Multi-omics comparison of malignant and normal uveal melanocytes reveals novel molecular features of uveal melanoma

Abstract

Uveal Melanoma (UM) is a rare cancer resulting from the transformation of melanocytes residing in the uveal tract. Integrative analysis has identified four molecular and clinical subsets in UM. To improve our understanding of UM we performed extensive multi-omics characterization comparing pure melanoma populations obtained from two aggressive UM patient-derived xenograft models with normal choroidal melanocytes. Our study addresses for the first time DNA optical mapping, specific histone mark modifications, DNA topology analysis by Hi-C. Gene expression and cytogenetic analyses suggest that genomic instability is a hallmark of UM. Our study also identified a recurrent deletion in the BAP1 promoter which results in the absence of expression of BAP1 which is associated with high risk of metastases in UM patients. Chromatin topology changes are associated with up-regulation of PRAME, a recognized independent prognostic biomarker in UM and potential therapeutic target. Our findings illustrate how multi-omics integrative approaches can improve the understanding of tumorigenesis and reveals two novel mechanisms of gene expression dysregulation in UM.

A prognostic nomogram for the cancer-specific survival rate of choroidal melanoma using the Surveillance, Epidemiology, and End Results database

“…The exclusion of data with missing or unclear information further exacerbates the risk of selection bias. Secondly, due to the absence of gene expression profile and chromosomal factors of primary uveal melanomas in the SEER database (i.e., BAP1 germline mutations, monosomy 3 and gain of chromosome 8q), which are key factors for clinical prognosis in uveal melanoma (41,42), the effectiveness of the nomogram may be impaired. Several important prognostic factors, including relapse free survival, microvascular density and mitotic index were not taken into consideration in the study (42).…”