GNAQ Mutations Research Articles

PKC-independent PI3K signalling diminishes PKC inhibitor sensitivity in uveal melanoma

Protein kinase C (PKC) is activated downstream of gain-of-function GNAQ or GNA11 (GNAQ/GNA11) mutations in over 90% of uveal melanoma (UM). Phase I clinical trials of PKC inhibitors have shown modest response rates with no survival benefit in metastatic UM. Although PKC inhibitors actively suppress mitogen-activated protein kinase (MAPK) signalling in UM, the effect on other UM signalling cascades is not well understood. We examined the transcriptome of UM biopsies collected pre- and post-PKC inhibitor therapy and confirmed that MAPK, but not PI3K/AKT signalling, was inhibited early during treatment with the second-generation PKC inhibitor IDE196. Similarly, in GNAQ/GNA11-mutant UM cell models, PKC inhibitor monotherapy effectively suppressed MAPK activity, but PI3K/AKT signalling remained active, and thus, concurrent inhibition of PKC and PI3K/AKT signalling was required to synergistically induce cell death in a panel of GNAQ/GNA11-mutant UM cell lines. We also show that re-activation of MAPK signalling has a dominant role in regulating PKC inhibitor responses in UM and that PI3K/AKT signalling diminishes UM cell sensitivity to PKC inhibitor monotherapy. Thus, combination therapies targeting PKC and PKC-independent signalling nodes, including PI3K/AKT activity, are required to improve responses in patients with metastatic UM.

Emerging therapeutic strategies for metastatic uveal melanoma: Targeting driver mutations.

Uveal melanoma (UM) is the most common primary malignant intraocular tumor in adults. Although primary UM can be effectively controlled, a significant proportion of cases (40% or more) eventually develop distant metastases, commonly in the liver. Metastatic UM remains a lethal disease with limited treatment options. The initiation of UM is typically attributed to activating mutations in GNAQ or GNA11. The elucidation of the downstream pathways such as PKC/MAPK, PI3K/AKT/mTOR, and Hippo-YAP have provided potential therapeutic targets. Concurrent mutations in BRCA1 associated protein 1 (BAP1) or splicing factor 3b subunit 1 (SF3B1) are considered crucial for the acquisition of malignant potential. Furthermore, in preclinical studies, actionable targets associated with BAP1 loss or oncogenic mutant SF3B1 have been identified, offering promising avenues for UM treatment. This review aims to summarize the emerging targeted and epigenetic therapeutic strategies for metastatic UM carrying specific driver mutations and the potential of combining these approaches with immunotherapy, with particular focus on those in upcoming or ongoing clinical trials.

The clinico-pathological spectrum of plaque-type blue naevi and their potential for malignant transformation.

Plaque-type blue naevi are rare melanocytic tumours presenting as large, pigmented plaques at birth or during childhood. There is a risk for malignant transformation, but no larger comprehensive studies exist and the diagnosis is challenging, especially on limited biopsy material. The aim is to describe the clinicopathological features and behaviour of the disease more comprehensively. We retrieved eight plaque-type blue naevi, presenting as large, pigmented plaques (median = 7 cm; range = 3-26) most frequently affecting the scalp (four) followed by the cheek, arm, abdominal wall and gluteal cleft (one each), with a slight female predilection. Median age at time of biopsy was 39.5 years (range = 15-90), but three tumours had been present at birth and one since childhood. Histopathologically, the tumours were poorly circumscribed and composed of cellular fascicles of uniform spindle cells in a background of variably prominent pigmented dendritic cells affecting dermis and subcutaneous tissues. The majority had mutations in GNAQ. One tumour showed malignant transformation, characterised by an expansile nodule of pleomorphic epithelioid melanocytes with rhabdoid morphology, high mitotic activity and areas of necrosis. This patient developed metastatic melanoma to lymph nodes. All patients are alive with a median follow-up of 60 months. Plaque-type blue naevi are diagnostically challenging tumours with risk for malignant transformation. Awareness and familiarity with the salient clinicopathological features are necessary for reliable diagnosis, and long-term clinical follow-up is required to monitor for malignant transformation.

