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Simple Summary: Uveal melanoma (UM) is an aggressive cancer emerging from mutations in the GNAQ and GNA11 genes. These mutations are also linked to other conditions with distinct morphological features (skin capillary malformations, hemangiomas, Sturge–Weber syndrome, choroidal nevi, blue nevi, hepatic small vessel neoplasm, Blitz nevi, iris and ciliary body melanocytoma, primary central nervous system melanocytic neoplasms, and aldosterone-producing adenomas). By examining the molecular pathways influenced by these mutations, we provide insights into potential targeted therapies for UM and related disorders. Additionally, we address the involvement of SOX10-positive perivascular cells in the complex pathophysiology of GNAQ/GNA11-related conditions. Uveal melanoma (UM), recognized as the most prevalent primary intraocular malignancy in adults, is primarily driven by mutations in the GNAQ and GNA11 genes. These genetic alterations are also implicated in other conditions, which exhibit distinct morphological characteristics. In this article, we investigate the role of GNAQ and GNA11 mutations across varied disorders (e.g., UM, skin blue nevi, and hemangiomas), emphasizing the shared pathogenic mechanisms that connect them despite their differing clinical manifestations. By investigating the molecular pathways affected by these mutations, we provide insights into the potential for targeted therapies that could address not only UM but also other disorders associated with GNAQ/GNA11 mutations. Moreover, we discuss the role of SOX10-positive perivascular cells that may be implicated in the complex pathophysiology of GNAQ/GNA11-related entities. Understanding the common molecular foundation of these conditions opens new ways for research and treatment opportunities, potentially leading to more effective, personalized therapeutic strategies. [ABSTRACT FROM AUTHOR]

Introduction: This report presents a case of an exceptionally delayed distant recurrence of a choroidal melanoma, occurring 4 decades after the enucleation of the affected eye. Case Presentation: In 1977, a 29-year-old man underwent enucleation for a choroidal melanoma. At the age of 68 years, he was diagnosed with advanced prostate cancer. Although the metastatic prostate cancer responded to treatment, a persistent lung lesion warranted further examination. A lung biopsy, somewhat surprisingly, confirmed the presence of melanoma metastasis, 4 decades after the enucleation. The cells were positive for Melan-A, while no BRAF mutation was identified. Two years later, new lesions appeared in the liver, and CT showed progression with multiple new sites. A liver biopsy revealed again melanoma recurrence, and its choroidal origin was verified by the presence of a GNA11 mutation. The patient underwent radiation therapy for the lung and liver lesions, followed by immunotherapy. However, the patient died 11 months after the recurrence in the liver. In this case report, the micrometastatic melanoma cells appear to have remained dormant for an extended period, before the patient’s treatment in 1977, but the reason for the late reactivation from the dormant state remains unclear. Conclusion: The recurrence of a choroidal melanoma is substantiated by the histopathological and molecular analyses, including the finding of a GNA11 mutation. This case exemplifies a remarkably delayed distant recurrence of a choroidal melanoma, which manifested clinically 40 years following enucleation. [ABSTRACT FROM AUTHOR]

Purpose: to analyze the frequency of GNAQ/GNA11 mutations in circulating tumor DNA and tumor tissue, and the frequency of genotypes of polymorphic marker C3435T of ABCB1 gene in patients with iris melanoma. Material and methods. The study included 139 patients with uveal melanoma (UM) followed in 2011–2023. The experimental group included 46 patients with iris melanoma (n = 20, group I) and ciliary body involvement (n = 26, group II), who underwent a molecular genetic study. The comparison group III consisted of 30 UM patients managed in 2012. Morphologically, uveal melanoma was verified in all cases. Results. No mutations in the GNAQ/GNA11 genes were identified in group I. In group II, one heterozygous mutation in the GNAQ/GNA11 genes was detected in 2 patients (7.7 %). No significant associations with clinical or pathomorphological features were found (p > 0.1). In the comparison group III, mutations in the GNAQ/ GNA11 genes were detected in 27 patients (90 %). When comparing the frequency of heterozygous mutations in the GNAQ/ GNA11 genes significant differences between the experimental groups and the comparison group were revealed (F = 0.0000001, χ2 = 56.45). The CC genotype of the C3435T polymorphic marker of the ABCB1 gene was found in 90 % (F = 0.026418, χ2 = 5.36, significantly more frequently than in group III), in group II — in 92.3 % (F = 0.006183, χ2 = 7.75, significantly more frequently than in group III), in group III it was found in 60 %. The TT genotype was not detected in any group. Conclusion. This study has shown that the frequency of mutations in GNAQ and GNA11 genes, the frequency of CT genotype of ABCB1 polymorphic marker C3435T gene in iris melanoma is significantly lower than that in choroid melanoma, indicating a relatively favorable tumor behaviour.

Introduction: This report presents a case of an exceptionally delayed distant recurrence of a choroidal melanoma, occurring 4 decades after the enucleation of the affected eye. Case Presentation: In 1977, a 29-year-old man underwent enucleation for a choroidal melanoma. At the age of 68 years, he was diagnosed with advanced prostate cancer. Although the metastatic prostate cancer responded to treatment, a persistent lung lesion warranted further examination. A lung biopsy, somewhat surprisingly, confirmed the presence of melanoma metastasis, 4 decades after the enucleation. The cells were positive for Melan-A, while no BRAF mutation was identified. Two years later, new lesions appeared in the liver, and CT showed progression with multiple new sites. A liver biopsy revealed again melanoma recurrence, and its choroidal origin was verified by the presence of a GNA11 mutation. The patient underwent radiation therapy for the lung and liver lesions, followed by immunotherapy. However, the patient died 11 months after the recurrence in the liver. In this case report, the micrometastatic melanoma cells appear to have remained dormant for an extended period, before the patient’s treatment in 1977, but the reason for the late reactivation from the dormant state remains unclear. Conclusion: The recurrence of a choroidal melanoma is substantiated by the histopathological and molecular analyses, including the finding of a GNA11 mutation. This case exemplifies a remarkably delayed distant recurrence of a choroidal melanoma, which manifested clinically 40 years following enucleation.

