Abstract 2903: Genomic evolution of uveal melanoma arising in ocular melanocytosis
Authors: Durante Michael A. , Field Matthew G. , Sanchez Margaret I. , Covington Kyle R. , Decatur Christina L. , Dubovy Sander R. , Harbour J. William 
Published: August 2019

Introduction: Ocular melanocytosis is an congenital condition characterized by the presence of excessive hyperpigmented melanocytes in the uveal tract. Epidemiological studies have shown that this condition is the strongest predisposing risk factor for development of uveal melanoma (UM). In UM patients, the presence of ocular melanocytosis doubles the risk of metastasis. UM has well-characterized driver mutations consisting of two groups. The first group consists of mutually exclusive gain-of-function mutations in members of the Gq signaling pathway (GNAQ, GNA11, CYSLTR2 and PLCB4), and are thought to represent initiating oncogenic events that are insufficient alone to cause full malignant transformation. The second group consists of near-mutually exclusive mutations in BAP1, SF3B1, and EIF1AX, which are thought to occur later in tumor progression. The genomics of ocular melanocytosis and matched UM have not been characterized previously. The purpose of this study was to investigate the genomic evolution of matched ocular melanocytosis and UM tumors.

Methods: Exome and deep-targeted sequencing data from two matched ocular melanocytosis and primary uveal melanomas were evaluated using a previously developed bioinformatic pipeline optimized to call mutations and CNVs in UM. Data from this analysis were used in downstream mutation subclone detection algorithms to determine genomic evolutionary patterns within these matched samples.

Results: For both cases, the initiating driver mutations that are characteristic of UM occur at the same genomic site in matched ocular melanocytosis and UM samples. This finding suggests that they arose within the melanocytosis and subsequently expanded in the tumor. Monosomy of chromosome 3 was absent from the melanocytosis but present in ~100% of tumor cells, indicating that it arose early during clonal tumor expansion. In Patient 1, the BAP1 mutation was present in a tumor subclone and chromosome 8q gain was present in a smaller subclone, indicating that they arose later during tumor evolution. In Patient 2, the BAP1 mutation and other copy number variations were present in ~100% of tumor cells indicating that tumor evolution was completed in this tumor. Additionally, no Gq signaling pathway driver mutations were found in the germline DNA of these patients indicating that that the mutations in ocular melanocytosis occurred somatically during development.

Conclusions: This study provides the first genomic evidence relating ocular melanocytosis to UM. This data shows that Gq signaling pathway driver mutations are early genomic events that are necessary but not sufficient for UM tumor development.These insights help further refine our genomic model of UM tumor evolution and may help to address persistent challenges in the field such as the failure of targeted therapies aimed at inhibiting the Gq pathway.

Citation Format: Michael A. Durante, Matthew G. Field, Margaret I. Sanchez, Kyle R. Covington, Christina L. Decatur, Sander R. Dubovy, J. William Harbour. Genomic evolution of uveal melanoma arising in ocular melanocytosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2903.