Uveal Melanoma: Molecular and Genetic Mechanisms of Development and Therapeutic Approaches

Uveal melanoma (UM) is a neuroectodermal tumor that results from malignant transformation of melanocytes in the eye uvea, including the iris, the ciliary body, and the choroid. UM accounts for 5% of all melanoma cases and is extremely aggressive with half of the UM patients developing metastases within the first 1-2 years after tumor development. Molecular mechanisms of UM carcinogenesis are poorly understood, but are known to differ from those of skin melanoma. Activating mutations of the GNAQ and GNA11 genes, which code for the large G protein subunits Gq and G11, respectively, are found in 90% of UM patients. The Gaq/PKC/MAPK signaling pathway is a main signaling cascade that leads to the transformation of melanocytes of the uveal tract, and major regulators of the cascade provide targets for the development of drugs. Metastatic UM (MUM) is most often associated with mutations of BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. A combination of a commercial expression test panel of 15 genes and a mutation panel of 7 genes, supplemented with data on the size of the primary tumor, is highly efficient in predicting the risk of metastasis. The risk of metastasis determines the choice of therapy and the patient follow-up regimen. However, no systemic therapy for MUM has been developed to date. New drugs undergoing clinical trials are mostly targeted drugs designed to inhibit the protein products of mutant genes or immunotherapeutic agents designed to stimulate the immune response against specific antigens. In addition to these approaches, potential therapeutic targets of epigenetic regulation of UM development are considered in the review.

Uveal melanoma: Recent advances in immunotherapy.

Uveal melanoma (UM) is the most common primary intraocular cancer in adults. The incidence in Europe and the United States is 6-7 per million population per year. Although most primary UMs can be successfully treated and locally controlled by irradiation therapy or local tumor resection, up to 50% of UM patients develop metastases that usually involve the liver and are fatal within 1 year. To date, chemotherapy and targeted treatments only obtain minimal responses in patients with metastatic UM, which is still characterized by poor prognosis. No standard therapeutic approaches for its prevention or treatment have been established. The application of immunotherapy agents, such as immune checkpoint inhibitors that are effective in cutaneous melanoma, has shown limited effects in the treatment of ocular disease. This is due to UM's distinct genetics, natural history, and complex interaction with the immune system. Unlike cutaneous melanomas characterized mainly by BRAF or NRAS mutations, UMs are usually triggered by a mutation in GNAQ or GNA11. As a result, more effective immunotherapeutic approaches, such as cancer vaccines, adoptive cell transfer, and other new molecules are currently being studied. In this review, we examine novel immunotherapeutic strategies in clinical and preclinical studies and highlight the latest insight in immunotherapy and the development of tailored treatment of UM.

Missense mutation of NRAS is associated with malignant progression in neurocutaneous melanosis

Neurocutaneous melanosis (NCM) is a rare congenital neurocutaneous syndrome characterized by congenital melanocytic nevus of skin and abnormal proliferation of leptomeningeal melanocytes. Early acquisition of post-zygotic somatic mutations has been postulated to underlie the pathogenesis of NCM. The pathogenesis of NCM remains to be fully elucidated, and treatment options have not been established. Here, we report for the first time, multiregional genomic analyses in a 3-year-old autopsied girl with leptomeningeal melanomatosis associated with NCM, in which a ventriculo-peritoneal (VP) shunt was inserted for the treatment of hydrocephalus. The patient expired six months after the onset due to respiratory failure caused by abdominal dissemination via VP shunt. We performed multiregional exome sequencing to identify genomic differences among brain and abdominal tumors, nevus, and normal tissues. A total of 87 somatic mutations were found in 71 genes, with a significantly large number of gene mutations found in the tumor site. The genetic alterations detected in the nevus were only few and not shared with other sites. Three mutations, namely GNAQ R183Q, S1PR3 G89S and NRAS G12V, considered pathogenic, were found, although S1PR3 mutations have not been previously reported in melanocytic tumors. GNAQ and S1PR3 mutations were shared in both tumor and normal sites. Moreover, the mutant allele frequencies of the two mutations were markedly higher in tumor sites than in normal sites, with copy-neutral loss-of-heterozygosity (CN-LOH) occurring in tumor. NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discovering novel driver mutations associated with tumorigenesis and targeted therapy.