ABSTRACT Importance Postzygotic mutations in the GNAQ/GNA11 genes, which encode the G‐protein nucleotide binding protein alpha subunits, have been identified in patients with phakomatosis pigmentovascularis (PPV). However, little is known about the Chinese population. Objective To identify pathogenic mutations in pediatric patients with PPV within the Chinese population. Methods We performed whole‐exome sequencing (WES) using skin lesion tissues from pediatric patients diagnosed with PPV. Additionally, ultradeep‐targeted sequencing was conducted to validate the somatic mutations. A genotype‐phenotype correlation was analyzed by integrating data from previous reports with the findings of the present study. Results Thirteen patients were enrolled, all diagnosed with the cesioflammea type of PPV, except for one patient with an unclassifiable type. We identified somatic GNA11 c.547C>T (p.R183C) variant in seven patients and GNAQ c.548G>A (p.R183Q) in four patients, with low allelic fractions ranging from 2.1% to 8.6% through ultradeep sequencing. Besides, a GNAQ c.548G>A (p.R183Q) variant was detected through targeted sequencing in one of two patients who did not exhibit detectable variants via WES. The genotype‐phenotype correlation analysis, involving 15 patients with a GNA11 variant and 10 with a GNAQ variant, revealed that facial capillary malformation (87% vs. 50%, P = 0.075) and ocular melanocytosis (80% vs. 40%, P = 0.087) appeared to be more frequent in patients with GNA11 mutation compared to those with GNAQ mutations. All four patients diagnosed with cesiomarmorata type or overlapping cesioflammea and cesiomarmorata type PPV carried the GNA11 variant. Interpretation Our study demonstrated that the majority of PPV patients in the Chinese population carried a postzygotic variant of GNAQ/GNA11, thus further confirming the pathogenic role of GNAQ/GNA11 mosaicism in the development of PPV cesioflammea type.

Simple Summary: Certain genetic changes, called driver mutations, can affect how uveal melanoma progresses and spreads. We reviewed and combined data from 13 studies to better understand these effects. A mutation in the BAP1 gene significantly increases the risk of metastatic disease. Other mutations in GNAQ, GNA11, or SF3B1 did not show a similar risk. The prognosis of uveal melanoma is significantly influenced by the risk of metastasis, which varies according to clinical and genetic features. Driver mutations can predict the likelihood of disease progression and survival, although the data in the literature are inconsistent. This meta-analysis aimed to evaluate the prognostic significance of driver mutations, including GNAQ, GNA11, BAP1, and SF3B1, in the advancement of uveal melanoma. A comprehensive search of databases yielded relevant studies, and data from 13 studies (848 eyes) were synthesized to assess the impact of these mutations on metastasis-free survival. The BAP1 mutation and negative immunohistochemistry were associated with a higher risk of metastasis (logHR = 1.44, 95% CI 1.05–1.83). GNAQ, GNA11, and SF3B1 mutations did not show a significant increase in risk. In summary, BAP1 has proven to reliably predict the likelihood of disease progression in uveal melanoma, while further studies are needed to establish the significance of other driver mutations. [ABSTRACT FROM AUTHOR]

Importance: Postzygotic mutations in the GNAQ/GNA11 genes, which encode the G‐protein nucleotide binding protein alpha subunits, have been identified in patients with phakomatosis pigmentovascularis (PPV). However, little is known about the Chinese population. Objective: To identify pathogenic mutations in pediatric patients with PPV within the Chinese population. Methods: We performed whole‐exome sequencing (WES) using skin lesion tissues from pediatric patients diagnosed with PPV. Additionally, ultradeep‐targeted sequencing was conducted to validate the somatic mutations. A genotype‐phenotype correlation was analyzed by integrating data from previous reports with the findings of the present study. Results: Thirteen patients were enrolled, all diagnosed with the cesioflammea type of PPV, except for one patient with an unclassifiable type. We identified somatic GNA11 c.547C>T (p.R183C) variant in seven patients and GNAQ c.548G>A (p.R183Q) in four patients, with low allelic fractions ranging from 2.1% to 8.6% through ultradeep sequencing. Besides, a GNAQ c.548G>A (p.R183Q) variant was detected through targeted sequencing in one of two patients who did not exhibit detectable variants via WES. The genotype‐phenotype correlation analysis, involving 15 patients with a GNA11 variant and 10 with a GNAQ variant, revealed that facial capillary malformation (87% vs. 50%, P = 0.075) and ocular melanocytosis (80% vs. 40%, P = 0.087) appeared to be more frequent in patients with GNA11 mutation compared to those with GNAQ mutations. All four patients diagnosed with cesiomarmorata type or overlapping cesioflammea and cesiomarmorata type PPV carried the GNA11 variant. Interpretation: Our study demonstrated that the majority of PPV patients in the Chinese population carried a postzygotic variant of GNAQ/GNA11, thus further confirming the pathogenic role of GNAQ/GNA11 mosaicism in the development of PPV cesioflammea type. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is a serious condition requiring immediate medical attention. It is the most common primary intraocular cancer in adults, with an incidence of around 5.2 cases per million people annually. Nearly half of UM patients develop metastatic disease, most often affecting the liver. UM refers to any malignant tumor arising from melanocytes in the uveal tract, which includes the iris, ciliary body, and choroid. Treatment options for UM depend on several factors, including tumor size, location, and the patient's overall health. These options may include radiation therapy, surgery, laser treatments, targeted therapies, and immunotherapy. UM is often described as an immune-privileged tumor, with a distinct immune profile compared to cutaneous melanoma (CM). This article aims to highlight the unique characteristics and challenges associated with this rare form of melanoma. By providing detailed information, the article seeks to enhance understanding and management of this rare form of melanoma.

Double somatic mutations in CTNNB1 and GNA11/Q have recently been identified in a small subset of aldosterone-producing adenomas (APAs). As a possible pathogenesis of APA due to these mutations, an association with pregnancy, menopause, or puberty has been proposed. However, because of its rarity, characteristics of APA with these mutations have not been well characterized. A 46-year-old Japanese woman presented with hypertension and hypokalemia. She had two pregnancies in the past but had no history of pregnancy-induced hypertension. She had regular menstrual cycle at presentation and was diagnosed as having primary aldosteronism after endocrinologic examinations. Computed tomography revealed a 2 cm right adrenal mass. Adrenal venous sampling demonstrated excess aldosterone production from the right adrenal gland. She underwent right laparoscopic adrenalectomy. The resected right adrenal tumor was histologically diagnosed as adrenocortical adenoma and subsequent immunohistochemistry (IHC) revealed diffuse immunoreactivity of aldosterone synthase (CYP11B2) and visinin like 1, a marker of the zona glomerulosa (ZG), whereas 11b-hydroxylase, a steroidogenic enzyme for cortisol biosynthesis, was mostly negative. CYP11B2 IHC-guided targeted next-generation sequencing identified somatic CTNNB1 (p.D32Y) and GNA11 (p.Q209H) mutations. Immunofluorescence staining of the tumor also revealed the presence of activated b-catenin, consistent with features of the normal ZG. The expression patterns of steroidogenic enzymes and related proteins indicated ZG features of the tumor cells. PA was clinically and biochemically cured after surgery. In conclusion, our study indicated that CTNNB1 and GNA11-mutated APA has characteristics of the ZG. The disease could occur in adults with no clear association with pregnancy or menopause. [ABSTRACT FROM AUTHOR]

