A BAP1 mutation in a Danish family predisposes to uveal melanoma and other cancers

Abstract

Truncating germline mutations in the tumor suppressor gene BRCA-1 associated protein-1 (BAP1) have been reported in families predisposed to developing a wide range of different cancer types including uveal melanoma and cutaneous melanoma. There has also been an association between amelanotic tumor development and germline BAP1 mutation suggesting a possible phenotypic characteristic of BAP1 mutation carriers. Though there have been many types of cancer associated with germline BAP1 mutation, the full spectrum of disease association is yet to be ascertained. Here we describe a Danish family with predominantly uveal melanoma but also a range of other tumor types including lung, neuroendocrine, stomach, and breast cancer; as well as pigmented skin lesions. Whole-exome sequencing identified a BAP1 splice mutation located at c.581-2A>G, which leads to a premature truncation of BAP1 in an individual with uveal melanoma. This mutation was carried by several other family members with melanoma or various cancers. The finding expands on the growing profile of BAP1 as an important uveal and cutaneous melanoma tumor suppressor gene and implicates its involvement in the development of lung, and stomach cancer.

Figure 1. Co-segregation analysis of a BAP1 splice mutation in a Danish family.

In the pedigree individuals that have uveal melanoma (UMM) are represented by black circles (female) or boxes (male) and individuals with cutaneous melanoma (CMM) are indicated by grey circles or boxes. The age of diagnosis of each melanoma is indicated in brackets. A line through a symbol indicates that the person is now deceased. If a person carries the BAP1 splice mutation it is indicated by an ‘M’ and if they are wild type for this variant it is indicated with a ‘WT’. Where the mutation status is indicated in brackets, the person is a presumed obligate carrier, ‘(M)’. Other cancer types are also indicated in the pedigree with the age of diagnosis in brackets. Asterisks indicate the two individuals that were exome sequenced. Unaffected siblings are represented by diamonds, with the number in the centre indicating the number of people.

Figure 2. Sanger sequencing trace and amino acid alignment showing the truncated BAP1 protein.

(A) The left panel shows the wild type chromatogram while the right panel shows that of the BAP1 splice mutation. (B) Wild type nucleotide and amino acid sequences are shown in the upper panel while the lower panel shows part of the truncated BAP1 protein resulting from the loss of exon 8.

Figure 3. RT-PCR showing the aberrantly spliced BAP1 transcript.

From the left, the first lane shows a size marker, the next two lanes show wild type BAP1 RT-PCR products, and the last two lanes show the aberrantly spliced product resulting from the c.581-2A>G mutation.