Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases

Abstract

The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a recently identified hereditary cancer syndrome. Germline mutations in this tumor suppressor gene predispose families to the development of various malignancies. The molecular functions of the gene as well as the clinical phenotype of the syndrome are still being clarified. We sought to conduct a comprehensive review of published research into BAP1-TPDS to more thoroughly delineate the clinical implications of germline BAP1 mutations. We also report two additional families with germline BAP1 mutations. Current evidence demonstrates that germline BAP1 mutations predispose families to uveal melanoma, renal cell carcinoma, malignant mesothelioma, cutaneous melanoma, and possibly to a range of other cancers as well. Some of these cancers tend to be more aggressive, have a propensity to metastasize, and onset earlier in life in patients with BAP1 mutations as compared to non-predisposed patients with equivalent cancers. Although further research is necessary, this information can aid in the management, diagnosis, and therapy of these patients and their families, and highlights the importance of genetic counseling.

Keywords: BAP1; cutaneous melanoma; germline; mesothelioma; renal cell carcinoma; uveal melanoma.

Fig. 1

Two new families with germline BAP1 mutation. (a, b) In FUM124, the proband (III-7) and his niece IV-8 showed a germline heterozygous c.539T>C, p.L180P. The proband presented with pleural malignant mesothelioma (MMe), basal cell carcinomas (BCC) and cutaneous melanoma (CM), a brother (obligate carrier) had uveal melanoma (UM) and BCC while the niece was unaffected at age 59. Five other individuals in the family with cancer (II-3: prostate Ca, III-2: liposarcoma, IV-3: CM, IV-6: Breast Ca and V-4: Schawannoma) tested negative for the mutation. Five unaffected relatives also tested negative for mutation (only three are shown). (c) In FUM, 128 the proband (III-2) presented with peritoneal MMe, other cancer in the families were peritoneal MMe, UM, pancreatic and bladder cancers. (d) Germline 2 bp deletion (c.256-4_256-2del) in intron 4. (e) The deletion causes aberrant splicing of the BAP1 (first lane genomic DNA, second lane patients cDNA and third lane a control individual cDNA). In both families, BAP1 mutation status is denoted as mutated (BAP1 +ve) or wild-type (BAP1 −ve). Some of the unaffected BAP1 −ve individuals are not shown.

Fig. 2

Venn diagrams of the cancers identified in BAP1 patients and families. (a) Individuals with BAP1 mutations diagnosed with uveal melanoma (UM), renal cell carcinoma (RCC), cutaneous melanoma (CM), and/or malignant mesothelioma (MMe). There are 118 patients who were diagnosed with at least one of the above cancers. Thirty individuals were only diagnosed with another cancer uncertain to be BAP1 related. Twelve individuals were diagnosed with atypical Spitz tumors (ASTs) only. Fourteen individuals were unaffected. (b) Families with BAP1 mutations with mutation-positive members diagnosed with UM, RCC, CM, and MMe. There were 57 families reported, of which 54 had at least member with one of the above diagnoses testing positive. One family presented with only ASTs and another cancer uncertain to be BAP1 related. Two families had a history of one of the above diagnoses, but those members were not tested.

Fig. 3

Gene location and mutation type of the reported germline pathogenic variants in BAP1 in the four main cancers associated with BAP1-TPDS. No genotype–phenotype correlation was observed. One mutation was found in a family not reporting a uveal melanoma (UM), malignant mesothelioma (MMe), cutaneous melanoma (CM), or renal cell carcinoma (RCC). Two family mutations were not tested in a member with a personal history of UM, MMe, CM, or RCC. ▲, splice-site mutation; ★, truncating mutation; ●, missense mutation; UCH, ubiquitin C-terminal hydrolase; BARD1, BARD1 binding domain; HCF1, HCF1 binding motif; BRCA1, BRCA1 binding domain; N, nuclear localization signal.