Genetic Variants Linked to Increased Risk of Uveal Melanoma

Recent research has established a correlation between germline pathogenic variants in mismatch repair (MMR) genes and uveal melanoma (UM), a rare form of eye cancer. This groundbreaking study, featured in JAMA Ophthalmology, highlights the potential genetic predisposition to UM, particularly among patients with alterations in MMR genes associated with Lynch syndrome.

Researchers conducted a prospective cohort study involving 381 patients diagnosed with UM from July 2021 to February 2023. Participants consented to extensive genetic testing, which included a panel of 122 cancer-predisposing genes analyzed through targeted sequencing of germline DNA.

Out of the 381 patients, the study identified 79 pathogenic variants (PVs) in 70 individuals. Notably, 21 of these variants were located in clinically significant genes, revealing a higher prevalence of MMR gene mutations. These findings suggest that individuals with MMR germline PVs may have a heightened risk of developing UM.

Among the tumors analyzed, one from a patient carrying an MLH1 germline PV displayed a monosomy 3, indicating the loss of the wild-type allele on chromosome 3. Immunohistochemical assessments confirmed the loss of MLH1 expression, and whole-genome sequencing of the tumor uncovered MMR variant signatures SBS6, ID1, and ID2. This evidence implies that MMR germline alterations could contribute significantly to the genetic landscape of UM, positioning it within the spectrum of Lynch syndrome.

The implications of these findings are critical for understanding the genetic factors that may lead to UM. By identifying MMR germline alterations as a potential risk factor, healthcare professionals can better assess patients for genetic predisposition to this rare cancer. The study underscores the importance of genetic testing and counseling for individuals with a family history of Lynch syndrome or those diagnosed with UM.

As the understanding of the genetic underpinnings of UM evolves, further research is necessary to explore the broader implications of MMR germline pathogenic variants in cancer predisposition. These insights may pave the way for improved screening, prevention, and treatment strategies aimed at individuals at risk.