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

BAP1

Heterozygous germline pathogenic or likely pathogenic BAP1 variants

Germline pathogenic or likely pathogenic BAP1 variants predispose to uveal melanoma, cutaneous melanoma, renal cell carcinoma and malignant mesothelioma, and higher risks of lung and breast cancer have been hypothesised. The authors included 26 families with 90 heterozygotes and estimated cumulative and relative risks with the Genotype-Restricted Likelihood (GRL) method, which corrects for ascertainment bias. Cumulative risks at 80 years are 7.3% for uveal melanoma, 16.1% for cutaneous melanoma, 49.4% for renal cell carcinoma, 8.5% for mesothelioma, 9.8% for lung cancer and 58.6% for breast cancer. Relative to population incidence, the relative risk reaches 383.4 at 50 years for uveal melanoma and remains modest for lung cancer (1.4 at 50 years, 1.7 at 80 years). The authors conclude that these estimates will help guide clinical management and surveillance, while calling for further studies to refine them.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Correcting for ascertainment bias is essential for a rare syndrome known mostly through heavily affected families, but 26 families yield very wide confidence intervals, from 6% to 83.9% for renal cell carcinoma. The 58.6% breast cancer risk at 80 years would, if confirmed, raise the question of dedicated breast surveillance; for now it is a hypothesis to replicate before changing protocols.

Analysis by Dr Thibaut Benquey