Clinical and pathologic features of Sturge-Weber syndrome in patients with refractory epilepsy.

We aimed to investigate the clinicopathologic features of and genetic changes in Sturge-Weber syndrome (SWS) in patients with refractory epilepsy. Clinical data were retrospectively analyzed. H&E and immunohistochemistry were performed to assess pathologic changes. Targeted amplicon sequencing was applied to investigate the somatic GNAQ (c.548G>A) mutation. The potential predictors of seizure outcomes were estimated by univariate and multivariate statistical analyses. Forty-eight patients with SWS and refractory epilepsy were enrolled. According to the imaging data and pathologic examination, ipsilateral hippocampal sclerosis (HS), calcification of leptomeningeal arteries, and focal cortical dysplasia were found in 14 (29.2%), 31 (64.6%), and 37 (77.1%) patients, respectively. A high frequency of GNAQ alteration was detected in both cerebral cortex (57.7%) and ipsilateral hippocampus (50.0%) from patients with SWS. During follow-up, 43 of 48 patients (85.4%) had achieved seizure control (Engel class I). Statistically, HS signs on imaging were found to be independent predictors of unfavorable seizure outcomes (P = .015). Calcification of leptomeningeal arteries, focal cortical dysplasia, and GNAQ alteration are common features in SWS pathology. Patients with refractory epilepsy caused by SWS can achieve satisfactory seizure control after surgery, but seizure control was compromised in patients with comorbid HS.

Discovery of Darovasertib (NVP-LXS196), a Pan-PKC Inhibitor for the Treatment of Metastatic Uveal Melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignancy in the adult eye. Despite the aggressive local management of primary UM, the development of metastases is common with no effective treatment options for metastatic disease. Genetic analysis of UM samples reveals the presence of mutually exclusive activating mutations in the Gq alpha subunits GNAQ and GNA11. One of the key downstream targets of the constitutively active Gq alpha subunits is the protein kinase C (PKC) signaling pathway. Herein, we describe the discovery of darovasertib (NVP-LXS196), a potent pan-PKC inhibitor with high whole kinome selectivity. The lead series was optimized for kinase and off target selectivity to afford a compound that is rapidly absorbed and well tolerated in preclinical species. LXS196 is being investigated in the clinic as a monotherapy and in combination with other agents for the treatment of uveal melanoma (UM), including primary UM and metastatic uveal melanoma (MUM).

10141-GMC-13 MULTIREGIONAL GENOMIC ANALYSIS: A NOVEL APPROACH FOR DETECTING PATHOGENIC DRIVER MUTATION ASSOCIATED WITH MALIGNANT PROGRESSION IN NEUROCUTANEOUS MELANOSIS

Abstract Neurocutaneous melanosis (NCM) is a rare congenital neurocutaneous syndrome characterized by congenital melanocytic nevus of skin and abnormal proliferation of leptomeningeal melanocytes. Early acquisition of post-zygotic somatic mutations has been postulated to underlie the pathogenesis of NCM. The pathogenesis of NCM remains to be fully elucidated and treatment options have not been established. Here, we report for the first time, multiregional genomic analyses in a 3-year-old autopsied girl with leptomeningeal melanomatosis associated with NCM, in which a ventriculo-peritoneal shunt was inserted for the treatment of hydrocephalus. The patient expired six months after the onset due to respiratory failure caused by abdominal dissemination via ventriculo-peritoneal shunt. We performed multiregional exome sequencing to identify genomic differences among brain and abdominal tumors, nevus, and normal tissues. A total of 87 somatic mutations were found in 71 genes, with a significantly large number of gene mutations found in the tumor site. The genetic alterations detected in the nevus were only few and not shared with other sites. Three pathogenic mutations, GNAQ R183Q, S1PR3 G89S and NRAS G12V were found. GNAQ and S1PR3 mutations were shared in both tumor and normal sites. Moreover, the mutant allele frequencies of the two mutations were markedly higher in tumor sites than in normal sites. NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discover novel driver mutations associated with tumorigenesis and targeted therapy.

