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Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4


Johansson, P and Aoude, LG and Wadt, K and Glasson, WJ and Warrier, SK and Hewitt, AW and Kiilgaard, JF and Heegaard, S and Isaacs, T and Franchina, M and Ingvar, C and Vermeulen, T and Whitehead, KJ and Schmidt, CW and Palmer, JM and Symmons, J and Gerdes, A-M and Jonsson, G and Hayward, NK, Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4, OncoTarget, 7, (4) pp. 4624-31. ISSN 1949-2553 (2015) [Refereed Article]


Copyright Statement

Copyright 2016 the authors. Licensed under Creative Commons Attribution Attribution 3.0 Unported (CC BY 3.0)

DOI: doi:10.18632/oncotarget.6614


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.

Item Details

Item Type:Refereed Article
Keywords:uveal melanoma, recurrent mutation, PLCB4, copy number variation, structural variants
Research Division:Biomedical and Clinical Sciences
Research Group:Ophthalmology and optometry
Research Field:Ophthalmology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Hewitt, AW (Professor Alex Hewitt)
ID Code:105385
Year Published:2015
Deposited By:Menzies Institute for Medical Research
Deposited On:2015-12-22
Last Modified:2017-11-07
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