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Jane M
authors.initials: JM
authors.lastname: Palmer
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Judith
authors.initials: J
authors.lastname: Symmons
authors.affiliation: Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Gerdes
authors.affiliation: Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008545:Melanoma / Q000175:diagnosis* / Q000235:genetics*; D009367:Neoplasm Staging; D054799:Phospholipase C beta / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014604:Uveal Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D000098943:Uveal Melanoma
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C518042:PLCB4 protein, human; D054799:Phospholipase C beta
keywords: PLCB4; copy number variation; recurrent mutation; structural variants; uveal melanoma