Comprehensive genomic profiling reveals prognostic signatures and insights into the molecular landscape of colorectal cancer.

Colorectal cancer (CRC) is a prevalent malignancy with diverse molecular characteristics. The NGS-based approach enhances our comprehension of genomic landscape of CRC and may guide future advancements in precision oncology for CRC patients. In this research, we conducted an analysis using Next-Generation Sequencing (NGS) on samples collected from 111 individuals who had been diagnosed with CRC. We identified somatic and germline mutations and structural variants across the tumor genomes through comprehensive genomic profiling. Furthermore, we investigated the landscape of driver mutations and their potential clinical implications. Our findings underscore the intricate heterogeneity of genetic alterations within CRC. Notably, BRAF, ARID2, KMT2C, and GNAQ were associated with CRC prognosis. Patients harboring BRAF, ARID2, or KMT2C mutations exhibited shorter progression-free survival (PFS), whereas those with BRAF, ARID2, or GNAQ mutations experienced worse overall survival (OS). We unveiled 80 co-occurring and three mutually exclusive significant gene pairs, enriched primarily in pathways such as TP53, HIPPO, RTK/RAS, NOTCH, WNT, TGF-Beta, MYC, and PI3K. Notably, co-mutations of BRAF/ALK, BRAF/NOTCH2, BRAF/CREBBP, and BRAF/FAT1 correlated with worse PFS. Furthermore, germline AR mutations were identified in 37 (33.33%) CRC patients, and carriers of these variants displayed diminished PFS and OS. Decreased AR protein expression was observed in cases with AR germline mutations. A four-gene mutation signature was established, incorporating the aforementioned prognostic genes, which emerged as an independent prognostic determinant in CRC via univariate and multivariate Cox regression analyses. Noteworthy BRAF and ARID2 protein expression decreases detected in patients with their respective mutations. The integration of our analyses furnishes crucial insights into CRC's molecular characteristics, drug responsiveness, and the construction of a four-gene mutation signature for predicting CRC prognosis.

Kinome profiling identifies MARK3 and STK10 as potential therapeutic targets in uveal melanoma

Most uveal melanoma cases harbor activating mutations in either GNAQ or GNA11. Despite activation of the mitogen-activated protein kinase (MAPK) signaling pathway downstream of Gαq/11, there are no effective targeted kinase therapies for metastatic uveal melanoma. The human genome encodes numerous understudied kinases, also called the “dark kinome”. Identifying additional kinases regulated by Gαq/11 may uncover novel therapeutic targets for uveal melanoma. In this study, we treated GNAQ-mutant uveal melanoma cell lines with a Gαq/11 inhibitor, YM-254890, and conducted a kinase signaling proteomic screen using multiplexed-kinase inhibitors followed by mass spectrometry. We observed downregulated expression and/or activity of 22 kinases. A custom siRNA screen targeting these kinases demonstrated that knockdown of microtubule affinity regulating kinase 3 (MARK3) and serine/threonine kinase 10 (STK10) significantly reduced uveal melanoma cell growth and decreased expression of cell cycle proteins. Additionally, knockdown of MARK3 but not STK10 decreased ERK1/2 phosphorylation. Analysis of RNA-sequencing and proteomic data showed that Gαq signaling regulates STK10 expression and MARK3 activity. Our findings suggest an involvement of STK10 and MARK3 in the Gαq/11 oncogenic pathway and prompt further investigation into the specific roles and targeting potential of these kinases in uveal melanoma.

