Twenty-one pathogenic variants found in clinically relevant genes, with an enrichment in mismatch repair genes
By Elana Gotkine HealthDay Reporter
FRIDAY, June 20, 2025 (HealthDay News) — Mismatch repair (MMR) germline alterations are enriched among patients with uveal melanoma (UM), according to a study published online June 18 in JAMA Ophthalmology.
Anaïs Le Ven, from Inserm U1339 in Paris, and colleagues conducted a prospective cohort study involving 381 consecutive patients diagnosed with UM between July 2021 and February 2023 to identify new genetic alterations predisposing for UM. All participants consented to extended genetic testing; a panel of 122 genes predisposing to cancer were analyzed by targeted sequencing on germline DNA.
The researchers identified 79 pathogenic variants (PVs) in 70 participants. Twenty-one of these were found in clinically relevant genes, with an enrichment in the MMR genes, involved in Lynch syndrome, suggesting that MMR germline PVs could predispose to UM. One tumor from a participant carrying an MLH1 germline PV exhibited a monosomy 3, with loss of the wild-type allele of MLH1, which is located on chromosome 3. Loss of MLH1 expression was seen by immunohistochemistry; whole-genome sequencing of this tumor identified MMR variant signatures SBS6, ID1, and ID2.
“These findings suggest that MMR germline alterations could explain at least a portion of UM genetics, and that UM could be part of the Lynch syndrome spectrum,” the authors write.
One author disclosed ties to the pharmaceutical industry; a second author holds related patents.
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