GNA11 mutation

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.

We were able to successfully conduct NGS studies in paraffin-embedded material archived for 10 years using both middlesized (OPA) and large (OCA v3) NGS panels. The identified S3FB1 mutation helps to explain the onset of metastases, even though the patient had spindle cell predominant UM with BAP-1 preservation, which are normally associated with decreased metastases risk. Our case highlights the value of using large NGS panels to unravel the molecular landscape of UM and further understand this unique eye cancer.

The distinct genomic profiling in Japanese patients, including lower TMB, compared to Caucasians, is associated with poorer treatment outcomes. This result underscores the need for more effective therapeutic agents.

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...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.

P2, N=4, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2024 --> Dec 2025

Baseline ctDNA and LDH are prognostic factors while ctDNA clearance might predict benefit from Tebe. Other analyses are ongoing to identify new predictive biomarkers.

P2, N=4, Active, not recruiting, National Cancer Institute (NCI) | N=35 --> 4

Although these subprotocols did not meet the primary end point for ORR, significant responses or prolonged SD noted in some disease subtypes warrants further investigation.

GNAQ and GNA11 mutations were identified to be the most frequent mutations among UM patients, with a mutual exclusivity relationship between the two genes. New therapeutic modalities should consider the comprehensive genomic profiling of UM patients to improve their overall survival rate and quality of life.

A decrease in the proliferation and metabolic activity was observed in Mel285GNAQ-KO and Mel285BAP1-KO cell lines in comparison to the wildtype cells. Furthermore, an increase of phosphorylated ATF2/7 was noted in Mel285GNAQ-KO and Mel285GNA11-KO cell lines by western blotting.A better understanding of the altered pathways in our GNAQ/11 or BAP1 mutant isogenic cell lines will help to identify new drugs targeting specifically metastatic UM cells.

Although GNA11 mutation and CDKN2A loss significantly correlated with progression-free survival in our study, our sample size is small. The prognostic significance of GNAQ/GNA11 mutation and CDKN2A loss would require further investigation.

This study is the first to report ctDNA detection rate and prognostic impact in UM patients eligible for surgical resection of their liver metastases. If confirmed by further studies in this setting, this non-invasive biomarker could inform treatment decisions in UM patients with liver metastases.

The molecular characteristics of Korean uveal melanoma patients were largely similar to those of Western patients, except for relatively higher frequency of 8q gain, which appears to develop in eariler ages before clinical dignosis of tumors.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Oct 2022 --> May 2023

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.

Furthermore, the palmitoylation inhibitor, 2-bromopalmitate, also specifically disrupted Gα downstream signaling by interfering with the MAPK pathway and BCL2 survival pathway in GNAQ/11-mutant UM cells and showed a notable synergistic effect when applied in combination with the BCL2 inhibitor, ABT-199, in vitro. The findings validate that GNAQ/11 palmitoylation plays a critical role in UM and may serve as a promising therapeutic target for GNAQ/11-driven UM.

We demonstrated three cases of anastomosing haemangiomas with one case harbouring a GNA11 mutation which, besides conforming to its clonal nature, also serves as an important molecular signature to distinguish AHs from well-differentiated ASs. We also addressed the potential molecular differences between these two entities. Nevertheless, due to the small sample size and its rarity, a larger scale study is needed to elucidate this issue.

More recently, the immune-mobilizing monoclonal T-cell receptor against the cancer molecule tebentafusp showed impressive antitumor effects. Meanwhile, oncolytic viruses and small molecule inhibitors have also gained ground. This review highlights recent progress in burgeoning treatments and provides innovative insights on feasible strategies for the treatment of UM.

We conclude that H3K27me2 loss is not specific for MPNST, and like H3K27me3, should be used in the appropriate clinicopathologic, immunohistochemical and molecular genetic context. Loss of H3K27me2 with retained H3K27me3 is a common feature of "blue nevus family" melanocytic tumors known to harbor GNAQ/GNA11 mutations.

GNA11 mutated uveal melanoma has worse prognosis and is associated with high risk cytogenetic, mutational and molecular tumor characteristics that might be determined at least in part by differential DNA-methylation.

Separately, a single GNA11 somatic mutation was identified to explain the CMTC. We suggest that genetic testing for germline mutations associated with Wilms tumor susceptibility be considered even in cases without known family history.

AMs are uncommon tumors with dismal survival, usually occurring in the elderly in various gross and microscopic appearances. In terms of molecular profile, BRAF and KIT mutations are rarely detected. Profiling of larger cohorts is required to elucidate the pathogenesis and to identify potential molecular indicators that may contribute to the development of individualized targeted therapies.