Driver mutations in GNAQ and GNA11 genes as potential targets for precision immunotherapy in uveal melanoma patients

ABSTRACT Uveal melanoma (UM) is the most common ocular malignancy in adults. Nearly 95% of UM patients carry the mutually exclusive mutations in the homologous genes GNAQ (amino acid change Q209L/Q209P) and GNA11 (aminoacid change Q209L). UM is located in an immunosuppressed organ and does not suffer immunoediting. Therefore, we hypothesize that driver mutations in GNAQ/11 genes could be recognized by the immune system. Genomic and transcriptomic data from primary uveal tumors were collected from the TCGA-UM dataset (n = 80) and used to assess the immunogenic potential for GNAQ/GNA11 Q209L/Q209P mutations using a variety of tools and HLA type information. All prediction tools showed stronger GNAQ/11 Q209L binding to HLA than GNAQ/11 Q209P. The immunogenicity analysis revealed that Q209L is likely to be presented by more than 73% of individuals in 1000 G databases whereas Q209P is only predicted to be presented in 24% of individuals. GNAQ/11 Q209L showed a higher likelihood to be presented by HLA-I molecules than almost all driver mutations analyzed. Finally, samples carrying Q209L had a higher immune-reactive phenotype. Regarding cancer risk, seven HLA genotypes with low Q209L affinity show higher frequency in uveal melanoma patients than in the general population. However, no clear association was found between any HLA genotype and survival. Results suggest a high potential immunogenicity of the GNAQ/11 Q209L variant that could allow the generation of novel therapeutic tools to treat UM like neoantigen vaccinations.

Prognostic fine needle aspiration biopsy of uveal melanoma: Molecular and genetic factors of metastasis risk

Introduction. Molecular genetic testing is actively used for prognostication in patients with uveal melanoma (UM). Tissue for genetic analysis may be obtained either by surgical excision or through fine-needle aspiration biopsy (FNAB). Performing genetic testing and FNAB in each institution can differ in surgical techniques and laboratory methodologies.Aim. To present our own experience of performing FNAB-based molecular genetic testing for prognostication in patients with uveal melanoma.Materials and methods. Prognostic FNAB (n = 151) were combined with brachytherapy or stereotactic surgery. Genetic testing was performed by methods based on polymerase chain reaction (GNAQ, GNA11, EIF1AX and SF3B1 mutations) and fluorescence in situ hybridization (copy numbers of PPARG and MYC genes); cytology of FNAB material was also assessed.Results. Fine-needle aspiration biopsy material was informative in 91 % of cases. At the median follow-up of 36 months, 12 cases of distant metastases were detected. Occurrence of the assessed mutations and copy numbers were related to other representative studies. PPARG deletion was shown to be a significant prognostic factor for metastasis-free survival (p <0,01), which was demonstrated for the first time; EIF1AX and SF3B1 mutations, MYC amplification and cytological class were not shown to be significantly associated with survival in our study.Conclusion. FNAB-based molecular genetic testing for prognostication in patients with uveal melanoma was shown to be a reliable and highly informative approach. Some of the prognostic factors need to be evaluated further with longer follow-up.

FRI144 Using Single Cell Technology To Predict The Cell Of Origin Of Aldosterone-producing Adrenal Adenomas

