Somatic mutations of the BRCA1 associated protein-1 (BAP1) gene, which maps to 3p21, have been found in several tumors including malignant mesothelioma, uveal melanoma, and renal cell carcinoma (RCC).
In the context of a mesothelial proliferation, the finding of homozygous deletion of p16 by FISH or loss of BAP1 by immunohistochemistry is, thus far, 100% specific for malignant mesothelioma.
Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers.
No exonic germline BAP1 mutations of known functional significance were observed, further supporting the notion that sporadic germline BAP1 mutations are not relevant to the genetic susceptibility of MM.
Our results suggested that, whereas WT BAP1 suppresses MM cell proliferation and restores cell survival after IR damage, some mutant BAP1 may also moderately retain these functions.
IHC revealed normal nuclear BAP1 staining in the eight MM containing wild-type BAP1, whereas no nuclear staining was detected in the 14 MM biopsies containing tumor cells with mutated BAP1.
These exhibited extended germline homozygosity and were in regions containing somatic mutations, leading to a loss of BAP1 and PBRM1 expression in MM cell line.
Analysis of the pooled cohort of germline BAP1 mutation MM showed that patients with peritoneal MM (median survival of 10 years, P = 0.0571), or with a second malignancy in addition to MM (median survival of 10 years, P = 0.0716), survived for a longer time compared with patients who only had pleural MM, or MM patients without a second malignancy, respectively.