Multi-Platform Omics Analysis for Identification of Molecular Characteristics and Therapeutic Targets of Uveal Melanoma

Abstract

Currently, there is no effective treatment for metastatic uveal melanoma (UVM). Here, we aimed to identify the mechanism involving intrinsic chemoresistance of metastatic UVM and the relevant therapeutic targets for UVM. We analyzed cohorts of 80 and 67 patients with primary UVM and skin cutaneous melanoma (SKCM), respectively, using The Cancer Genome Atlas dataset. Mutational burdens identified by whole exome sequencing were significantly lower in UVM than in SKCM patients. COSMIC mutational signature analysis identified that most of the mutations in UVM patients (>90%) were associated with spontaneous deamination of 5-methylcytosine or defective mismatch repair. Transcriptome analysis revealed that the MYC signature was more enriched in UVM patients, as compared to SKCM patients. Fifty-nine (73.8%) of 80 UVM patients showed gains in MYC copy number, and a high MYC copy number was associated with aggressive clinicopathological features of tumors and poor survival. Kinome-wide siRNA library screening identified several therapeutic targets, reported as synthetic lethal targets for MYC-addicted cancers. Notably, UVM cell lines showed high susceptibility to a WEE1 inhibitor (MK-1775; adavosertib) at a clinically tolerable dose. Overall, our study identified high MYC activity in UVM, and suggested G2/M checkpoint inhibitors as effective therapeutic targets for UVM.

Changes in microRNA expression associated with metastasis and survival in patients with uveal melanoma

“…Several key transcription regulators (TP53, MYC, SP1, TP63, E2F1), growth factors (EGF, TGFB1, FGF2, HGF) and other key regulators including PTEN, ERBB2, ESR1, KRAS and PI3K-complex were found as key targets using this analysis. Previous studies have also reported constitutive activation of these oncogenic pathways in primary UM [34,35]. Biological functions related to metastasis including cell cycle progression, cell proliferation, invasion, movement and migration were significantly enriched in the target genes.…”

Novel Prognostic Immunohistochemical Markers in Uveal Melanoma-Literature Review

“…It is worth looking at the research on long non-coding RNA, which can also serve as a potential prognostic factor [102]. The use of Multi-Platform OMICS Analysis also seems prospective [103]. Single-cell analysis, single-cell RNA sequencing, and molecular profiling are also highly promising and interesting methods [104][105][106].…”

Coexisting and Second Primary Cancers in Patients with Uveal Melanoma: A 10-Year Nationwide Database Analysis

“…Our findings suggest that uveal melanoma may also be associated with non-Hodgkin lymphoma. Recent studies have shown that GNAQ mutations appear repeatedly in certain types of non-Hodgkin lymphoma, and other studies have suggested that MYC alterations are associated with aggressive non-Hodgkin lymphoma or a poor prognosis of uveal melanoma [ 41 , 42 , 43 ]. In addition, both skin melanoma and uveal melanoma arise from the melanocytes derived from the neural crest, and therefore, immune perturbations may also promote tumorigenesis in uveal melanoma [ 44 ].…”