Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O'Brien JM et al.Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457:599-602

Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T1Z3, Canada.
Nature (Impact Factor: 41.46). 01/2009; 457(7229):599-602. DOI: 10.1038/nature07586
Source: PubMed


BRAF and NRAS are common targets for somatic mutations in benign and malignant neoplasms that arise from melanocytes situated in epithelial structures, and lead to constitutive activation of the mitogen-activated protein (MAP) kinase pathway. However, BRAF and NRAS mutations are absent in a number of other melanocytic neoplasms in which the equivalent oncogenic events are currently unknown. Here we report frequent somatic mutations in the heterotrimeric G protein alpha-subunit, GNAQ, in blue naevi (83%) and ocular melanoma of the uvea (46%). The mutations occur exclusively in codon 209 in the Ras-like domain and result in constitutive activation, turning GNAQ into a dominant acting oncogene. Our results demonstrate an alternative route to MAP kinase activation in melanocytic neoplasia, providing new opportunities for therapeutic intervention.

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Available from: Jürgen Bauer, Jul 21, 2014
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    • "Activating mutations on GNAS are also associated to McCune-Albright syndrome [25], [26]. Along with well-established GNAS mutations, somatic mutations in other Gα family members, namely GNAQ and GNA11, have been linked to tumorigenesis in melanocytic neoplasms [27], [28]. "
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    ABSTRACT: Pituitary adenomas are neoplasms of the anterior pituitary lobe and account for 15–20% of all intracranial tumors. Although most pituitary tumors are benign they can cause severe symptoms related to tumor size as well as hypopituitarism and/or hypersecretion of one or more pituitary hormones. Most pituitary adenomas are sporadic, but it has been estimated that 5% of patients have a familial background. Germline mutations of the tumor suppressor gene aryl hydrocarbon receptor-interacting protein (AIP) predispose to hereditary pituitary neoplasia. Recently, it has been demonstrated that AIP mutations predispose to pituitary tumorigenesis through defective inhibitory GTP binding protein (Gαi) signaling. This finding prompted us to examine whether germline loss-of-function mutations in inhibitory guanine nucleotide (GTP) binding protein alpha (GNAI) loci are involved in genetic predisposition of pituitary tumors. To our knowledge, this is the first time GNAI genes are sequenced in order to examine the occurrence of inactivating germline mutations. Thus far, only somatic gain-of-function hot-spot mutations have been studied in these loci. Here, we have analyzed the coding regions of GNAI1, GNAI2, and GNAI3 in a set of young sporadic somatotropinoma patients (n = 32; mean age of diagnosis 32 years) and familial index cases (n = 14), thus in patients with a disease phenotype similar to that observed in AIP mutation carriers. In addition, expression of Gαi proteins was studied in human growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH)-secreting and non-functional pituitary tumors. No pathogenic germline mutations affecting the Gαi proteins were detected. The result suggests that loss-of-function mutations of GNAI loci are rare or nonexistent in familial pituitary adenomas.
    PLoS ONE 10/2014; 9(10):e109897. DOI:10.1371/journal.pone.0109897 · 3.23 Impact Factor
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    • "Interestingly, the downstream effectors of BRAF and NRAS, MEK, ERK and ELK, were constitutively activated in uveal melanomas [11]. These mutations remained undetected in uveal melanomas until recently GNAQ and GNA11 mutations in uveal melanoma were identified [12]–[14]. "
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    ABSTRACT: Purpose To examine whether GNAQ and GNA11 somatic mutations previously identified in uveal melanomas of Caucasians are associated with uveal melanomas in Chinese patients. Methods Uveal melanomas treated by primary enucleation in Chinese patients underwent a mutation analysis of GNAQ and GNA11 with sequencing of exon 5 and exon 4. Results The study included 50 patients with uveal melanoma and with a mean age of 47.6±13.0 years. During the follow-up of at least 3 years, 20 (40%) patients developed extraocular metastases. The frequencies of GNAQ and GNA11 somatic mutations in uveal melanoma were 18% (9/50) and 20% (10/50), respectively. The mutations occurred exclusively in codon 209 of exon 5. No mutations were detected in exon 4. Mutations affecting codon 209 in GNAQ were c.626A>C(Q209P) (78%) and c.626A>T(Q209L) (22%). Mutations affecting codon 209 in GNA11 were exclusively c.626A>T(Q209L) (100%). In none of the tumors, mutations of BRAF and NRAS were detected. GNAQ/11 mutations were marginally (P = 0.045) associated with optic disc involvement. In Kaplan-Meier analysis, metastasis-free survival was not significantly (P = 0.94) associated with GNAQ/11 mutations. Conclusions Mutations of GNAQ and GNA11 can be found in Chinese patients as in Caucasian patients with uveal melanoma, with a higher frequency reported for Caucasian patients.
    PLoS ONE 10/2014; 9(10):e109699. DOI:10.1371/journal.pone.0109699 · 3.23 Impact Factor
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    • "Interestingly, hyperactivation of the MAPK signal cascade is not due to mutations in the BRAF or RAS genes as commonly seen in cutaneous melanoma. Over 80% of UM have upstream mutations in the GNAQ/GNA11 genes, resulting in constitutive MAPK pathway activation (Van Raamsdonk et al., 2010, 2009). Recent studies have demonstrated that the transcriptional coactivator YAP mediates the oncogenic activity of mutant Gq/11 in UM development (Feng et al., 2014; Yu et al., 2014). "
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    ABSTRACT: Although rare, uveal melanoma (UM) is the most common primary intraocular tumor in adults. About half of UM patients develop metastatic disease typically in the liver and die within a short period, due to ineffective systemic therapies. UM has unique and distinct genetic features predictive of metastasis. Animal models are required to improve our understanding of therapeutic options in disseminated UM. Since spontaneous murine UM models are lacking, our aim was to analyze the suitability of the established transgenic melanoma mouse model Tg(Grm1) as a new UM model system. We demonstrated that adult Grm1 transgenic mice develop choroidal thickening and uveal melanocytic neoplasia with expression of the melanocytic markers S100B and MelanA. Further, we showed that GRM1 is expressed in human UM, similar to skin melanoma. This study presents a new mouse model for spontaneous UM and suggests that the glutamate signaling pathway is a possible target for UM therapy.
    Experimental Eye Research 10/2014; 127. DOI:10.1016/j.exer.2014.07.009 · 2.71 Impact Factor
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