Malignant mesothelioma (MM) is an aggressive
tumor arising primarily from the pleural or peritoneal cavities. It develops by
asbestos exposure after a long latency, which is characterized by insidious growth and clinical presentation at an advanced stage of disease. MM is highly refractory to conventional
therapies even with a combination of aggressive surgical intervention and multimodality strategies, with cure remaining elusive. Molecular genetic analysis has revealed several key genetic alterations, which are responsible for the development and progression of MM. The
cyclin-dependent kinase inhibitor 2A/alternative reading frame (CDKN2A/ARF),
neurofibromatosis type 2 (NF2) and BRCA1-associated protein-1 (BAP1) genes are the most frequently mutated tumor suppressor genes detected in MM cells; the alterations of the latter two are relatively characteristic of MM.
Merlin, which is encoded by NF2, regulates multiple cell signaling cascades including the Hippo and
mammalian target of rapamycin pathways, which regulate cell proliferation and growth. BAP1 is involved in
histone modification and its inactivation induces the disturbance of global gene expression profiling. The discovery of a new familial
cancer syndrome with germline mutation of BAP1 also indicates the importance of genetic factors in MM susceptibility. Meanwhile, although frequent expression and functional activations of
oncogene products such as
receptor tyrosine kinases are observed in MM cells, activating mutations of these genes are rare. With further comprehensive genome analyses, new genetic and epigenetic alterations in MM cells are expected to be revealed more precisely, and the new knowledge based on them will be applied for developing new diagnostic tools and new target
therapies against MMs.