Germline BAP1 mutation in a family with high incidence of multiple primary cancers and a potential gene-environment interaction

Abstract

We report a high-risk cancer family with multiple mesotheliomas, cutaneous melanomas, basal cell carcinomas, and meningiomas segregating with a germline nonsense mutation in BAP1 (c.1938T>A; p.Y646X). Notably, most (four of five) mesotheliomas were peritoneal rather than the usually more common pleural form of the disease, and all five mesothelioma patients also developed second or third primary cancers, including two with meningiomas. Another family member developed both cutaneous melanoma and breast cancer. Two family members had basal cell carcinomas, and six others had melanocytic tumors, including four cutaneous melanomas, one uveal melanoma, and one benign melanocytic tumor. The family resides in a subtropical area, and several members had suspected exposure to asbestos either occupationally or in the home. We hypothesize that the concurrence of a genetic predisposing factor and environmental exposure to asbestos and UV irradiation contributed to the high incidence of multiple cancers seen in this family, specifically mesothelioma and various uveal/skin tumors, respectively.

Keywords: Asbestos; BAP1; Cancer predisposition; Familial cancer; Malignant mesothelioma.

Figure 1

Pedigree of family reported here, whose germline DNA contained a nonsense mutation in BAP1 exon 15 (c.1938T>A). The family of the proband (III-07, arrow) shows numerous malignancies, including six family members (I-02, II-03, III-05, III-07, III-09, and III-10) with two or more primary cancers. Predominant tumors include malignant mesothelioma and cutaneous melanoma, each observed in five family members.

Figure 2

Electropherogram of BAP1 mutation of the index case. The nonsense mutation c.1938T>A is predicted to lead to a BAP1 protein truncation (p.Y646X) or nonsense-mediated decay of the BAP1 mRNA.

Figure 3

H&E and immunohistochemical staining of meningioma and mesothelioma tissues from patient III-10. A) H&E staining of meningioma. B) BAP1 immunohistochemistry of meningioma, showing absence of nuclear BAP1 staining in tumor (T) and both cytoplasmic and strong nuclear staining in adjacent normal brain parenchyma (N). C) H&E staining of peritoneal mesothelioma. D) BAP1 immunohistochemistry of same mesothelioma, showing absence of nuclear BAP1 staining in tumor (T) and both cytoplasmic and strong nuclear staining in normal stroma (S).

Figure 4

DNA sequencing and chromosome microarray analysis of DNA from FFPE meningioma tissue of patient III-10. A) Oncoscan DNA copy number and allele analysis revealing loss of one copy of chromosome 3. B) Sequence analysis of BAP1 analysis of tumor sample showing loss predominantly of the wild-type BAP1 allele and retention of the mutated BAP1 allele.