Abstract Disclosure: K. Laycock: None. C. Cabrera: None. E. Wozniak: None. C. Mein: None. E. Azizan: None. X. Wu: None. G. Argentesi: None. E. Goodchild: None. W. Drake: None. M.J. Brown: None. Background: Aldosterone-producing adrenal adenomas (APAs) are the commonest surgically curable cause of hypertension, but individual prediction of postoperative outcome is challenging. Emerging data suggest that outcomes are influenced by APA genotype; identifying the cell of origin of APAs could facilitate a greater understanding of why certain genotypes are more/less likely to be associated with residual/recurrent autonomous aldosterone production(1, 2). Aims: 1. To develop an adult adrenal single cell atlas. 2. To identify the likely cell of origin for APAs with different mutations. Methodology: Bulk RNA sequencing from 67 APAs discovered known or novel somatic genotypes in 55, and replicated or discovered distinctive transcriptomes for each genotype. Single nuclei RNA sequencing was performed on 13 adrenals adjacent to the genotyped APAs. After aggregation of all 13 datasets, cluster analysis was undertaken to identify cell types and some of the transitions between these. Similarities were sought between the genotype-enriched transcriptomes of APAs, and the transcriptomes of individual cell clusters in adjacent adrenal. Results: A single nuclei atlas of 56,442 nuclei was developed. Clusters included each of the 3 cortical zones, aldosterone-producing micronodules, capsular cells, adrenal medulla, macrophages, T cells, stromal cells, endothelial cells and neurones. Several zona glomerulosa selective transcripts in previous laser-capture studies(3, 4) clustered separately from CYP11B2-positive cells (e.g. LGR5, GABBR2) or in distinct non-steroidogenic clusters (e.g. KIAA1210, RSPO3, PTGDS).A sub-cluster of stromal cells, positive for KIAA1210, RSPO3, CDH13 and MFAP5 (each p<10-254 cf other clusters) is likely to represent the distinctive KIAA1210+ capsular/interstitial cells on adrenal immunohistochemistry (www.proteinatlas.org). Bulk RNA sequencing of a rare CLCN2-mutant APA showed 13-30-fold higher expression of these and multiple other genes localising to the single nuclei stromal-cell cluster. Conclusion: Single nuclei sequencing documents the heterogeneity of adrenal cells, and potential for multiple different cell-types to develop into APAs. Ongoing analysis is underway to replicate the CLCN2-mutant transcriptome and identify cells-of-origins for tumours with commoner mutations. 1.Wu X et al. 11C metomidate PET-CT versus AVS for diagnosing surgically curable PA: a prospective within-patient trial. Nat Med. In press 2.Zhou J et al. Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant APAs presenting in puberty, pregnancy or menopause. Nat Genet. 2021 3.Nishimoto K et al. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc Natl Acad Sci USA. 2015 4.Shaikh LH et al. LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal. J Clin Endocrinol Metab. 2015 Presentation: Friday, June 16, 2023

GNAQ/GNA11 Mosaicism Is Associated with Abnormal Serum Calcium Indices and Microvascular Neurocalcification

Mosaic mutations in genes GNAQ or GNA11 lead to a spectrum of diseases including Sturge-Weber syndrome and phakomatosis pigmentovascularis with dermal melanocytosis. The pathognomonic finding of localized "tramlining" on plain skull radiography, representing medium-sized neurovascular calcification and associated with postnatal neurological deterioration, led us to study calcium metabolism in a cohort of 42 children. In this study, we find that 74% of patients had at least one abnormal measurement of calcium metabolism, the commonest being moderately low serum ionized calcium (41%) or high parathyroid hormone (17%). Lower levels of ionized calcium even within the normal range were significantly associated with seizures, and with specific antiepileptics despite normal vitamin D levels. Successive measurements documented substantial intrapersonal fluctuation in indices over time, and DEXA scans were normal in patients with hypocalcemia. Neurohistology from epilepsy surgery in five patients revealed not only intravascular, but perivascular and intraparenchymal mineral deposition and intraparenchymal microvascular disease in addition to previously reported findings. Neuroradiology review clearly demonstrated progressive calcium deposition in individuals over time. These findings and those of the adjoining paper suggest that calcium deposition in the brain of patients with GNAQ/GNA11 mosaicism may not be a nonspecific sign of damage as was previously thought, but may instead reflect the central postnatal pathological process in this disease spectrum.

