The BAP1 gene should be targeted to develop specific therapies for mesothelioma
Genetic mutations can be inherited at birth, and some of them cause disease and cancer, such as the BAP1 cancer syndrome. Alternatively, the same genes or others can become mutated in cancer cells. Most mutations found in cancer cells are acquired during tumor growth and do not play a critical role in tumor initiation or growth. Some mutations, instead, are called driver mutations because they drive tumor growth. Driver mutations are usually frequent in a given tumor type.
We found that BAP1 is the most commonly acquired mutation in sporadic mesothelioma, which means mesothelioma that does not occur because of inherited germline mutation (for example, mesothelioma caused by asbestos exposure). We found that over 60% of sporadic mesotheliomas have mutated BAP1. This finding underscores the critical role of BAP1 in mesothelioma and points to BAP1 as the critical gene that should be targeted to develop specific therapies for mesothelioma.
Our findings have been validated by several other independent studies, including those of Drs. Harvey Pass, Rafael Bueno, Giorgio Scagliotti, and others, which are reviewed in The Journal of Thoracic Oncology publication Recent insights emerging from malignant mesothelioma genome sequencing.
Authors: Masaki Nasu, Mitsuri Emi, Sandra Pastorino, Mika Tanji, Amy Powers, Hugh Lik, Francine Baumann, Yu-An, Mitsuru Emi, Sandra Pastorino, Mika Tanil, Amy Powers, Hugh Luk, Francine Baumann, Yu-an Zhang, Adi Gazdar, Shreya Kanodia, Maarit Tirikainen, Erin Flores, Giovanni Gaudino, Michael J. Becich, Harvey I. Pass, Haining Yang, Michele Carbone, MD, PhD.
Oncogene - Short Communication
Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated with professional exposure to asbestos. However, to date, we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos
This study shows that hyper-acetylated HMGB1 is an accurate biomarker to differentiate malignant mesothelioma patients from individuals occupationally exposed to asbestos and unexposed controls. A trial to independently validate these findings will start soon.
Our multinational team discovered that four apparently unrelated US families share a common ancestor, a couple who immigrated from Germany in the early 1700s.
Online journal: Expert Review of Respiratory Medicine
Malignant mesothelioma is an aggressive cancer whose pathogenesis is causally linked to occupational exposure to asbestos. Familial clusters of mesotheliomas have been observed in settings of genetic predisposition. Mesothelioma incidence is anticipated to increase worldwide in the next two decades. Novel treatments are needed, as current treatment modalities may improve the quality of life, but have shown modest effects in improving overall survival. Increasing knowledge on the molecular characteristics of mesothelioma has led to the development of novel potential therapeutic strategies, including: molecular targeted approaches, that is the inhibition of vascular endothelial growth factor with bevacizumab; immunotherapy with chimeric monoclonal antibody, immunotoxin, antibody drug conjugate, vaccine and viruses; inhibition of asbestos-induced inflammation, that is aspirin inhibition of HMGB1 activity may decrease or delay mesothelioma onset and/or growth. We elaborate on the rationale behind new therapeutic strategies, and summarize available preclinical and clinical results, as well as efforts still ongoing.
Authors: Angela Bononi, Andrea Napolitano, Harvey I Pass, Haining Yang, and Michele Carbone