Germline variants in cancer predisposition genes in patients with uveal melanoma

Abstract

AbstractPurpose: Patients with uveal melanoma (UM) have an increased risk of other primary tumours; up to 12% of patients belong to families with other cancers.[1] ~2% of unselected patients and 25% of patients with a family history of UM harbour a pathogenic germline variant in the BAP1 gene.[2] Additionally, 12 other genes might contribute to UM susceptibility [3] whereas 75% of patients with familial UM remain without a genetic explanation for UM susceptibility.Methods: We sequenced 312 consecutively enrolled patients with UM for germline variants in 15 genes driving UM tumorigenesis or having a BAP1 association using next‐generation sequencing. Additional 191 cancer‐associated genes were analysed from 108 high‐risk patients who had another cancer, UM at <45 years of age, or either bilateral or familial UM.Results: 6.5% (7/108; 95% CI 2.6–12.9) of the high‐risk patients had a pathogenic or likely pathogenic germline variant in AR, CHEK2, DDX41, RAD50, RET, or SDHB and 8.3% (9/108; 95% CI 3.9–15.2) harboured a cancer‐associated VUS in BMPR1A or CHEK2. Germline variants in UM drivers other than BAP1 did not contribute to UM predisposition.Conclusions: Germline variants in known cancer genes are relatively frequent in selected patients with UM. The family history of cancer should be obtained and the threshold to offer genetic counselling should be low.