Germline Mismatch Repair Variants May Increase Risk of Uveal Melanoma

Recent research has identified a notable association between germline mutations in mismatch repair (MMR) genes and the development of uveal melanoma (UM), a type of eye cancer. Published in JAMA Ophthalmology on June 18, 2025, this study suggests that genetic alterations linked to Lynch syndrome, which involves MMR gene mutations, could predispose individuals to UM.

The study was a prospective cohort involving 381 patients diagnosed with uveal melanoma between July 2021 and February 2023. All participants underwent extensive genetic testing through targeted sequencing of a panel of 122 cancer-related genes in germline DNA. The researchers found 79 pathogenic variants in 70 patients, with 21 located in genes associated with Lynch syndrome, particularly in MMR genes.

One significant case involved a tumor from a patient carrying an MLH1 germline mutation. This tumor exhibited monosomy 3 and loss of the wild-type MLH1 allele, confirmed through immunohistochemistry. Whole-genome sequencing revealed MMR-associated mutation signatures (SBS6, ID1, and ID2), indicating a potential mechanistic link between MMR variants and tumor development.

The findings imply that MMR germline alterations could be a contributing genetic factor in UM, expanding the known spectrum of Lynch syndrome-associated tumors. The authors emphasized that these insights could lead to better genetic screening and personalized management for patients at risk. Some researchers disclosed ties to the pharmaceutical industry, underscoring the ongoing research interest in this area.

This study highlights the importance of genetic factors in uveal melanoma and suggests new avenues for understanding its etiopathogenesis, potentially guiding future diagnostic and therapeutic strategies.

For more detailed information, see the original publication here.