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

Sci Rep. 2019 Dec 17;9(1):19235. doi: 10.1038/s41598-019-55513-z.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cell Line, Tumor
  • Databases, Nucleic Acid*
  • Exome Sequencing
  • Female
  • Gene Dosage
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • Melanoma / drug therapy
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Melanoma, Cutaneous Malignant
  • Middle Aged
  • Mutation
  • Proto-Oncogene Proteins c-myc / biosynthesis*
  • Proto-Oncogene Proteins c-myc / genetics
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology
  • Uveal Neoplasms / drug therapy
  • Uveal Neoplasms / genetics
  • Uveal Neoplasms / metabolism*
  • Uveal Neoplasms / pathology

Substances

  • MYC protein, human
  • Proto-Oncogene Proteins c-myc

Supplementary concepts

  • Uveal melanoma