We conclude that blue nevi can involve lymph nodes and are associated with benign clinical behavior, and probably represent so-called "benign" metastasis. Awareness of these lesions is important when evaluating lymph nodes to avoid misdiagnosis as metastatic melanoma.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Jan 2022 --> Oct 2022

Coexisting BAP1/SF3B1 and GNAQ/11 mutations were unique to UM. SF3B1 mutations were reported to be UM-specific in melanoma and associated with rare/no metastasis. The finding of mutated SF3B1 in 14.8% (n = 27) of UMs suggests its role should be further evaluated. The correlation of BAP1/SF3B1 mutation with survival also warrants investigation.

We provide evidence that 2 novel GCM2 R67C inactivating mutations with inability to bind DNA are causative of hypoparathyroidism. Additionally, we provide evidence that two novel GCM2 variants increased transactivation of the PTH promoter in vitro and are associated with FIHP. Furthermore, our studies suggest that activating GCM2 variants may contribute to facilitating more aggressive parathyroid disease.

Thereby, the isolation and structure elucidation of novel FR analogs of low abundance is enabled. Further, we explore the antiproliferative activities of fifteen chromodepsins against uveal melanoma cell lines harboring Gq/11 mutations and characterize the major metabolite of FR formed in plasma.

P=N/A, N=102, Recruiting, University of Catania

Interestingly, Met-to-Death was longer in patients with GNAQ Q209P compared to GNAQ/GNA11 Q209L mutations, suggesting the difference in mutation type in GNAQ/GNA11 might determine the prognosis of MUM. Structural alterations of the GNAQ/GNA11 protein and their impact on survival of MUM patients should be further investigated.

One year later, intracranial extension of the melanocytoma necessitated a ventriculoperitoneal shunt and immunotherapy. Future work is needed to determine how GNA11 mutations in melanocytomas influence prognosis and monitoring strategies.

Genetic analyses can help differentiate between central nervous system origin and metastasis of a cutaneous melanoma with the presence of a GNAQ and GNA11 mutations or a BRAF mutation, respectively. First choice treatment is complete resection, and in case of incomplete resection or recurrence additional radiotherapy is advised.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Sep 2020 --> Jan 2022

Detection of ctDNA in plasma can provide a diagnostic lead time over the clinical diagnosis of metastases or tumor recurrence. Longer lead times are to be expected if intervals between sampling are shortened.

Associations between large melanocytic nevi and neurocutaneous melanosis have been described, though are considered relatively rare. In our patient, the skin lesion was diagnosed on pathology examination as a benign blue nevus, with distinctive histological and immunohistochemical features, thus ruling out primary as well as metastatic melanoma. Lesion’s size and clinical appearance were outstanding, making the extremely large nevus a peculiar finding itself.

Concentrations of baseline ctDNA have been shown to be of prognostic significance.Patients and methods 42 pre-treatment plasma samples from the NADIM clinical trial (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with Nivolumab, were analyzed by NGS, using the Oncomine Pan-Cancer Cell-Free Assay™ (Thermo Fisher Scientific®)...Finally, ctDNA levels at Mutant Allele Frequency (MAF) below 1% at baseline were associated with improved PFS (P=0.025). At 30 months, PFS was 80.30% for these patients compared with 58.33% in patients with ctDNA levels ≥ 1%.Conclusions Molecular profiling of liquid biopsies collected before neoadjuvant chemo-immunotherapy using NGS can identify patients at high risk of progression who might require more aggressive adjuvant treatment in order to achieve a better control of the disease.

P2, N=4, Active, not recruiting, National Cancer Institute (NCI) | N=35 --> 4 | Trial primary completion date: Feb 2021 --> Sep 2020

P2, N=40, Suspended, National Cancer Institute (NCI) | N=28 --> 40 | Trial primary completion date: Aug 2018 --> Jun 2022

In this dataset, liquid biopsy of ctDNA was useful for genetic characterization of aPCa and reveal differences in the molecular phenotype of AA and Ca in aPCa with potential clinical implications. These findings support ongoing research on the clinical utility of non-invasive genotyping and therapeutic response monitoring with a focus on AA population.

Clinical presentation, histopathological characteristics and copy number alterations are associated with survival in ocular melanoma. Tissue material is needed to classify ocular melanoma in the different subgroups, which creates a need for the use of noninvasive techniques to prognosticate patients who underwent eye preserving treatment.