Understanding Tumorigenesis and Tumor Evolution of Uveal Melanoma

Speaker

• Adriana Agnese Amaro: Ospedale Policlinico San Martino - Genova 

Abstract

Uveal melanoma (UM) is the most frequent primary ocular cancer with an annual incidence of about 5 cases per million. Despite a good knowledge of the molecular characteristics of the primary tumor, metastatic disease remains incurable with a very short 5-year survival which has been unchanged for decades. Like cutaneous melanoma (CM) it originates from melanoblasts deriving from the neural crest and is more frequent in subjects with light skin and eyes, but it differs for the mutational profile and the mutational signature not traceable to UV rays. Among the environmental factors, only working as a welder is significantly associated, attributing a role to blue light, in the etiogenesis of the MU.
Integrated multi-platform analyses made it possible to clearly divide the MU into two prognostically distinct classes (high and low risk of metastasis). Increasing evidence linked to clear genetic, histopathological, and molecular differences between the two classes would indicate a different melanocytic origin. Therefore, single-cell transcriptomics studies on healthy uveal biopsies will allow the identification of the two presumed melanocytic lineages capable of generating them.
Exposure to blue light and the introduction of GNA11 and BAP1 driver mutations (not UV-induced) in mouse embryonic melanocytes Melan-A, employing CRISPR genome editing, will allow retracing the entire tumorigenesis of MU in a syngeneic mouse model, by analysis of blue light-induced mutational signatures, concerning the tumor microenvironment (TME).
The results of this study could open interesting clinical scenarios and possible prevention strategies, confirm two distinct melanocytic origins and ascertain the role of blue light in tumorigenesis.