Research Papers:

Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4

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

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Oncotarget. 2016; 7:4624-4631. https://doi.org/10.18632/oncotarget.6614

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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

Correspondence to:

Peter Johansson, e-mail: [email protected]

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.

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