Constitutive activation of GNAQ/11 is the initiative oncogenic event in uveal melanoma (UM). Direct targeting GNAQ/11 has yet to be proven feasible as they are vital for a plethora of cellular functions. In search of genetic vulnerability for UM, we found that inhibition of euchromatic histone lysine methyltransferase 2 (EHMT2) expression or activity significantly reduced the proliferation and migration capacity of cancer cells. Notably, elevated expression of EHMT2 had been validated in UM samples. Furthermore, Kaplan–Meier survival analysis indicated high EHMT2 protein level was related to poor recurrence-free survival and a more advanced T stage. Chromatin immunoprecipitation sequencing analysis and the following mechanistic investigation showed that ARHGAP29 was a downstream target of EHMT2. Its transcription was suppressed by EHMT2 in a methyltransferase-dependent pattern in GNAQ/11- mutant UM cells, leading to elevated RhoA activity. Rescuing constitutively active RhoA in UM cells lacking EHMT2 restored oncogenic phenotypes. Simultaneously blocking EHMT2 and GNAQ/11 signaling in vitro and in vivo showed a synergistic effect on UM growth, suggesting the driver role of these two key molecules. In summary, our study shows evidence for an epigenetic program of EHMT2 regulation that influences UM progression and indicates inhibiting EHMT2 and MEK/ERK simultaneously as a therapeutic strategy in GNAQ/11- mutant UM. EHMT2-dependent epigenetic program promotes RhoA signaling in GNAQ/11 -mutant uveal melanoma and targeting EHMT2 and MEK/ERK simultaneously is a therapeutic strategy to overcome resistance. [Display omitted] [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVES: Cutaneous capillary malformations (CMs) describe a group of vascular birthmarks with heterogeneous presentations. CMs may present as an isolated finding or with other associations, including glaucoma and leptomeningeal angiomatosis (i.e., Sturge-Weber syndrome) or pigmentary birthmarks (i.e., phakomatosis pigmentovascularis). The use of targeted genetic sequencing has revealed that postzygotic somatic variations in GNAQ and GNA11 at codon 183 are associated with CMs. We report five patients with early-onset hypertension and discuss possible pathogenesis of hypertension. METHODS: Twenty-nine patients with CMs, confirmed GNAQ/11 postzygotic variants, and documented past medical history were identified from a multi-institutional vascular anomalies study. Early-onset hypertension was defined as hypertension before the age of 55 years. Clinical data were reviewed for evidence of hypertension, such as documentation of diagnosis or elevated blood pressure measurements. RESULTS: Five of the 29 patients identified as having GNAQ/11 postzygotic variants had documented early-onset hypertension. Three individuals harbored a GNAQ p.R183Q variant, and two individuals harbored a GNA11 p.R183C variant. All individuals had extensive cutaneous CMs involving the trunk and covering 9%-56% of their body surface area. The median age of hypertension diagnosis was 15 years (range 11-24 years), with three individuals having renal abnormalities on imaging. CONCLUSIONS: Early-onset hypertension is associated with extensive CMs harboring somatic variations in GNAQ/11. Here, we expand on the GNAQ/11 phenotype and hypothesize potential mechanisms driving hypertension. We recommend serial blood pressure measurements in patients with extensive CMs on the trunk and extremities to screen for early-onset hypertension.

Purpose: to analyze the mutation frequency of the GNAQ/GNA11 gene in circulating tumor DNA and genotypes of the polymorphic marker C3435T of the ABCB1 gene in a large sample of patients with intraocular melanocytic neoplasms (IMN).Material and methods. In an open prospective study performed in 2015–2022, 272 IMN patients with intraocular melanocytic neoplasms aged 28 to 87 (ave. 58.3 ± 12.6), including 187 females (68.8 %) and 85 males (31.2 %), were divided into three groups depending on the nature of the tumor focus: Group I, n = 141, progressing choroidal melanomas; Group II, n = 67, stationary melanomas, and Group III, n = 64, choroidal nevi.Results. In Group I, at least one mutation in the GNAQ/GNA11 gene was detected in 134 patients (95.0 %). Of these, 35 patients (24.8 %) revealed two mutations, and 16 patients (11.3 %) had 3 mutations. In Group II, one mutation was detected in 49 patients (73.1 %), of which three patients (4.5 %) had two mutations. In Group III, one mutation in the GNAQ/GNA11 gene was detected in 13 patients (20.3 %). When comparing the overall frequency of mutations in the GNAQ/GNA11 genes in Groups I and II, significant differences were obtained (OR = 7.03 (2.77 to 17.86), F = 0.000015, ξ2 = 20.6), with Group I having mutations identified in 95 % of cases and Group II, in 73.1 %. Significant differences were also obtained when comparing the frequency of the studied mutations in Groups I and III (OR = 75.1 (28.36 to 198.86), F = 0.0000001, ξ2 = 121.15) with a frequency of 20.3 % in Group III. The frequency of mutations in the GNAQ/GNA11 genes was significantly higher in Group II than in Group III (OR = 10.68 (4.73 to 24.1), F = 0.0000001, ξ2 = 36.64). The frequencies of heterozygous mutations in all 4 exons were significantly higher in Group I than in Groups II and III, except for the GNAQ183 gene when comparing Groups I and II. Heterozygous mutations in all 4 exons were significantly more frequent in Group II than in Group III. Homozygous mutations were found only in Group I patients, but, in spite of this, no significant differences were detected when comparing them with other groups. The frequency of genotype CC of the polymorphic marker C3435T of ABCB1 gene was significantly lower in Group I as compared to Group II, whilst the frequency of genotype CT was significantly higher than in group II.Conclusion. The general analysis of molecular genetic studies of 272 patients with intraocular melanocytic neoplasms showed a direct correlation between the frequency of detection of mutations in genes and the size and source of the tumor. The obtained results substantiate both screening of patients from risk groups and differentiation of patients depending on the size and source of the tumor.

ABSTRACTUveal 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.

