Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers

Abstract

Objective: To investigate the potential contribution of germline sequence alterations in the BAP1 gene in uveal melanoma (UM) patients with possible predisposition to hereditary cancer.

Design: A total of 53 unrelated UM patients with high risk for hereditary cancer and five additional family members of one proband were studied. Mutational screening was carried out by direct sequencing.

Results: Of the 53 UM patients studied, a single patient was identified with a germline BAP1 truncating mutation, c. 799 C→T (p.Q267X), which segregated in several family members and was associated with UM and other cancers. Biallelic inactivation of BAP1 and decreased BAP1 expression were identified in the UM, lung adenocarcinoma and meningioma tumours from three family members with this germline BAP1 mutation. Germline BAP1 variants of uncertain significance, likely non-pathogenic, were also identified in two additional UM patients.

Conclusion: This study reports a novel hereditary cancer syndrome caused by a germline BAP1 mutation that predisposes patients to UM, lung carcinoma, meningioma, and possibly other cancers. The results indicate that BAP1 is the candidate gene in only a small subset of hereditary UM, suggesting the contribution of other candidate genes.

Figures

Figure 1

Pedigree of family FUM036. Individuals III.1, II.2, III.2, III.6, III.9 were heterozygous for a truncating mutation (c. 799 C→T, p.Q267X) in BAP1 (designated Q267X/N in the figure). Individuals II.1 and II.3 are obligate carriers (inferred genotypes are shown in parentheses). Individual III.11 was negative for the mutation (designated N/N). No other individuals were tested. CM, cutaneous melanoma; UM, uveal melanoma.

Figure 2

Biallelic loss of BAP1 in tumours of the patients with germline mutation. (A) A germline truncating mutation (c. 799 C→T, p.Q267X) was observed in two patients with uveal melanoma (UM) (III.1 PB and III.6 PB) from the same family (FUM036). The mutation was also observed in the tumour tissues (III.1 T, a lung adenocarcinoma, and III.6 T, a UM) with loss of the wild type allele. (B) Genotyping of lung adenocarcinoma (from individual III.1) and UM (from individual III.6) tumours shows loss of heterozygosity of markers in close proximity to BAP1. PB, peripheral blood DNA; T, tumour DNA; WT, wild type.