Genetic Advances Could Change Management of Uveal Melanoma

New advances in understanding uveal melanoma (UM) could lead to better patient management, according to a new review article.

The authors outlined the latest research regarding the risk of metastasis and long-term patient prognosis in Frontiers in Oncology.

They said that while tumor control for UM is “excellent,” the cancer leads to metastases in about half of patients within 10 years, most commonly in the liver. Further, patients whose cancer spreads tend to have relatively poor survival rates. However, they added that there is reason for optimism about the future of UM care.

“Current learning on UM biology and genetics will enable further development of prognostic tests, as well as patient stratification based on long-term prognosis and metastatic risk,” they wrote. “Moreover, advances in UM molecular characterization may support the development of therapeutic strategies by targeting relevant signaling pathways.”

The investigators said histologic findings such as cell type, greatest thickness, and proliferative activity, among others, are useful prognostic tools. They also said the presence of prominent tumor-infiltrating lymphocytes and tumor-associated macrophages have been linked with the potential for metastasis and thus ought to be measured by clinicians.

MRI is a useful tool, the authors noted, because it can be used to obtain accurate 3D volumetric data and a qualitative evaluation of whole lesion pigmentation, which some investigators believe could be linked with a poorer prognosis.

Turning to cytogenetics, they wrote there has been significant work recently to understand how cytogenetic rearrangements affect the risk of metastasis in UM. Research has noted that primary tumors and metastases have different mutations. This has led to an increased focus on the genetic evolution of UM. They outlined several cytogenetic alterations that have been identified and linked with prognosis. Among them are the monosomy of chromosome 3, gain of the long arm of chromosome 8, loss of the short arm of chromosome 1, and gain of the short arm at chromosome 6.

The bulk of the review focused on genetic analysis of tumors. They noted that GNAQ and GNA11 mutations, which appear to be mutually exclusive in most cases, have been described in UM but do not appear to be correlated with metastasis or survival rates.

BAP1, SF3B1, and EIF1AX, on the other hand, do have prognostic value, they said. BAP1 mutations, for instance, correlate with early metastasis and lower survival, and SF3B1 mutations are linked with late-onset metastasis. However, the authors said EIF1AX mutations have been associated with more favorable outcomes.

A number of other mutations have also been described, although the authors said most have been found in just a single region of the primary tumor or in the metastases alone.

“[F]or this reason, they may be considered as tertiary driver mutations and are supposed to arise later during progression,” they said. They then outlined several candidate genes that have been explored.

The investigators closed with a discussion of genome-wide gene expression profiling, which they said can provide superior prognostic value compared with cytogenetic methods, and they outlined a number of molecular and biochemical pathways related to metastasis development.

The authors concluded that genetic analysis would provide for better management and follow-up of patients, but they also said a holistic approach is needed.

“As clinical, pathological, and radiological features have important roles in determining UM prognosis, it would be valuable to use a staging system that incorporates both clinical and genetic data,” they concluded.

Reference

Gallenga CE, Franco E, Adamo GG, et al. Genetic basis and molecular mechanisms of uveal melanoma metastasis: a focus on prognosis. Front Oncol. Published online April 11, 2022. doi:10.3389/fonc.2022.828112