Molecular Genetics of Malignant Mesothelioma

Abstract

Abstract Malignant mesothelioma (MM) is an aggressive tumour arising primarily from the pleural or peritoneal cavities. MM develops by asbestos exposure after a long latency, which is highly refractory to conventional therapeutic modalities. Molecular genetic analysis has revealed several key genetic alterations which are responsible for the development and progression of MM. The frequently mutated tumour suppressor genes detected in MM cells are CDKN2A/ ARF , NF2 , BAP1 , and LATS2 . In contrast, frequent activating mutation of any oncogenes has not been clearly identified yet, which is one of the reasons that current molecular target therapy is not very effective for MM patients. Recent studies have also indicated characteristic epigenetic alterations in MM, which include distinct deoxyribonucleic acid (DNA) methylation patterns and the involvement of noncoding ribonucleic acid (RNA) . Aberrant histone modification caused by BAP1 inactivation may also lead to the disturbance of global expression profiling. 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 would be applied for developing a new diagnostic tool and new target therapies against MMs. Key Concepts: Malignant mesothelioma cells harbour multiple key genetic mutations, which mainly inactivate tumour suppressor genes. Asbestos fibre induces chromosome and DNA damages in normal mesothelial cells with several possible mechanisms, but it is not clear why it takes so long from asbestos exposure to mesothelioma development. People differ in their susceptibility to development of mesothelioma after similar levels of asbestos exposure, possibly due to the differences in genetic polymorphisms or expression levels of genes involved in the DNA repair system and epigenetics modification. Mesothelioma has long been considered a representative type of tumour primarily caused by environmental factors, especially asbestos, but familial cases of mesothelioma with a specific gene mutation have challenged this idea. Neurofibromatosis type 2 (NF2) gene inactivation is found in a nearly half of mesothelioma cases and the inactivation of one of its downstream signal transduction cascades, Hippo signalling, plays a significant role in dysregulation of cell proliferation. Epigenetic alterations such as aberrant histone modification by BAP1 gene inactivation play significant roles in mesothelioma development. The overall picture of the genetic abnormality landscape of mesothelioma cells lags behind other common human malignancies. If an oncogene‐type gene with frequent activating mutation in mesothelioma cells were discovered, molecular target strategies aiming at controlling the activated molecule could be aggressively pursued to develop new therapeutic tools against mesothelioma.