Gna11

PURPOSE: Uveal melanoma is a rare and aggressive subset of melanoma that is minimally responsive to traditional therapies. Greater than 80% of uveal melanomas have a mutation in GNAQ or GNA11 which lead to downstream signaling through the MAPK pathway. Ulixertinib (BVD-523) is a potent and reversible small molecule ATP-competitive inhibitor of both ERK1 and ERK2 protein kinases. PATIENTS AND METHODS: We performed a phase II study to determine the efficacy and safety of BVD-523 in patients with metastatic uveal melanoma...

This study investigated the clinicopathological, immunohistochemical, and molecular features of primary leptomeningeal melanocytic neoplasms (LMNs). 12 LMN cases were retrospectively reviewed. We performed Fluorescence in-situ hybridization (including a 4-probe FISH assay with CDKN2A and MYC assay) and Next-Generation sequencing analyses on available cases. Histologically, two tumours were classified as melanocytomas (MC), two as intermediate-grade melanocytomas (IMC), and eight as leptomeningeal melanoma (LMM)...

Uveal melanoma (UVM) is the most common primary tumor in adult human eyes. Costimulatory molecules (CMs) are important in maintaining T cell biological functions and regulating immune responses. To investigate the role of CMs in UVM and exploit prognostic signature by bioinformatics analysis. This study aimed to identify and validate a CMs associated signature and investigate its role in the progression and prognosis of UVM. The expression profile data of training cohort and validation cohort were downloaded from The Cancer Genome Atlas (TCGA) dataset and the Gene Expression Omnibus (GEO) dataset...

Malignant melanoma with brain metastasis has a high mortality rate. New approaches for diagnosis and treatment are urgently required to improve prognosis. Here we present a 60-year-old male with metastatic melanoma to the brain. Using a transcriptomics pipeline, we analyzed whole blood and resected tumor tissue, identifying enriched gene expression biomarkers and pathways - including seven upregulated ( BRAF, CDK4, EIF1AX, IK, NRAS, PIK3R2, and TP53) and 11 downregulated (CASP8, CDK10, CDKN2A, CTLA4, GNA11, HERC2, IRF4, MC1R, PLA2G6, RREB1, and TPCN2) genes in the blood (across 15 pathways), showing 14% enrichment, and 16 upregulated (CCND1, CDK4, CTLA4, EIF1AX, IK, IRF4, MITF, NRAS, PIK3CB, PIK3R2, PMEL, RREB1, SLC45A2, SOX10, TYR, and TYRP1) and three downregulated ( GNA11, KITLG, and PLA2G6) genes in tissue (across 17 pathways), showing 33% enrichment, with five shared markers and 12 shared pathways...

PURPOSE: To explore the genetic background of choroidal and ciliary body melanoma among children and young adults, with special focus on BAP1 germline variants in this age group. METHODS: Patients under the age of 25 and with confirmed choroidal or ciliary body melanoma were included in this retrospective, multicenter observational study. Nuclear BAP1 immunopositivity was used to evaluate the presence of functional BAP1 in the tumor. Next-generation sequencing using Ion Torrent platform was used to determine pathogenic variants of BAP1, EIF1AX, SF3B1, GNAQ and GNA11 and chromosome 3 status in the tumor or in DNA extracted from blood or saliva...

Fibroblast Growth Factor 23 (FGF23) production has recently been shown to increase downstream of G⍺q/11-PKC signaling in osteocytes. Inactivating mutations in the gene encoding G⍺11 (GNA11) cause familial hypocalciuric hypercalcemia (FHH) due to impaired calcium-sensing receptor signaling. We explored the impact of G⍺11 deficiency on FGF23 production in mice with heterozygous (Gna11+/-) or homozygous (Gna11-/-) ablation of Gna11. Both Gna11+/- and Gna11-/- mice demonstrated hypercalcemia and mildly raised parathyroid hormone levels, consistent with FHH...

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...

CONTEXT: Although a monoallelic mutation in the calcium-sensing receptor ( CASR ) gene causes familial hypocalciuric hypercalcemia (FHH), the functional characterization of the identified CASR mutation linked to the clinical response to calcimimetics therapy is still limited. OBJECTIVE: A 45-year-old male presenting with moderate hypercalcemia, hypocalciuria, and inappropriately high parathyroid hormone (PTH) had a good response to cinacalcet (total serum calcium (Ca2+ ) from 12...

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...