Lung cancer is a leading cause of cancer-related deaths worldwide, with a low 5-year survival rate due in part to a lack of clinically useful biomarkers. Recent studies have identified DNA methylation changes as potential cancer biomarkers. The present study identified cancer-specific CpG methylation changes by comparing genome-wide methylation data of cfDNA from lung adenocarcinomas (LUAD) patients and healthy donors in the discovery cohort. A total of 725 cell-free CpGs associated with LUAD risk were identified. Then XGBoost algorithm was performed to identify seven CpGs associated with LUAD risk. In the training phase, the 7-CpGs methylation panel was established to classify two different prognostic subgroups and showed a significant association with overall survival (OS) in LUAD patients. We found that the methylation of cg02261780 was negatively correlated with the expression of its representing gene GNA11. The methylation and expression of GNA11 were significantly associated with LAUD prognosis. Based on bisulfite PCR, the methylation levels of five CpGs (cg02261780, cg09595050, cg20193802, cg15309457, and cg05726109) were further validated in tumor tissues and matched non-malignant tissues from 20 LUAD patients. Finally, validation of the seven CpGs with RRBS data of cfDNA methylation was conducted and further proved the reliability of the 7-CpGs methylation panel. In conclusion, our study identified seven novel methylation markers from cfDNA methylation data which may contribute to better prognosis for LUAD patients. [ABSTRACT FROM AUTHOR]

BackgroundUveal melanoma is a disease characterized by constitutive activation of the G alpha pathway and downstream signaling of protein kinase C (PKC) and the mitogen-activated protein kinase (MAPK) pathway. While limited clinical activity has been observed in patients with metastatic disease with inhibition of PKC or MEK alone, preclinical data has demonstrated synergistic antitumor effects with concurrent inhibition of PKC and MEK.MethodWe conducted a phase Ib study of the PKC inhibitor sotrastaurin in combination with the MEK inhibitor binimetinib in patients with metastatic uveal melanoma using a Bayesian logistic regression model guided by the escalation with overdose control principle (NCT01801358). Serial blood samples and paired tumor samples were collected for pharmacokinetic (PK) and pharmacodynamic analysis.ResultsThirty-eight patients were treated across six dose levels. Eleven patients experienced DLTs across the five highest dose levels tested, most commonly including vomiting (n=3), diarrhea (n=3), nausea (n=2), fatigue (n=2) and rash (n=2). Common treatment related adverse events included diarrhea (94.7%), nausea (78.9%), vomiting (71.1%), fatigue (52.6%), rash (39.5%), and elevated blood creating phosphokinase (36.8%). Two dose combinations satisfying criteria for the maximum tolerated dose (MTD) were identified: (1) sotrastaurin 300 mg and binimetinib 30 mg; and, (2) sotrastaurin 200 mg and binimetinib 45 mg. Exposure to both drugs in combination was consistent with single-agent data for either drug, indicating no PK interaction between sotrastaurin and binimetinib. Stable disease was observed in 60.5% of patients treated. No patient achieved a radiographic response per RECIST v1.1.ConclusionsConcurrent administration of sotrastaurin and binimetinib is feasible but associated with substantial gastrointestinal toxicity. Given the limited clinical activity achieved with this regimen, accrual to the phase II portion of the trial was not initiated.

Phacomatosis pigmentovascularis (PPV) comprises a family of rare conditions that feature vascular abnormalities and melanocytic lesions that can be solely cutaneous or multisystem in nature. Recently published work has demonstrated that both vascular and melanocytic abnormalities in PPV of the cesioflammea and cesiomarmorata subtypes can result from identical somatic mosaic activating mutations in the genes GNAQ and GNA11. Here, we present three new cases of PPV with features of the cesioflammea and/or cesiomarmorata subtypes and mosaic mutations in GNAQ or GNA11. To better understand the risk of potentially occult complications faced by such patients we additionally reviewed 176 cases published in the literature. We report the frequency of clinical findings, their patterns of co-occurrence as well as published recommendations for surveillance after diagnosis. Features assessed include: capillary malformation; dermal and ocular melanocytosis; glaucoma; limb asymmetry; venous malformations; and central nervous system (CNS) anomalies, such as ventriculomegaly and calcifications. We found that ocular findings are common in patients with phacomatosis cesioflammea and cesiomarmorata. Facial vascular involvement correlates with a higher risk of seizures (p = .0066). Our genetic results confirm the role of mosaic somatic mutations in GNAQ and GNA11 in phacomatosis cesioflammea and cesiomarmorata. Their clinical and molecular findings place these conditions on a clinical spectrum encompassing other GNAQ and GNA11 related disorders and inform recommendations for their management.

Activating mutations in GNAQ/GNA11, encoding Gαq G proteins, are initiating oncogenic events in uveal melanoma (UM). However, there are no effective therapies for UM. Using an integrated bioinformatics pipeline, we found that PTK2, encoding focal adhesion kinase (FAK), represents a candidate synthetic lethal gene with GNAQ activation. We show that Gαq activates FAK through TRIO-RhoA non-canonical Gαq-signaling, and genetic ablation or pharmacological inhibition of FAK inhibits UM growth. Analysis of the FAK-regulated transcriptome demonstrated that GNAQ stimulates YAP through FAK. Dissection of the underlying mechanism revealed that FAK regulates YAP by tyrosine phosphorylation of MOB1, inhibiting core Hippo signaling. Our findings establish FAK as a potential therapeutic target for UM and other Gαq-driven pathophysiologies that involve unrestrained YAP function.

Aims: Blue naevi are benign melanocytic lesions that typically occur in the dermis. Melanoma arising in blue naevus is rare, and shows a molecular profile distinct from conventional forms of cutaneous melanoma and more similar to uveal melanoma and central nervous system (CNS) melanocytomas. In contrast to conventional cutaneous melanoma, these tumour types typically show activating driver mutations in GNAQ or GNA11, a low mutational burden without evidence of a UV signature and a reproducible pattern of chromosomal copy number changes. Blue naevi can also occur at extracutaneous sites. Here we report two cases of melanoma arising in extracutaneous blue naevus and compare their molecular features to cohorts of melanoma arising in cutaneous blue naevus (five patients) and uveal melanoma (six patients). Methods and results: We describe the clinical, histomorphological, immunohistochemical and molecular findings in these two cases of melanoma arising in extracutaneous blue naevus. We compare their molecular profiles to melanomas arising in cutaneous blue naevus and uveal melanoma using a targeted next-generation DNA sequencing platform and find striking similarities between all three groups. Conclusions: The close relationship between blue naevus-associated melanomas, regardless of their anatomical site, supports and validates the concept of melanoma arising in extracutaneous blue naevus and suggests that the two groups share common pathogenic mechanisms. The similarity of both groups to uveal melanoma in turn supports the close relationship between blue naevus-associated melanoma, uveal melanoma and CNS melanocytoma, and their distinction from conventional UV-associated melanoma. These findings have important implications for prognosis and therapy. [ABSTRACT FROM AUTHOR]

