Risk estimates in BAP1 tumor predisposition syndrome using the Genotype-Restricted Likelihood (GRL) method

Germline BAP1 (likely) pathogenic variants ((L)PV) confer predisposition to uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and malignant mesothelioma (MM). Higher risks of lung cancer (LC) and breast cancer (BC) have been hypothesized with risk estimates using bias-correcting methods.

We included 26 families with 90 heterozygotes for a germline BAP1 (L)PV. Cumulative risk (CR) and relative risk (RR) were estimated using the Genotype-Restricted Likelihood (GRL) method to correct for ascertainment bias.

The CR at 80 years are 7.3% (95% CI: 1.3-37.9) for UM, 16.1% (2.9-74.4) for CM, 49.4% (6-83.9) for RCC, 8.5% (2.5-73.8) for MM, 9.8% (6.5-55.9) for LC and 58.6 (19-91.8) for BC. Corresponding RR to population incidence at 50 and 80 years are respectively 383.4 (72.4-779.1) and 95.9 (17.3-501) for UM, 5.7 (1-24.4) and 8.2 (1.5-37.9) for CM, 61.1 (11.7-157) and 29.9 (3.7-50.8) for RCC, 7.5 (1.1-1530.7) and 55.7 (16.5-482) for MM, 1.4 (1-26.4) and 1.7 (1.1-9.6) for LC and 7.4 (1-17.2) and 4.7 (1.5-7.4) for BC.

These GRL-based tumor risk estimates for individuals with heterozygous BAP1 (L)PV will help guide clinical management and surveillance strategies. Further studies are needed to refine these values.