Genetics of Uveal Melanoma

Abstract

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and is associated with high rates of metastasis and death. Unlike many other solid cancers, UM harbours a relatively small number of conserved genetic alterations, which lead to oncogenesis and metastatic progression. Chromosomal alterations are largely restricted to chromosomes 1, 3, 6 and 8. Progression from melanocyte to nevus is characterised by acquisition of specific pathogenic genetic variants in either GNAQ or GNA11 , followed by pathogenic genetic variants in either SF3B1 / EIF1AX to form low metastatic risk UMs or in BAP1 to form high metastatic risk UMs. Gene expression profiling and multiplex ligation‐dependent probe amplification offer excellent prognostic accuracy regarding metastatic risk and mortality. Despite this extensive knowledge of UM genetics, the mechanisms by which these specific genetic variants lead to melanomagenesis and metastatic progression are only beginning to be understood and have yet to lead to the development of effective targeted therapies for metastatic UM. Key Concepts Primary uveal melanoma is characterised by a relatively small number of conserved genetic alterations that lead to oncogenesis and metastatic progression. Melanocytes acquire initial pathogenic variants in either GNAQ or GNA11 to activate the ARF6‐Hippo‐YAP pathway and form a uveal melanocytic nevus, then in either SF3B1 / EIF1AX or in BAP1 during the course of their subsequent progression to primary uveal melanoma. Common chromosome derangements include gains and losses in chromosomes 1, 3, 6 and 8. The most significant chromosomal derangement is complete or partial loss of chromosome 3, which leads to highly metastatic tumours. Prognostic testing is highly accurate and currently relies on gene expression profiling (GEP) or multiplex ligand probe amplification (MLPA) to assess for microscopic chromosomal deletions. While clinical and pathologic features are incorporated into the prognostic algorithm for some of these techniques, these clinical features now play a relatively minor role compared to molecular phenotyping with GEP or MLPA. Primary uveal melanoma tumours generally fall into two prognostic classes: GEP class 1 tumours have a low (0–21% 5‐year) risk of metastatic progression, are associated with disomy of chromosome 3, gain of chromosome 6p, presence of mutations in SF3B1 or EIF1AX , and no loss of BAP1 . GEP class 2 tumours have a high (72% 5‐year) risk of metastatic progression, are associated with monosomy of chromosome 3, loss of chromosome 1p or 8q, and loss of BAP1 .