We report on a 19-year-old patient with Sturge-Weber syndrome (SWS), accompanied by a Naevus flammeus, secondary glaucoma, and glaucomatous optic atrophy of the right eye. The painful and blind eye was enucleated. Histopathological analysis revealed a circumscribed choroidal hemangioma around the optic nerve and a smaller extrascleral hemangioma. Molecular genetic testing excluded GNA11, GNAQ, or GNAS mutations. Our work illuminates the clinical, histological, and molecular genetic aspects of this rare case, contributing to the differential diagnosis of ocular conditions in patients with SWS., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

GNAQ, GNA11, and GNA14 are paralogues in the GNAQ family that are mutually exclusively mutated in a group of vascular neoplasms with thin-walled capillary-like vasoformative growth, which occur at multiple sites. The primary liver tumor in this category is termed hepatic small vessel neoplasm (HSVN), which is a rare infiltrative vascular neoplasm that can be misdiagnosed as hepatic angiosarcoma and which has been described as having likely very low malignant potential. In this study, we report on a novel primary malignant hepatic vascular neoplasm with infiltrative low grade regions morphologically resembling HSVN, as well as regions suggestive of high grade transformation. Next generation sequencing demonstrated a GNA11 p.Gln209Leu mutation (in high grade regions) and a RAF1 p.Met469Ile mutation (in low grade and high grade regions). On radiographic and gross examination, the tumor was unencapsulated, poorly circumscribed, and multifocal throughout the liver. Splenic metastases were identified and were histologically similar to high grade liver tumor regions, and shared the same RAF1 mutation. These findings argue that high grade morphology and/or additional oncogenic mutations in hepatic vascular neoplasms with GNAQ family mutations heighten concern for malignant potential and we advise next generation sequencing of HSVN for risk stratification.

Kidney renal clear cell carcinoma (KIRC) is one of the most prevalent and deadly types of renal cancer in adults. Recent research has identified circadian genes as being involved in the development and progression of KIRC by altering their expression. This study aimed to identify circadian genes that are differentially expressed in KIRC and assess their role in KIRC progression. In KIRC, there were 553 differentially expressed rhythm genes (DERGs), with 300 up-regulated and 253 down-regulated DERGs. Functional enrichment analyses showed that DERGs were greatly enriched in the circadian rhythm and immune response pathways. Survival analyses indicated that higher expression levels of CSNK1E were related to shorter overall survival of KIRC patients, whereas lower expression levels of GNA11, KLF9, and THRAP3 were associated with shorter overall survival of KIRC patients. Through cell assay verification, the mRNA level of CSNK1E was significantly up-regulated, whereas the mRNA levels of GNA11, KLF9, and THRAP3 were dramatically down-regulated in KIRC cells, which were consistent with the bioinformatics analysis of KIRC patient samples. Age, grade, stage, TM classification, and CSNK1E expression were all shown to be high-risk variables, whereas GNA11, KLF9, and THRAP3 expression were found to be low-risk factors in univariate Cox analyses. Multivariate Cox analyses showed that CSNK1E and KLF9 were also independently related to overall survival. Immune infiltration analysis indicated that the proportion of immune cells varied greatly between KIRC tissues and normal tissue, whereas CSNK1E, GNA11, KLF9, and THRAP3 expression levels were substantially linked with the infiltration abundance of immune cells and immunological biomarkers. Moreover, interaction networks between CSNK1E/GNA11/KLF9/THRAP3 and immune genes were constructed to explore the stream connections. The findings could help us better understand the molecular mechanisms of KIRC progression, and CSNK1E/GNA11/KLF9/THRAP3 might be used as molecular targets for chronotherapy in KIRC patients in the near future. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of uveal melanoma is a multifactorial and multi-step process, in which specific and recurrent mutations arise early. Among the recurrently mutated genes, GNAQ and GNA11 are involved in the process of carcinogenesis and are mutated in 80–90% of these tumours. Historically, there has been speculation as to whether these two genes are involved in the progression of primary uveal melanoma to metastatic disease, in addition to the oncogenic process itself. For this reason, both genes have been the subject of multiple research studies. Additionally, due to their high mutation rate in uveal melanoma, these genes and the downstream signaling pathways in which they are involved have been postulated as interesting therapeutic targets. This review aims to provide a current comprehensive view of what we know about GNAQ and GNA11 genes on oncogenesis, prognosis and therapeutic opportunities in uveal melanoma. The GNAQ and GNA11 genes are mutated in almost 80–90% of uveal melanomas in a mutually exclusive pattern. These genes encode the alpha subunits of the heterotrimeric G proteins, Gq and G11; thus, mutations of these genes result in the activation of several important signaling pathways, including phospholipase C, and activation of the transcription factor YAP. It is well known that both of them act as driver genes in the oncogenic process and it has been assumed that they do not play a role in the prognosis of these tumours. However, it has been hypothesised that mutations in these genes could give rise to molecularly and clinically distinct types of uveal melanomas. It has also been questioned whether the type and location of mutation in the GNAQ and GNA11 genes may affect the progression of these tumours. All of these questions, except for their implications in carcinogenesis, remain controversial. Uveal melanoma has a distinctive genetic profile, and specific recurrent mutations, which make it a potential candidate for treatment with targeted therapy. Given that the most frequent mutations are those observed in the GNAQ and GNA11 genes, and that both genes are involved in oncogenesis, these molecules, as well as the downstream signalling pathways in which they are involved, have been proposed as promising potential therapeutic targets. Therefore, in this review, special attention is paid to the current data related to the possible prognostic implications of both genes from different perspectives, as well as the therapeutic options targeting them. [ABSTRACT FROM AUTHOR]

Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.

Constitutive activation of Gαq signaling by mutations in GNAQ or GNA11 occurs in over 80% of uveal melanomas (UMs) and activates MAPK. Protein kinase C (PKC) has been implicated as a link, but the mechanistic details remained unclear. We identified PKC δ and ɛ as required and sufficient to activate MAPK in GNAQ mutant melanomas. MAPK activation depends on Ras and is caused by RasGRP3, which is significantly and selectively overexpressed in response to GNAQ/11 mutation in UM. RasGRP3 activation occurs via PKC δ- and ɛ-dependent phosphorylation and PKC-independent, DAG-mediated membrane recruitment, possibly explaining the limited effect of PKC inhibitors to durably suppress MAPK in UM. The findings nominate RasGRP3 as a therapeutic target for cancers driven by oncogenic GNAQ/11.

