Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4
Metrics: PDF 1931 views | HTML 2750 views | ?
Peter Johansson1, Lauren G. Aoude1, Karin Wadt2, William J. Glasson3, Sunil K. Warrier3, Alex W. Hewitt4,5, Jens Folke Kiilgaard6, Steffen Heegaard6,7, Tim Isaacs5, Maria Franchina5, Christian Ingvar8, Tersia Vermeulen9, Kevin J. Whitehead10, Christopher W. Schmidt1, Jane M. Palmer1, Judith Symmons1, Anne-Marie Gerdes2, Göran Jönsson8, Nicholas K. Hayward1
1QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
2Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark
3The Terrace Eye Centre, Brisbane, QLD, Australia
4Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
5Lions Eye Institute, University of Western Australia, Perth, WA, Australia
6Department of Ophthalmology, Rigshospitalet-Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark
7Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
8Department of Clinical Sciences, Lund University, Lund, Sweden
9The Royal Perth Hospital, Perth, WA, Australia
10Sullivan Nicolaides Pathology, Brisbane, QLD, Australia
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
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.