Microdissection of Distinct Morphological Regions Within Uveal Melanomas Identifies Novel Drug Targets

<b>Background/Objectives</b>: Uveal melanomas (UMs) are rare but often deadly malignancies that urgently require viable treatment options. UMs often exhibit tumour heterogeneity, with macroscopic and microscopic differences in morphology between different regions of the same tumour. However, to date, the clinical significance of this and how it may help guide personalised therapy have not been realised. <b>Methods</b>: Using targeted DNA and RNA sequencing of a small case series of large, high-risk primary UMs, we explored whether morphologically distinct regions of the same tumour were associated with distinct molecular profiles. <b>Results</b>: In four of the seven tumours analysed, we detected different sets of genetic variants following the separate analysis of microdissected melanotic and amelanotic regions of the same tumour. These included a <i>MET</i> exon 14 skipping RNA transcript that predicts sensitivity to crizotinib and variants in other genes that are important in active clinical trials for patients with UM and advanced solid tumours. The integration of TCGA data also identified recurrent mutational events in genes that were not previously implicated in UM development (<i>FANCA</i>, <i>SLX4</i>, <i>BRCA2</i>, and <i>ATRX</i>). <b>Conclusions</b>: Our findings show that the molecular analysis of spatially separated and morphologically distinct regions of the same tumour may yield additional, therapeutically relevant genetic variants in uveal melanomas and have implications for the future molecular testing of UMs to identify targeted therapies.