Melanoma, a highly aggressive skin cancer, is characterized by rapid progression and high mortality. Recent advances in molecular pathogenesis have shed light on genetic and epigenetic changes that drive melanoma development. This review provides an overview of these developments, focusing on molecular mechanisms in melanoma genesis. It highlights how mutations, particularly in the BRAF , NRAS , c-KIT , and GNAQ/GNA11 genes, affect critical signaling pathways. The evolution of diagnostic techniques, such as genomics, transcriptomics, liquid biopsies, and molecular biomarkers for early detection and prognosis, is also discussed...

Acral and mucosal melanoma are uncommon variants of melanoma. Acral melanoma has an age-adjusted incidence of approximately 1.8 cases per million individuals per year, accounting for about 2% to 3% of all melanoma cases. On the other hand, mucosal melanoma, with an incidence of 2.2 cases per million per year, makes up around 1.3% of all melanoma cases. These melanomas, in addition to being biologically and clinically distinct from cutaneous melanoma, share certain clinical and pathologic characteristics. These include a more aggressive nature and a less favorable prognosis...

PURPOSE: To report a case of metastatic uveal melanoma treated with immune checkpoint inhibition in which serial circulating tumor DNA (ctDNA) was assessed throughout treatment. OBSERVATIONS: A 33-year-old man was diagnosed with metastatic uveal melanoma and initially had progression of disease following hepatic embolization and nivolumab/ipilimumab. At the time, plasma ctDNA GNA11 and SF3B1 were measurable and repeat ctDNA showed increased variant allele frequency following further progression of disease on vorinostat...

Common capillary malformations are red vascular skin lesions, most commonly associated with somatic activating GNAQ or GNA11 mutations. We focused on capillary malformations lacking such a mutation to identify previously unreported genetic causes. We used targeted next-generation sequencing on 82 lesions. Bioinformatic analysis allowed the identification of 9 somatic pathogenic variants in PIK3R1 and PIK3CA, encoding for the regulatory and catalytic subunits of phosphoinositide 3-kinase, respectively. Recharacterization of these lesions unraveled a common phenotype: a pale capillary malformation associated with visible dilated veins...

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...

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...

PURPOSE: Epigenetic alterations in uveal melanoma (UM) are still neither well characterized, nor understood. In this pilot study, we sought to provide a deeper insight into the possible role of epigenetic alterations in the pathogenesis of UM and their potential prognostic relevance. To this aim, we comprehensively profiled histone post-translational modifications (PTMs), which represent epigenetic features regulating chromatin accessibility and gene transcription, in UM formalin-fixed paraffin-embedded (FFPE) tissues, control tissues, UM cell lines, and healthy melanocytes...

Capillary malformations (CMs) are the most common type of vascular anomalies, affecting around 0.3% of newborns. They are usually caused by somatic pathogenic variants in GNAQ or GNA11. PIK3CA and PIK3R1, part of the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin pathway, are mutated in fainter CMs such as diffuse CM with overgrowth and megalencephaly CM. In this study, we present two young patients with a CM-like phenotype associated with cerebral anomalies and severe epilepsy. Pathogenic variants in PIK3CA and PIK3R1, as well as GNAQ and GNA11, were absent in affected cutaneous tissue biopsies...

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...

BACKGROUND: Adverse clinical events cause significant morbidity in patients with glioblastoma (GBM). We examined whether genomic alterations were associated with adverse events (AEs) in GBM patients. METHODS: We identified adults with histologically confirmed IDH-wildtype GBM with targeted next-generation sequencing (OncoPanel) at Dana Farber Cancer Institute from 2013-2019. Seizure at presentation, lymphopenia, thromboembolic events, pseudoprogression, and early progression (within 6 months of diagnosis) were identified as AEs...

Activating mutations in GNAQ/GNA11 occur in over 90% of uveal melanomas (UMs), the most lethal melanoma subtype; however, targeting these oncogenes has proven challenging and inhibiting their downstream effectors show limited clinical efficacy. Here, we performed genome-scale CRISPR screens along with computational analyses of cancer dependency and gene expression datasets to identify the inositol-metabolizing phosphatase INPP5A as a selective dependency in GNAQ/11-mutant UM cells in vitro and in vivo. Mutant cells intrinsically produce high levels of the second messenger inositol 1,4,5 trisphosphate (IP3) that accumulate upon suppression of INPP5A, resulting in hyperactivation of IP3-receptor signaling, increased cytosolic calcium and p53-dependent apoptosis...