Circumscribed choroidal hemangioma (CCH) is a rare congenital ocular tumor type that is usually benign and asymptomatic. CCH has only been reported once previously in the literature in association with a visceral neoplasm. Here, we present a newly described association between CCH and hepatic hemangioma (HH). We report the case of a 57-year-old woman diagnosed with asymptomatic HHs who presented with a 2- to 3-month history of central scotoma and blurred vision in her left eye. Assessment identified an orange-red elevated lesion with a central serous retinal detachment and subretinal edema. Complementary tests suggested a CCH. To our knowledge, CCH has only been reported once previously in association with a visceral neoplasm, making this newly described association between CCH and HH of clinical relevance. Ophthalmologists should be aware of the possible association between CCH and other visceral tumors as this association offers an opportunity for the early detection of this pathology.

Segmental overgrowth has been widely described in patients with congenital vascular anomalies. However, segmental undergrowth has been poorly characterized, and no large series of patients have been published. We present the clinical and molecular characteristics a cohort of 37 patients with vascular malformations and segmental undergrowth. True undergrowth was only considered when the musculoskeletal system was involved to avoid confusion with other causes of segmental reduction, as in lipodystrophy or the long‐term osteopenia seen in patients with Servelle–Martorell syndrome. Deep high‐throughput sequencing was performed in tissue samples from 20 patients using a custom panel. We identified three groups: undergrowth associated with (1) venous, (2) capillary‐venous, and (3) lymphatic‐capillary‐venous malformations. Congenital or early childhood onset undergrowth can occur with or without associated overgrowth. Different likely pathogenic or pathogenic variants were detected in 13 of 20 (65%) tissue samples in the PIK3CA, TEK, GNAQ, or GNA11 genes. In conclusion, the eponymous Servelle–Martorell syndrome should not be used as a synonym for undergrowth. Segmental undergrowth should be considered a characteristic associated with vascular malformations. Patients with PIK3CA variants show all different combinations of overgrowth and undergrowth. Thus, the term PROS (PIK3CA‐related overgrowth spectrum) does not cover the entire spectrum. [ABSTRACT FROM AUTHOR]

The study aims to explore the diagnostic value of anti-GNA11 autoantibody in esophageal squamous cell carcinoma (ESCC) from multiple levels. Autoantibody against GNA11 with the highest diagnostic performance was screened out from the customized protein microarray. A total of 486 subjects including ESCC patients and matched normal controls were recruited in the verification and validation phases by using enzyme-linked immunosorbent assay (ELISA). Western blotting analysis was used to verify the ELISA results. Immunohistochemistry (IHC) was used to evaluate GNA11 expression in ESCC tissues and para-tumor tissues. In addition, a bioinformatics approach was adopted to investigate the mRNA expression of GNA11 in ESCC. Results indicated that the level of anti-GNA11 autoantibody in ESCC patients was significantly higher than that in the normal controls, and it can be used to distinguish ESCC patients from normal individuals in clinical subgroups (p < 0.05), as revealed by both ELISA and Western blotting. The receiver operating characteristic (ROC) curve analysis showed that anti-GNA11 autoantibody could distinguish ESCC patients from normal controls with an area under the ROC curve (AUC) of 0.653, sensitivity of 10.96%, and specificity of 98.63% in the verification cohort and with an AUC of 0.751, sensitivity of 38.24%, and specificity of 88.82% in the validation cohort. IHC manifested that the expression of GNA11 can differentiate ESCC tissues with para-tumor tissues (p < 0.05), but it cannot be used to differentiate different pathological grades and clinical stages (p > 0.05). The mRNA expression of GNA11 in ESCC patients and normal controls was different with a bioinformatics mining with The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data in Gene Expression Profiling Interactive Analysis (GEPIA). In summary, anti-GNA11 autoantibody has the potential to be a new serological marker in the diagnosis of ESCC. [ABSTRACT FROM AUTHOR]

Uveal melanoma is the most common intraocular malignancy although it is a rare subset of all melanomas. Uveal melanoma has distinct biology relative to cutaneous melanoma, with widely divergent patient outcomes. Patients diagnosed with a primary uveal melanoma can be stratified for risk of metastasis by cytogenetics or gene expression profiling, with approximately half of patients developing metastatic disease, predominately hepatic in location, over a 15-yr period. Historically, no systemic therapy has been associated with a clear clinical benefit for patients with advanced disease, and median survival remains poor. Here, as a joint effort between the Melanoma Research Foundation's ocular melanoma initiative, CURE OM and the National Cancer Institute, the current understanding of the molecular and immunobiology of uveal melanoma is reviewed, and on-going laboratory research into the disease is highlighted. Finally, recent investigations relevant to clinical management via targeted and immunotherapies are reviewed, and next steps in the development of clinical therapeutics are discussed.

The study aims to explore the diagnostic value of anti-GNA11 autoantibody in esophageal squamous cell carcinoma (ESCC) from multiple levels. Autoantibody against GNA11 with the highest diagnostic performance was screened out from the customized protein microarray. A total of 486 subjects including ESCC patients and matched normal controls were recruited in the verification and validation phases by using enzyme-linked immunosorbent assay (ELISA). Western blotting analysis was used to verify the ELISA results. Immunohistochemistry (IHC) was used to evaluate GNA11 expression in ESCC tissues and para-tumor tissues. In addition, a bioinformatics approach was adopted to investigate the mRNA expression of GNA11 in ESCC. Results indicated that the level of anti-GNA11 autoantibody in ESCC patients was significantly higher than that in the normal controls, and it can be used to distinguish ESCC patients from normal individuals in clinical subgroups (p < 0.05), as revealed by both ELISA and Western blotting. The receiver operating characteristic (ROC) curve analysis showed that anti-GNA11 autoantibody could distinguish ESCC patients from normal controls with an area under the ROC curve (AUC) of 0.653, sensitivity of 10.96%, and specificity of 98.63% in the verification cohort and with an AUC of 0.751, sensitivity of 38.24%, and specificity of 88.82% in the validation cohort. IHC manifested that the expression of GNA11 can differentiate ESCC tissues with para-tumor tissues (p < 0.05), but it cannot be used to differentiate different pathological grades and clinical stages (p > 0.05). The mRNA expression of GNA11 in ESCC patients and normal controls was different with a bioinformatics mining with The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data in Gene Expression Profiling Interactive Analysis (GEPIA). In summary, anti-GNA11 autoantibody has the potential to be a new serological marker in the diagnosis of ESCC.