Radiation Therapy for Ocular Melanoma – a Narrative Review with Insides from TRIUMF, Canada’s Only Proton Beam Therapy Center

"Ocular melanoma (OM) originates from melanocytes in the eye, predominantly in the uvea, particularly the choroid. The yearly incidence is around six cases per million. OM is not primarily driven by ultraviolet exposure like skin melanoma, but is usually caused by mutations in GNAQ or GNA11. Symptoms like blurry vision and visual field defects appear late. Diagnosis is often made via eye exams, specialized ultrasound, and rarely biopsy. This narrative review describes the radiation treatment modalities of OM and highlights the landscape of proton beam irradiation in Canada. Historically, enucleation was the standard of care for OM. However, current strategies consider tumor size, location, patient age, visual potential, and metastatic presence. Primary treatments include radiation therapy and surgery. Radiation therapy includes plaque brachytherapy (PB), proton beam irradiation (PBI), stereotactic radiosurgery (SRS), and stereotactic radiotherapy (SRT). Surgery includes endoresection, exoresection, and enucleation. Tebentafusp-tebn has been FDA-approved for metastatic cases. PB, the most common radiation therapy for OM, involves radioisotopes delivering radiation into the tumor. Comparable survival rates between PB and enucleation for medium choroidal melanoma have made PB the standard of care. PB has certain limitations, mainly surgical complications. PBI uses a particle accelerator for focused, high-energy proton radiation, yielding high tumor control and survival rates, though the availability of proton facilities is a significant limitation. Vancouver is the only center in Canada for PBI, administered not in a healthcare facility but at TRIUMF (Tri-University Meson Facility). TRIUMF, the world's largest cyclotron particle accelerator, in partnership with BC Cancer and UBC Department of Ophthalmology and Eye Care Center, has treated over 200 ocular melanoma patients between 1995 and 2017, achieving a 91% tumor control rate and 82% five-year survival rate. Emerging combination therapies like Ataxia Telangiectasia Mutated (ATM) protein kinase inhibition before PBI show potential, possibly reducing radiation dose and resistance."

Papillary Hemangioma Harbors Somatic GNA11 and GNAQ Mutations.

Papillary hemangioma (PH) is a small, primarily dermal lesion occurring predominantly in the head and neck in both children and adults. Its signature characteristics are dilated thin-walled channels containing papillary clusters of mainly capillary-sized vessels and endothelial cytoplasmic eosinophilic inclusions. Given certain histopathologic similarities to congenital hemangioma which harbor mutations in GNAQ and GNA11 , we investigated whether similar mutations are present in PH. Seven PH specimens were studied. All presented in the first 4 years of life, with one being noted at birth. With the exception of one lesion, all were in the head and neck. Lesions were bluish and ranged in size from 0.5 to 2.8cm. Four samples had GNA11 p.Q209L and 3 had GNAQ p.Q209L missense mutations. Mutations in GNA11 and GNAQ are associated with other types of somatic vascular lesions including capillary malformation, congenital hemangioma, anastomosing hemangioma, thrombotic anastomosing hemangioma, and hepatic small cell neoplasm. Shared mutations in GNA11 and GNAQ may account for some overlapping clinical and pathologic features in these entities, perhaps explicable by the timing of the mutation or influence of the germline phenotype.

FDA Approves Tebentafusp-Tebn For Unresectable Or Metastatic Uveal Melanoma.

