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Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4

2015; Impact Journals LLC; Volume: 7; Issue: 4 Linguagem: Inglês

10.18632/oncotarget.6614

1949-2553

Peter A. Johansson, Lauren G. Aoude, Karin Wadt, William Glasson, Sunil Warrier, Alex W. Hewitt, Jens Folke Kiilgaard, Steffen Heegaard, Tim Isaacs, Maria Franchina, Christian Ingvar, Tersia Vermeulen, Kevin J. Whitehead, Christopher Schmidt, Jane M. Palmer, Judith Symmons, Anne–Marie Gerdes, Göran Jönsson, Nicholas K. Hayward,

Retinal and Macular Surgery

// Peter Johansson 1 , Lauren G. Aoude 1 , Karin Wadt 2 , William J. Glasson 3 , Sunil K. Warrier 3 , Alex W. Hewitt 4, 5 , Jens Folke Kiilgaard 6 , Steffen Heegaard 6, 7 , Tim Isaacs 5 , Maria Franchina 5 , Christian Ingvar 8 , Tersia Vermeulen 9 , Kevin J. Whitehead 10 , Christopher W. Schmidt 1 , Jane M. Palmer 1 , Judith Symmons 1 , Anne-Marie Gerdes 2 , Göran Jönsson 8 , Nicholas K. Hayward 1 1 QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia 2 Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark 3 The Terrace Eye Centre, Brisbane, QLD, Australia 4 Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia 5 Lions Eye Institute, University of Western Australia, Perth, WA, Australia 6 Department of Ophthalmology, Rigshospitalet-Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark 7 Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark 8 Department of Clinical Sciences, Lund University, Lund, Sweden 9 The Royal Perth Hospital, Perth, WA, Australia 10 Sullivan Nicolaides Pathology, Brisbane, QLD, Australia Correspondence to: Peter Johansson, e-mail: Peter.Johansson@qimrberghofer.edu.au Keywords: uveal melanoma, recurrent mutation, PLCB4, copy number variation, structural variants Received: September 14, 2015 Accepted: November 26, 2015 Published: December 14, 2015 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.