In cancer, BAP1 can function both as a
tumor suppressor and as a
metastasis suppressor.
Somatic mutations in cancer • BAP1
somatic mutations were identified in a small number of breast and lung cancer cell lines, • In 2010,
J. William Harbour and colleagues published a landmark article in
Science, in which they used
exome sequencing of patient tumor samples and identified inactivating mutations in BAP1 in 47% of
uveal melanomas. They were also the first to show germline BAP1 mutations, and that BAP1 mutation was strongly associated with
metastasis. These
mutations included multiple
nonsense mutations and
splice site mutations throughout the gene.
Missense mutations were only found within the UCH and ULD domains, further supporting the requirement for BAP1 catalytic function. This study also identified a
germline mutation in one of the
uveal melanoma patients, suggesting that, besides being a
metastasis suppressor, BAP1 could
predispose certain people to more aggressive
uveal melanoma tumors. • BAP1 mutations have been identified in aggressive
mesotheliomas with similar mutations as seen in melanomas,. • Mutations in the tumor suppressor gene BAP1 occur in approximately 15% of clear cell renal cell carcinoma (CCRCC) cases. Sequencing efforts demonstrated worse outcomes in patients with BAP1 mutated clear cell renal cell carcinoma.
BAP1 tumor predisposition syndrome Two studies used
genome sequencing independently to identify
germline mutations in BAP1 in families with
genetic predispositions to
mesothelioma and
melanocytic skin tumors The atypical melanocytic lesions resemble Spitz nevi and have been characterized as "atypical Spitz tumors" (ASTs), although they have a unique histology and exhibit both BRAF and BAP1 mutations. Further studies have identified germline BAP1 mutations associated with other cancers. These studies suggest that
germline mutation of BAP1 results in a Tumor Predisposition Syndrome linking BAP1 to many more cancers. == Immunochemistry ==