The BAP1 (BRCA1 associated protein 1) gene is a tumour suppressor gene that functions in the BRCA1 growth control pathway and thereby has a role in cell proliferation and growth inhibition. The BAP1 gene locates in the 3p21 region, which is frequently affected by LOH or deletions in several cancer types including lung, breast and ovarian cancer, but also in uveal melanoma and mesothelioma.
Recent research suggests that uveal melanoma with monosomy of chromosome 3 (frequency 50-60% of all uveal melanomas) represents a distinct pathological entity as compared to uveal melanoma with normal disomy 3. The putative target gene on the 3p arm is BAP1, as inactivating somatic mutations of BAP1 are identified in >80% of patients with metastasizing uveal melanoma (Harbour JW et al., 2010, Science. 330:1410-3). Moreover, BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma (Nasu M et al., 2015, J Thorac Oncol. 10:565-76; Testa JR et al., 2011, Nat Genet. 43:1022-5; Bott M et al., 2011, Nat Genet. 43:668-72). In addition, germline mutations and copy number alterations in BAP1 predispose to melanocytic tumours (Wiesner T et al., 2011, Nat Genet. 43:1018-21) and to uveal melanoma (Boru G et al., 2019, Genes Chromosomes Cancer. DOI: 10.1002/gcc.22752), lung carcinoma and meningioma (Abdel-Rahman MH et al., 2011, J Med Genet. 48:856-9). When a subset of these familial melanoma samples were analysed with array CGH, a frequent loss of the 3p21 region was detected suggesting a second hit to eliminate the remaining wild-type allele of BAP1.
The BAP1 gene (17 exons) spans ~9 kb of genomic DNA and is located on chromosome 3p21.1, ~52.4 Mb from the p-telomere. This P417-B2 BAP1 probemix contains one probe for each exon of the BAP1 gene (17 exons). In addition, 10 flanking probes for the BAP1 gene and 15 reference probes are included in this probemix. Reference probes included in this mix detect autosomal chromosomal locations, which are relatively stable both in melanocytic tumours and in mesothelioma.
This SALSA® MLPA® probemix is designed to detect deletions/duplications of one or more sequences in the BAP1 gene in a DNA sample. Heterozygous deletions of recognition sequences should give a 35-50% reduced relative peak height of the amplification product of that probe. Note that a mutation or polymorphism in the sequence detected by a probe can also cause a reduction in relative peak height, even when not located exactly on the ligation site! In addition, some probe signals are more sensitive to sample purity and small changes in experimental conditions. Therefore, deletions and duplications detected by MLPA should always be confirmed by other methods. Not all deletions and duplications detected by MLPA will be pathogenic; users should always verify the latest scientific literature when interpreting their findings. We have no information on what percentage of defects in these genes is caused by deletions/duplications of complete exons. Finally, note that most defects in this gene are expected to be small (point) mutations which will not be detected by this SALSA® MLPA® test.