What hope for the future? GNAQ and uveal melanoma

TLDR: The background to GNAQ in UM is reviewed and what makes it such an interesting target for the future treatment of patients is explored.

Abstract: Uveal melanomas (UM) are aggressive ocular tumours that spread to the liver. They are characterised by alterations of chromosome 3 and 8, which are highly predictive of a poor prognosis. Unfortunately, being able to identify those patients with aggressive disease has not, as yet, translated into improved survival. Recently, mutations of guanine nucleotide-binding protein G(q) subunit alpha (GNAQ, or G-alpha-q), which effectively turn it into a dominantly acting oncogene, have been identified in approximately half of UM. These mutations are specific to UM and other non-cutaneous melanomas, and are not found in normal tissues, thus making them potential therapeutic targets. Here, the authors review the background to GNAQ in UM and explore what makes it such an interesting target for the future treatment of patients.

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What hope for the future? GNAQ and Uveal Melanoma.
Karen Sisley, Rachel Doherty, Neil Cross
To cite this version:
Karen Sisley, Rachel Doherty, Neil Cross. What hope for the future? GNAQ and Uveal
Melanoma.. British Journal of Ophthalmology, BMJ Publishing Group, 2011, 95 (5), pp.620.
�10.1136/bjo.2010.182097�. �hal-00618791�

1
What hope for the future? GNAQ and Uveal Melanoma.
Karen Sisley
1
, Rachel Doherty
2
and Neil A Cross
2
Academic Unit of Ophthalmology and Orthoptics, University of Sheffield
1
and
Department of Biosciences, Sheffield Hallam University
2
, Sheffield, United
Kingdom.
Address for correspondence:
K.Sisley, Academic Unit of Ophthalmology and Orthoptics, Department of Oncology,
K Floor, School of Medicine & Biomedical Sciences, Faculty of Medicine Dentistry &
Health, University of Sheffield Beech Hill Road S10 2RX.
Telephone: +44 (0114) 271 13199
Fax: +44 (0114) 271 3344
Email:k.sisley@sheffield.ac.uk
Keywords:
Melanoma, Genetics, Uveal, Mutations, GNAQ
Word Count:
2023

2
Declarations:
"The Corresponding Author has the right to grant on behalf of all authors and does
grant on behalf of all authors, an exclusive licence (or non exclusive for government
employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees
to permit this article (if accepted) to be published in BJO editions and any other
BMJPGL products to exploit all subsidiary rights, as set out in our licence
(http://group.bmj.com/products/journals/instructions-for-authors/licence-forms/
)."
Competing Interest
"Competing Interest: None to declare."

3
Abstract
Uveal melanomas (UM) are aggressive ocular tumours that spread to the liver. They
are characterised by alterations of chromosome 3 and 8 which are highly predictive
of a poor prognosis. Unfortunately, being able to identify those patients with
aggressive disease has not, as yet, translated into improved survival. Recently
mutations of Guanine nucleotide-binding protein G(q) subunit alpha (GNAQ, or G-
alpha-q), that effectively turn it into a dominantly acting oncogene, have been
identified in approximately half of UM. These mutations are specific to UM and other
non-cutaneous melanomas and are not found in normal tissues, making them
potential therapeutic targets. Here we review the background to GNAQ in UM and
explore what makes it such an interesting target for the future treatment of patients.

4
Introduction:
Treatment for cancer increasingly benefits from research and technological
advances, for example mutated c-kit targeted therapy in leukaemia and
gastrointestinal tumours, although not necessarily curative certainly offer hope for
prolonged survival.[1] For other malignancies these advances have not yet heralded
comparable benefits, a case in point being uveal melanoma (UM). UM is the most
common primary intraocular malignancy of adults, with tumours arising in the Iris,
ciliary body and choroid. Approximately 5 - 7 cases per million population are
diagnosed annually.[2] Iris melanomas are relatively benign, but posterior UM
(ciliary body and choroid) still present enormous challenges, and despite successful
and conservative treatment of primary tumours, survival rates over the last 25 years
remain unchanged.[2-4] Metastasis invariably targets the liver, and the detection of
hepatic lesions signifies a dismal outcome, with median survival only 6 months.[5]
There has been a slight improvement recently in survival rates following detection of
hepatic metastases, possibly reflecting earlier detection,[5,6] due in part to research
that has established how to reliably determine those patients that will die usually
within 5 -7 years. This categorization depends on the detection of genetic changes
of chromosomes 3 and 8.[7-10] Thus a very thorny problem arises, that although
we can reliably identify patients with the poorest outcome, there is very little to be
offered for their effective further treatment. For a woefully small percentage of
patients surgical resection of hepatic metastases and liver embolization have
achieved remarkable successes.[5,11] What hope though for the future treatment of
most patients with UM?

Frequently asked questions

Q1. What have the authors contributed in "What hope for the future? gnaq and uveal melanoma" ?

Sisley et al. this paper found that mutations of BRAF and RAS activate the MAPK pathway, through stimulation of mitogen-activated protein kinase kinase or MEK, and are present in 66 % and 15 % of cutaneous melanomas, respectively.