Kidney renal clear cell carcinoma (KIRC) is one of the most prevalent and deadly types of renal cancer in adults. Recent research has identified circadian genes as being involved in the development and progression of KIRC by altering their expression. This study aimed to identify circadian genes that are differentially expressed in KIRC and assess their role in KIRC progression. In KIRC, there were 553 differentially expressed rhythm genes (DERGs), with 300 up-regulated and 253 down-regulated DERGs. Functional enrichment analyses showed that DERGs were greatly enriched in the circadian rhythm and immune response pathways. Survival analyses indicated that higher expression levels of CSNK1E were related to shorter overall survival of KIRC patients, whereas lower expression levels of GNA11, KLF9, and THRAP3 were associated with shorter overall survival of KIRC patients. Through cell assay verification, the mRNA level of CSNK1E was significantly up-regulated, whereas the mRNA levels of GNA11, KLF9, and THRAP3 were dramatically down-regulated in KIRC cells, which were consistent with the bioinformatics analysis of KIRC patient samples. Age, grade, stage, TM classification, and CSNK1E expression were all shown to be high-risk variables, whereas GNA11, KLF9, and THRAP3 expression were found to be low-risk factors in univariate Cox analyses. Multivariate Cox analyses showed that CSNK1E and KLF9 were also independently related to overall survival. Immune infiltration analysis indicated that the proportion of immune cells varied greatly between KIRC tissues and normal tissue, whereas CSNK1E, GNA11, KLF9, and THRAP3 expression levels were substantially linked with the infiltration abundance of immune cells and immunological biomarkers. Moreover, interaction networks between CSNK1E/GNA11/KLF9/THRAP3 and immune genes were constructed to explore the stream connections. The findings could help us better understand the molecular mechanisms of KIRC progression, and CSNK1E/GNA11/KLF9/THRAP3 might be used as molecular targets for chronotherapy in KIRC patients in the near future.

Circumscribed choroidal hemangioma (CCH) is a rare congenital ocular tumor type that is usually benign and asymptomatic. CCH has only been reported once previously in the literature in association with a visceral neoplasm. Here, we present a newly described association between CCH and hepatic hemangioma (HH). We report the case of a 57-year-old woman diagnosed with asymptomatic HHs who presented with a 2- to 3-month history of central scotoma and blurred vision in her left eye. Assessment identified an orange-red elevated lesion with a central serous retinal detachment and subretinal edema. Complementary tests suggested a CCH. To our knowledge, CCH has only been reported once previously in association with a visceral neoplasm, making this newly described association between CCH and HH of clinical relevance. Ophthalmologists should be aware of the possible association between CCH and other visceral tumors as this association offers an opportunity for the early detection of this pathology. [ABSTRACT FROM AUTHOR]

Double somatic mutations in CTNNB1 and GNA11/Q have recently been identified in a small subset of aldosterone-producing adenomas (APAs). As a possible pathogenesis of APA due to these mutations, an association with pregnancy, menopause, or puberty has been proposed. However, because of its rarity, characteristics of APA with these mutations have not been well characterized. A 46-year-old Japanese woman presented with hypertension and hypokalemia. She had two pregnancies in the past but had no history of pregnancy-induced hypertension. She had regular menstrual cycle at presentation and was diagnosed as having primary aldosteronism after endocrinologic examinations. Computed tomography revealed a 2 cm right adrenal mass. Adrenal venous sampling demonstrated excess aldosterone production from the right adrenal gland. She underwent right laparoscopic adrenalectomy. The resected right adrenal tumor was histologically diagnosed as adrenocortical adenoma and subsequent immunohistochemistry (IHC) revealed diffuse immunoreactivity of aldosterone synthase (CYP11B2) and visinin like 1, a marker of the zona glomerulosa (ZG), whereas 11β-hydroxylase, a steroidogenic enzyme for cortisol biosynthesis, was mostly negative. CYP11B2 IHC-guided targeted next-generation sequencing identified somatic CTNNB1 (p.D32Y) and GNA11 (p.Q209H) mutations. Immunofluorescence staining of the tumor also revealed the presence of activated β-catenin, consistent with features of the normal ZG. The expression patterns of steroidogenic enzymes and related proteins indicated ZG features of the tumor cells. PA was clinically and biochemically cured after surgery. In conclusion, our study indicated that CTNNB1 and GNA11 -mutated APA has characteristics of the ZG. The disease could occur in adults with no clear association with pregnancy or menopause., Competing Interests: KN received a research grant from AstraZeneca, which is unrelated to the current work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nanba, Blinder, Udager, Hirokawa, Miura, Okuno, Moriyoshi, Yamazaki, Sasano, Yasoda, Satoh-Asahara, Rainey and Tagami.)

Background. Ocular melanoma is the most common cancer of adult eye and is represented by two main subtypes of uveal (UM) and conjunctival (CM) melanoma with distinct clinical (frequency, localization, histology) and genomic features. The objective is to compare molecular and genetic characteristics of tumors in patients with melanoma of the eye. Materials and methods. In this study molecular profiling of 78 tumors including 73 UM (choroidea, ciliar body and iris) and 5 СM, was evaluated. DNA was isolated from tumor cells collected by macrodissection of FEPE sections of tumor biopsies using proteinase K. The following genes were studied by Sanger sequencing: GNAQ, GNA11, KIT, BRAF, NRAS. Results. Mutations in GNAQ and GNA11 were found in 81 % (59/73) of UM, in 42 % (31/73) and 38 % (28/73) of cases correspondently. GNAQ mutations were more frequent in primary UM (63 %), while GNA11 mutations dominated in metastatic UM (42 %). There was а correlation between frequency of GNAQ/GNA11 mutations and histologic type of UM. GNAQ mutations were identified in 55 % of spindle cell UM, while GNA11 mutations were more frequent in epithelioid cell UM (42 %). There were no differences in frequency of GNAQ/GNA11 mutations in UM of patients of different age (younger and elder 50 years). There was no statistically difference in UM patient outcome with GNAQ or GNA11 mutations. We also detected 3 UM with KIT mutations and 2 UM with BRAF mutations. There was no big difference in frequency of «driver mutations» in UM of choroidea, ciliar body and iris. Molecular profiling of conjunctival melanoma (CM) resembles that of cutaneous melanoma of skin: in 3 (60 %) CM BRAF V600E was identified and in 1 (20 %) – NRAS Q61K. Conclusion. Genetic analysis reveals wide diversity of melanoma of eye and is important for it characterization and treatment.

