Germline Cancer Susceptibility Variants in Patients With Uveal Melanoma

Area of Science:

• Genetics
• Oncology
• Ophthalmology

Background:

• Uveal melanoma (UM) shows genetic cancer predisposition in ~2% of patients, primarily linked to BAP1 variants.
• A significant portion (up to 75%) of familial UM (FUM) cases lack a genetic diagnosis, indicating other contributing genes.
• Identifying novel genetic factors is crucial for understanding UM etiology and improving risk assessment.

Purpose of the Study:

• To investigate the genetic landscape of UM beyond BAP1 in patients with increased cancer risk.
• To identify pathogenic germline variants in dominant and recessive cancer genes associated with UM predisposition.
• To explore the role of multilocus variants in UM development.

Main Methods:

• Exome sequencing of blood samples from 106 UM patients with higher-than-average cancer risk and no BAP1 pathogenic or likely pathogenic (P/LP) variants.
• Analysis focused on identifying P/LP variants in known cancer-associated dominant and recessive genes.
• Comparison of age at diagnosis between patients with and without identified P/LP variants.

Main Results:

• 15% of UM patients (16/106) carried at least one P/LP variant in dominant (e.g., CHEK2, FANCM) or recessive cancer genes.
• CHEK2 and FANCM were newly implicated in UM predisposition.
• 6% of patients had multilocus P/LP variants, with an earlier median age of UM diagnosis (51 vs. 60 years).

Conclusions:

• Genetic predisposition to UM extends beyond BAP1, with novel genes like CHEK2 and FANCM playing a role.
• Co-occurring pathogenic variants, potentially indicating multilocus inherited neoplasia allele syndrome (MINAS), may contribute to UM.
• Further research is needed to explore additional genes, lower penetrance variants, and multi-gene effects in UM predisposition, especially in familial cases.