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

Authors
 Yong Joon Kim  ;  Seo Jin Park  ;  Kyung Joo Maeng  ;  Sung Chul Lee  ;  Christopher Seungkyu Lee 
Citation
 SCIENTIFIC REPORTS, Vol.9(1) : 19235, 2019 
Journal Title
 SCIENTIFIC REPORTS 
Issue Date
2019
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.
Files in This Item:
T201905703.pdf Download
DOI
10.1038/s41598-019-55513-z
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Yong Joon(김용준)
Lee, Sung Chul(이성철) ORCID logo https://orcid.org/0000-0001-9438-2385
Lee, Christopher Seungkyu(이승규) ORCID logo https://orcid.org/0000-0001-5054-9470
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/174845
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