Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi

Raamsdonk, Catherine D. Van; Bezrookove, Vladimir; Green, Gary; Bauer, Jürgen; Gaugler, Lona; O’Brien, Joan M.; Simpson, Elizabeth M.; Barsh, Gregory S.; Bastian, Boris C.

doi:10.1038/nature07586

Cited by 1,439 publications

(1,373 citation statements)

References 23 publications

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“…Further abnormalities described in UM include loss of 1p, which is associated with poor prognosis in the context of M3 15, and gains on 6p, which, in the absence of additional chromosomal abnormalities, correspond with a good prognosis 16, 17. More recently, mutations occurring in UM have been identified in several genes, including GNAQ , GNA11 , BAP1 , SF3B1 , EIF1AX , PLCB4 , and CYSLTR2 11, 18, 19, 20, 21, 22. In particular, inactivating BAP1 mutations are associated with a poor outcome, being present in ∼84% of all UMs that went on to produce metastases 19, 23, 24.…”

Section: Introductionmentioning

confidence: 99%

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma

Farquhar

Thornton

Coupland

et al. 2017

The Journal of Pathology CR

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Uveal melanoma (UM) is a rare aggressive intraocular tumour with a propensity for liver metastases, occurring in ∼50% of patients. The tumour suppressor BAP1 is considered to be key in UM progression. Herein, we present the largest study to date investigating cellular expression patterns of BAP1 protein in 165 UMs, correlating these patterns to prognosis. Full clinical, histological, genetic, and follow‐up data were available for all patients. BAP1 gene sequencing was performed on a subset of 26 cases. An independent cohort of 14 UMs was examined for comparison. Loss of nuclear BAP1 (nBAP1) protein expression was observed in 54% (88/165) UMs. nBAP1 expression proved to be a significant independent prognostic parameter: it identified two subgroups within monosomy 3 (M3) UM, which are known to have a high risk of metastasis. Strikingly, nBAP1‐positiveM3 UMs were associated with prolonged survival compared to nBAP1‐negative M3 UMs (Log rank, p = 0.014). nBAP1 protein loss did not correlate with a BAP1 mutation in 23% (6/26) of the UMs analysed. Cytoplasmic BAP1 protein (cBAP1) expression was also observed in UM: although appearing ‘predominantly diffuse’ in most nBAP1‐negative UM, a distinct ‘focal perinuclear’ expression pattern – localized immediately adjacent to the cis Golgi – was seen in 31% (18/59). These tumours tended to carry loss‐of‐function BAP1 mutations. Our study demonstrates loss of nBAP1 expression to be the strongest prognostic marker in UM, confirming its importance in UM progression. Our data suggest that non‐genetic mechanisms account for nBAP1 loss in a small number of UMs. In addition, we describe a subset of nBAP1‐negative UM, in which BAP1 is sequestered in perinuclear bodies, most likely within Golgi, warranting further mechanistic investigation.

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Section: Introductionmentioning

confidence: 99%

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma

Farquhar

Thornton

Coupland

et al. 2017

The Journal of Pathology CR

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“…An important finding was the identification of chromosome 3 loss correlating with metastasis and poor prognosis. 9,10 Recently, BAP1, a gene located in the area frequently lost on chromosome 3, was found to carry inactivating mutations in a large proportion (84%) of metastasizing uveal melanomas. 11 BAP1 is an ubiquitin hydroxyl carboxy-terminal hydrolase.…”

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confidence: 99%

“…13 Uveal melanomas lack activating mutations in BRAF or NRAS, 14 which commonly occur in cutaneous melanoma (approximately 50% and 20%, respectively). 15 Eighty to 90% of uveal melanomas harbor activating mutations in GNAQ or GNA11 9,16 in a mutually exclusive pattern. The original report of GNA11 mutations showed a substantial difference in the distribution of mutations in primary and metastatic tumors.…”

