Abstract 66P
Background
Oncogenomic analyses of uveal melanoma (UM) have revealed widespread alterations in the GNAQ and GNA11 driver genes. These mutations constitutively activate key mediators of Hippo kinase cascade, influencing the balance between dormancy and proliferation in tumor cells. Hippo signaling pathway emerges as a major regulator of tumor progression and may represent a promising target for novel therapies in UM. Therefore, we investigated the genomic alterations and correlating expression of Hippo pathway components with patient outcome.
Methods
Quantitative Real-Time PCR (qRT-PCR) was performed on 47 prospective UM cases to measure the mRNA expression level of Hippo pathway components. Targeted whole exome sequencing was conducted to determine genomic variations in driver genes. Immunohistochemistry and western blot were performed on representative cases to assess the expression levels of central mediators YAP/TAZ proteins and known prognostic markers BAP1 and PRAME. The mRNA and protein expressions were correlated with clinicopathological parameters and patient outcome.
Results
Exome sequencing revealed GNAQ (28/47) and GNA11 (19/47) mutations in a mutually exclusive pattern. The central mediators YAP and TAZ were downregulated in 72% and 78% cases, respectively, with concordant results at the protein level. Nuclear expression of YAP/TAZ proteins was observed in 27.85% of cases. Downregulation of LATS1, LATS2, SAV1, MOB1A genes was observed in over 60% of cases. Conversely, MST1, MST2, MOB1B, 14-3-3, TEAD and VGLL4 showed upregulation in more than 50% of cases. Statistical analysis revealed significant correlations between protein expression with high pigmentation, advanced tumor staging, and loss of nBAP1. Eight patients developed distant metastasis, of which five died due to the disease.
Conclusions
The dysregulation of Hippo pathway components at mRNA and protein levels highlights their importance in UM pathogenesis, which paves the way for the development of novel biomarkers and mutation-specific therapeutic strategies to improve patient outcomes. However, further studies are required to elucidate the precise mechanisms of Hippo signaling components in suppressing oncogenesis.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Indian Council of Medical Research.
Disclosure
All authors have declared no conflicts of interest.