medwireNews: Genetic analysis of patients with uveal melanoma (UM) has identified 79 pathogenic variants (PVs), with a greater incidence of mismatch repair (MMR) germline alterations compared with the general population.
“These finding support UM as part of the Lynch syndrome spectrum,” say Chrystelle Colas, from the Centre National de la Recherche Scientifique in Paris, France, and colleagues, writing in JAMA Ophthalmology.
Therefore, patients with UM “might benefit from germline testing and genetic counselling,” they say.
The researchers analyzed a prospective cohort of 381 consecutive participants with UM for PVs using targeted sequencing with a panel of 122 cancer predisposing genes. The analysis included only class 5 (pathogenic) and 4 (likely pathogenic) variants with minor allelic frequency less than 1% and variant allelic frequency greater than 15%.
A total of 79 PVs were identified in 70 participants (59% women) who had a mean age of 61 years. Among these individuals, 21 had a PV in clinically relevant genes, with eight germline PVs in the four main MMR genes – MLH1, MSH2, MSH6, and PMS2.
Moreover, the frequency of PVs in MLH1, MSH2, and MSH6 was significantly higher in patients with UM than in a control cohort of non-Finnish Europeans, with an odds ratio of 10.4. This finding suggests that “MMR germline PVs could also predispose to UM,” say the investigators.
There was one tumor specimen available for further workup from an 80-year-old female patient with the MLH1 variant who developed UM that was treated by enucleation. She had breast cancer and multiple tumors related to Lynch syndrome.
Immunohistochemistry analysis showed a “loss of the chromosome 3 carrying the MLH1 wildtype allele, loss of expression of MLH1 and PMS2 in immunohistochemistry, a prominent SBS6 variant signature, and an uncommon GNAQ variant that could be related to this variant signature,” the study authors report.
“These findings support the implication of MLH1 in the development of this UM,” they comment.
The tumor burden was found to be low for an MMR-deficient tumor but higher than most UM tumors, and the number of altered microsatellites just reached the threshold for instability, “one of the hallmarks of MMR deficiency,” the researchers note.
Colas et al recognize that their sample size was small because UM is rare, and that the low frequency of UM cases in the general population means that the penetrance of UM in the Lynch syndrome spectrum is probably low, but they point out that this is also true of other associated rare cancers, such as pancreatic, glioma, or biliary tract tumors.
They recommend adding MMR genes to the diagnostic gene panel for UM; “[g]iven the high metastatic risk in patients with UM and the limitation of therapeutic options, identifying these cases might be critical for treatment as immune checkpoint inhibitors were shown to be highly effective in tumors related to MMR deficiency.”
The team continues: “Furthermore, identifying Lynch syndrome in these UM cases enables offering cascade testing to relatives and implementing an adapted surveillance and prevention for Lynch syndrome–associated tumors.”
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JAMA Ophthalmol 2025; doi:10.1001/jamaophthalmol.2025.1779