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confidence: 99%

Genetic and clinico-pathologic analysis of metastatic uveal melanoma

et al. 2014

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Uveal melanoma is the most common malignant tumor of the adult eye. Fifty percent of tumors will eventually metastasize, and there are no effective treatments for them. Recent studies of uveal melanoma have identified activating mutations in GNAQ and GNA11, loss-of-function mutations in the tumor suppressor gene BAP1, and recurrent mutations in codon 625 of SF3B1. Previous studies have reported the existence of a higher frequency of GNA11 than GNAQ mutations, frequent BAP1 loss, and rare SF3B1 mutations in metastatic uveal melanoma. We analyzed a cohort of 30 uveal melanoma metastases for the occurrence of GNAQ, GNA11, and SF3B1 mutations, as well as BAP1 loss, and correlated these parameters with clinical and histopathologic features. Most (92%) tumors were composed of cells with an epithelioid or mixed (o100% spindle cells) morphology. Tumor samples composed exclusively of spindle cells were rare (n ¼ 2, 8%). Most tumors showed a moderate to marked degree of nuclear pleomorphism (n ¼ 24, 96%), and contained hyperchromatic, vesicular nuclei with variably conspicuous nucleoli. GNA11 mutations were considerably more frequent than GNAQ mutations (GNA11, GNAQ, and wild-type in 18 (60%), 6 (20%), and 6 (20%) cases, respectively). SF3B1 mutation was found in 1 of 26 tumors (4%), whereas loss of BAP1 expression was present in 13 of 16 tumors (81%). Patients with GNA11-mutant tumors had poorer disease-specific survival (60.0 vs 121.4 months, P ¼ 0.03) and overall survival (50.6 vs 121.4 months, P ¼ 0.03) than those with tumors lacking GNA11 mutations. The survival data, combined with the predominance of GNA11 mutations in metastases, raises the possibility that GNA11-mutant tumors may be associated with a higher risk of metastasis and poorer prognosis than GNAQ-mutant tumors. Further studies of uveal melanoma are required to investigate the functional and prognostic relevance of oncogenic mutations in GNA11 and GNAQ.

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“…Either of these two G-protein subunits was found to be mutated in over 80% of uveal melanomas, which are almost exclusively BRAF and NRAS wild type. 18,44,45 To the best of our knowledge this is the first study to extend GNAQ and GNA11 mutation analysis to desmoplastic malignant melanoma and our data provide evidence that tumorigenesis in desmoplastic malignant melanoma (whether of pure or mixed form) is not driven by GNAQ and GNA11 mutations.…”

Section: Mutations In Desmoplastic Melanomamentioning

confidence: 56%

Mutational dichotomy in desmoplastic malignant melanoma corroborated by multigene panel analysis

et al. 2015

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Desmoplastic malignant melanoma is a distinct melanoma entity histologically subtyped into mixed and pure forms due to significantly reduced lymph node metastases in the pure form. Recent reports investigating common actionable driver mutations have demonstrated a lack of BRAF, NRAS, and KIT mutation in pure desmoplastic melanoma. In search for alternative driver mutations next generation amplicon sequencing for hotspot mutations in 50 genes cardinal to tumorigenesis was performed and in addition the RET G691S polymorphism was investigated. Data from 21 desmoplastic melanomas (12 pure and 9 mixed) were retrieved. Pure desmoplastic melanomas were either devoid of mutations (50%) or displayed mutations in tumor suppressor genes (TP53, CDKN2A, and SMAD4) singularly or in combination with the exception of a PIK3CA double-mutation lacking established biological relevance. Mixed desmoplastic melanomas on the contrary were frequently mutated (89%), and 67% exhibited activating mutations similar to common-type cutaneous malignant melanomas (BRAF, NRAS, FGFR2, and ERBB2). Separate analysis of morphologically heterogeneous tumor areas in four mixed desmoplastic malignant melanomas displayed no difference in mutation status and RET G691 status. GNAQ and GNA11, two oncogenes in BRAF and NRAS wild-type uveal melanomas, were not mutated in our cohort. The RET G691S polymorphism was found in 25% of pure and 38% of mixed desmoplastic melanomas. Apart from RET G691S our findings demonstrate absence of activating driver mutations in pure desmoplastic melanoma beyond previously investigated oncogenes (BRAF, NRAS, and KIT). The findings underline the therapeutic dichotomy of mixed versus pure desmoplastic melanoma with regard to activating mutations primarily of the mitogen-activated protein kinase pathway.

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Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi

Cited by 1,439 publications

References 23 publications

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma

Genetic and clinico-pathologic analysis of metastatic uveal melanoma

Mutational dichotomy in desmoplastic malignant melanoma corroborated by multigene panel analysis

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