GNAQ Q209P

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.

Coupled with allele-specific PCR, it constitutes a sensitive platform for liquid biopsy detection, capable of sensing GNAQ Q209P in plasma samples with a low ctDNA concentration and fractional abundance. Finally, our method was validated using plasma samples from metastatic UM patients.

While mediastinal anastomosing haemangiomas can microscopically mimic angiosarcoma, awareness of this entity and radiological correlation may help to circumvent this diagnostic pitfall.

The established ddPCR assays are a valuable tool to detect the most frequent mutations in UM patients from ctDNA. These assays will allow serum and plasma genotyping, detection of MRD and monitoring of response to treatment to benefit UM patients and might support discrimination of uveal nevi from UM lesions.

Results may affect MUM care, treatment development, and trial stratification. More research is needed to confirm these findings.

We now compare the anti-cancer efficacy of 64B to two different tyrosine kinase inhibitors (TKIs) that are in clinical testing for UM, sunitinib and selumetinib. 1 Dong L et al, Clin Cancer Res. 2019;25(7):2206-18.

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.

Our work also suggests a novel difference in sensitivity between the Gα Q209L, Gα Q209P, and Gα R183C mutants. We propose that disrupting the interaction between CA Gα and Gβγ can be a novel therapeutic target in UM.

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.

We examined the activity of ASTX029, a novel dual-mechanism ERK inhibitor, which inhibits both the catalytic activity of ERK and its phosphorylation by MEK, and belinostat, a pan-HDAC inhibitor, in one GNAQQ209L- (92.1) and GNAQQ209P- (OMM1.3) and two GNA11Q209L-mutant (MP41, OMM1) uveal melanoma cell lines...We explored other drug candidates for combinatorial approaches including the BCL-2 inhibitor navitoclax, but no combination effect was observed...We also observed increased surface expression of immunological markers HLA-A, B, C (MHC Class 1), PD-L1, gp100 and MART-1. These results support that a combination strategy targeting ERK and HDAC in uveal melanoma should be investigated further.

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.

Our ddPCR assays will be a valuable tool to detect the most frequent genetic alterations in uveal melanoma patients from ctDNA. These assays will allow plasma genotyping, detection of MRD and monitoring of response to treatment.

The mammary condition can be the origin of primary mammary melanocytic tumors. Mosaicism of the GNAQ Q209P mutation can be a characteristic genetic alteration to extensive blue nevi, including plaque-type blue nevus.

Here we found that YM-254890, a cyclic depsipeptide, inhibited downstream signaling induced by GNAQQ209L and GNA11Q209L, but not GNA14Q205L, GNA15Q212L and GNASQ227L in 293T cells, confirming that it is a GNAQ/11-specific inhibitor...Concordantly, an engineered GNA11 with the two mutations in cis was resistant to the compound. Our data suggest that targeting mutant GNAQ/11 is promising but will require combinatorial targeting of EDNR signaling and possibly other pathways to reach maximal clinical efficacy.