Dear Editor, Uveal melanoma is the most prevalent intraocular malignant tumor in adults. Contrary to cutaneous melanomas, which typically have a BRAF or NRAS mutation, UMs are typically caused by a mutation in GNAQ =+or GNA11.1 It is typically asymptomatic but can present with loss of vision, visual field defect, floaters and photopsia. Epithelioid cell type of UM carries the poorest prognosis among all types. The Western population is more likely to have uveal melanoma than Asian population. In a study conducted, people living in the West were reported to have a 5–6 case/million annual incidence of UM whereas the incidence ranges from 0.2 to 0.6 per million in various regions of Asia.2 The FDA approved Tebentafusp at the end of January’22 to treat patients with inoperable or metastatic cases of uveal melanoma. It is the first medication demonstrated to increase overall survival in patients with UM. Additionally, the remdy is the first T-cell receptor treatment to enter the market.3 Tebentafusp is novel immunotherapy that marks glycoprotein 100, associated with melanoma. Its highly potent TCR binding site and anti-CD 3 T-cell site, stimulates T cells to destroy gp-100 expressing melanoma cells.5 In a randomized control trial, the mean survival rate of the tebentafusp group was 76% as opposed to 26% for the placebo group. The tebentafusp group reported rash 83%, pyrexia 76%, and itching 69%, which were the most frequent side effects of the treatment. These symptoms were caused by T-cell stimulation or by glycoprotein 100-positive melanocytes. After the initial doses, the frequency and severity of these side effects decreased. There were no deaths attributed to the treatment.5 Uveal melanoma carries a poor prognostic outcome with a one-year survival rate after metastasis of about 10-40%. The anti-tumor effectiveness seen in tebentafusp trials raises the possibility of tebentafusp's wide therapeutic potential in malignancies with both a high and low mutational burden.1 However, additional studies on a larger population of various entities are required to determine the efficacy and potency of tebentafusp against different stages of UM.

Differences in the Clinical and Molecular Profiles of Subungual Melanoma and Acral Melanoma in Asian Patients.

Subungual melanoma (SUM) is a rare type of malignant melanoma that arises beneath the nails. SUM is categorized as a type of acral melanoma (AM), which occurs on the hands and feet. SUM is an aggressive type of cutaneous melanoma that is most common among Asian patients. Recent studies reveal that SUM and AM might have different molecular characteristics. Treatment of melanoma relies on analysis of both clinical and molecular data. Therefore, the clinical and molecular characteristics of SUM need to be established, especially during metastasis. To define the mutation profiles of SUM and compare them with those of AM, we performed next-generation sequencing of primary and metastatic tumors of SUM and AM patients. Subungual location was a better independent prognostic factor than acral location for better overall survival (p = 0.001). Patients with SUM most commonly had the triple wild-type (75%) driven by GNAQ (58%) and KIT (25%) mutations, whereas patients with AM had BRAF (28.6%) and RAF (14.3%) molecular types of mutations. Single-nucleotide variations (SNVs) were more common in SUM than in AM, whereas copy number alterations (CNAs) were more common metastatic lesions of AM. Metastatic tumors in patients with SUM and AM showed increases in CNAs (43% and 80%, respectively), but not in SNVs. The number of CNAs increased during metastasis. When compared with AM, SUM has distinct clinical and molecular characteristics.

Combined Mcl-1 and YAP1/TAZ inhibition for treatment of metastatic uveal melanoma.

Uveal melanoma is the most common intraocular tumor in adults, representing approximately 5% of all melanoma cases. Up to 50% of uveal melanoma patients develop metastases that are resistant to most of the commonly used antineoplastic treatments. Virtually all uveal melanoma tumors harbor activating mutations in GNAQ or GNA11 , encoding Gαq and Gα11, respectively. Constant activity of these proteins causes deregulation of multiple downstream signaling pathways including PKC, MAPK and YAP1/TAZ. While the importance of YAP1 signaling for the proliferation of uveal melanoma has recently been demonstrated, much less is known about the paralog of YAP1 transcriptional coactivator, named TAZ; however, similar to YAP1, TAZ is expected to be a therapeutic target in uveal melanoma. We performed a small-scale drug screen to discover a compound synergistically inhibiting uveal melanoma proliferation/survival in combination with YAP1/TAZ inhibition. We found that the combination of genetic depletion of YAP1/TAZ together with Mcl-1 inhibition demonstrates a synergistic inhibitory effect on the viability of uveal melanoma cell lines. Similarly, indirect attenuation of the YAP1/TAZ signaling pathway with an inhibitor of the mevalonate pathway, that is, the geranyl-geranyl transferase inhibitor GGTI-298, synergizes with Mcl-1 inhibition. This combination could be potentially used as a treatment for metastatic uveal melanoma.