Anastomosing hemangioma (AH) is a distinct benign vascular tumor that may be histologically confused with an angiosarcoma. Recently, recurrent GNAQ and GNA14 mutations were identified in AH. GNA11, another paralogue of GNAQ and the one that shows the highest degree of homology to GNAQ, has not yet been found to be mutated in AH. In this study, we investigated the clinicopathological and molecular features of 26 AHs. By Sanger sequencing and MassARRAY analysis, mutually exclusive mutations in exon 5 of GNAQ, GNA11, and GNA14 were identified in 10, 5, and 5 tumors, respectively, of the 22 investigated tumors, with an overall mutation rate of 91%. No notable differences in the clinicopathological features were observed between GNAQ-, GNA11-, or GNA14-mutated tumors. Our results implicated GNA11 mutations, as well as previously known mutations of its paralogues GNAQ and GNA14, as essential drivers in the pathogenesis of AH. [ABSTRACT FROM AUTHOR]

We report a series of 21 compound blue nevi, a rare variant in the vast clinical and morphological spectrum of blue melanocytic proliferations. Clinically, they presented in young adults, with a slight female predominance. One-third were located on the dorsum of the foot. Morphologically, all cases displayed large dendritic melanocytes restricted to the deep layers of the epidermis. The compound component was central and evenly distributed. Melanocytic density ranged from scarce isolated cells to a confluent lentiginous architecture. In 12 of the 21 cases, junctional nests of small, bland, weakly pigmented melanocytes were associated. These nests became confluent in the most cellular cases. In all cases, a dermal component was immediately present underneath, mainly of cellular blue nevus-type. All cases were genetically confirmed to harbor either a GNAQ or GNA11 hotspot mutation. This study expands the morphological spectrum of blue nevi that should not be restricted to a strictly intradermal melanocytic proliferation. [ABSTRACT FROM AUTHOR]

Vascular tumors are neoplasms of endothelial cells, a significant number of which present in childhood. Recent studies have examined the mutational landscape of many subtypes of vascular tumors, identifying mutations primarily within the Ras–mitogen-activated protein kinase (MAPK) pathway and providing a unique opportunity to consider targeted therapeutics. This review will summarize the current understanding of childhood vascular tumor pathobiology.

Benjamin A Krantz,1 Nikita Dave,2 Kimberly M Komatsubara,2 Brian P Marr,3,4 Richard D Carvajal5 1Division of Hospital Medicine, 2Division of Hematology/Oncology, Columbia University Medical Center, 3Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, 4Department of Ophthalmology, Weill Cornell Medical College, 5Division of Hematology/Oncology, Columbia University Medical Center, New York, NY, USA Abstract: Uveal melanoma (UM) is the most common intraocular malignancy and arises from melanocytes in the iris, ciliary body, or choroid. Early diagnosis and local treatment is crucial, as survival correlates with primary tumor size. However, approximately 50% of patients will develop metastatic disease with 6–12 months’ survival from metastatic diagnosis. Genomic analyses have led to the development of gene-expression profiles that effectively predict metastatic progression; unfortunately, no adjuvant therapy has been shown to prolong survival to date. New insights into the molecular biology of UM have found frequent activating mutations in genes encoding for the G-protein α-subunit, GNAQ and GNA11, and improved understanding of the downstream signaling pathways MAPK, PI3K/Akt, and Hippo have afforded an array of new targets for treatment of this disease. Studies are under way with rationally developed regimens targeting these pathways, and novel agents are under development. We review the diagnosis, management, and surveillance of primary UM and the adjuvant therapy trials under way. Keywords: uveal melanoma, ocular melanoma, GNAQ, GNA11, MAP kinase, MEK

Circumscribed choroidal hemangioma (CCH) and early non-pigmented choroidal melanoma (CM) have similar clinical, ultrasound and morphometric features, which in some cases makes their differential diagnosis difficult. There are few studies in the literature devoted to a comparative analysis of the molecular genetic features of CCH and non-pigmented CM, and the results of those studies are contradictory., Purpose: This study attempts to develop a method of non-invasive molecular genetic differential diagnostics of CCH and non-pigmented CM., Material and Methods: Based on the results of clinical and instrumental examination methods, 60 patients (60 eyes) with CCH ( n =30) and non-pigmented CM ( n =30) were included in this prospective study. The control group consisted of 30 individuals without intraocular tumors. Mutations in the GNAQ / GNA11 genes were determined by real-time PCR using the analysis of genomic circulating tumor DNA isolated from peripheral blood plasma. The average follow-up period was 12.1±1.8 months., Results: The study revealed a significant association of mutations in exons 4 and 5 of the GNAQ / GNA11 genes with the presence of non-pigmented CM (27/30; 90%). These mutations were not detected in the group of patients with CCH. Mutations in exons 4 and 5 of the GNAQ / GNA11 genes were also not detected in the control group of healthy individuals., Conclusion: This study proposes a method of non-invasive and low-cost differential diagnostics based on molecular genetic analysis and detection of mutations in exons 4 and 5 of the GNAQ and GNA11 genes, which are specific for CM (90%).

We review advancing and overlapping stages for our understanding of the expressions of six hyperparathyroid (HPT) syndromes: multiple endocrine neoplasia type 1 (MEN1) or type 4, multiple endocrine neoplasia type 2A (MEN2A), hyperparathyroidism‐jaw tumor syndrome, familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated hyperparathyroidism. During stage 1 (1903 to 1967), the introduction of robust measurement of serum calcium was a milestone that uncovered hypercalcemia as the first sign of dysfunction in many HPT subjects, and inheritability was reported in each syndrome. The earliest reports of HPT syndromes were biased toward severe or striking manifestations. During stage 2 (1959 to 1985), the early formulations of a syndrome were improved. Radioimmunoassays (parathyroid hormone [PTH], gastrin, insulin, prolactin, calcitonin) were breakthroughs. They could identify a syndrome carrier, indicate an emerging tumor, characterize a tumor, or monitor a tumor. During stage 3 (1981 to 2006), the assembly of many cases enabled recognition of further details. For example, hormone non‐secreting skin lesions were discovered in MEN1 and MEN2A. During stage 4 (1985 to the present), new genomic tools were a revolution for gene identification. Four principal genes ("principal" implies mutated or deleted in 50% or more probands for its syndrome) (MEN1, RET, CASR, CDC73) were identified for five syndromes. During stage 5 (1993 to the present), seven syndromal genes other than a principal gene were identified (CDKN1B, CDKN2B, CDKN2C, CDKN1A, GNA11, AP2S1, GCM2). Identification of AP2S1 and GCM2 became possible because of whole‐exome sequencing. During stages 4 and 5, the newly identified genes enabled many studies, including robust assignment of the carriers and non‐carriers of a mutation. Furthermore, molecular pathways of RET and the calcium‐sensing receptor were elaborated, thereby facilitating developments in pharmacotherapy. Current findings hold the promise that more genes for HPT syndromes will be identified and studied in the near future. © 2018 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]