GWAS meta-analysis provides new insights into uveal melanoma risk

Cancer research · Melanoma

We identify nine linkage disequilibrium (LD)-independent loci with an IVW P value of less than 5 × 10⁻⁸.

The aim of this research is to identify germline genetic variants that predispose to uveal melanoma (UM) using data from nine studies involving 5,839 individuals with UM and 349,863 healthy controls. Five novel UM GWAS were performed and included for meta-analysis with four previously published UM GWAS. A fixed‑effects inverse-variance weighted (IVW) meta-analysis was performed by combining data from these nine UM case–control cohorts. A follow‑up transcriptome‑wide association study (TWAS) was conducted to identify candidate target genes at UM risk loci. Genetic correlations with melanoma‑related phenotypes were measured to elucidate UM’s genetic architecture. We identify nine linkage disequilibrium (LD)-independent loci (three novel) with an IVW P value of less than 5 × 10⁻⁸. TWAS analysis indicates five potential target genes, including MOB3B, RBAK, and MTSS1, which have established links to multiple cancer types. We note a significant genetic correlation (rg = 0.31, P = 0.01) between UM and cutaneous melanoma (CM), and a non‑significant but consistent correlation with naevus count (rg = 0.25, P = 0.08). This meta‑analysis offers new insights into the genetic architecture of UM, highlights potential therapeutic targets, and explores the genetic relationship with CM and skin pigmentation.

Identifying germline variants that predispose to uveal melanoma provides genetic risk markers that could inform screening, elucidate biological pathways, and reveal potential therapeutic targets, which is critical given the poor prognosis of metastatic UM and the lack of effective treatments.

Evidence level: Sejtvonalas. Laboratóriumi sejtekben vizsgálták.

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