In the present study, we analyzed genomic alterations of BRCA1-associated protein 1 (BAP1) in 23 malignant mesotheliomas (MMs), 16 epithelioid and seven non-epithelioid, consisting of 18 clinical specimens and five established cell lines. In examining these samples for homozygous deletions and sequence-level mutations, we found biallelic BAP1 gene alterations in 14 of 23 MMs (61%). Seven of these 14 MMs had homozygous deletions of the partial or entire BAP1 gene, another five had sequencelevel mutations, including small deletions, a nonsense mutation, and missense mutations with additional monoallelic deletions, and the remaining two had homozygous mutations without allelic loss. All but one of the 14 BAP1 gene mutations were found in the epithelioid-type MMs; BAP1 mutations were found in 13 of 16 epithelioid-type MMs, but in only one of seven non-epithelioid-type MMs (13/16 vs 1/7; P = 0.005). There was no BAP1 mRNA expression in MMs with biallelic deletion and repressed expression was confirmed in MM specimens with deletion/mutation as compared with Met5a, SV40-transformed normal mesothelial cells. Western blot showed that seven of eight epithelioid MMs analyzed were BAP1 negative. Immunostaining with anti-BAP1 antibody in normal lung tissues revealed clear nuclear staining of normal mesothelial cells. No nuclear staining was observed among BAP1 mutation-positive MM tumors, whereas nuclear staining was observed among BAP1 mutation-negative MM tumors. These results suggest that the lack of the tumor suppressor BAP1 may be more specifically involved in the pathogenesis of epithelioid MM rather than non-epithelioid MM, and would be useful for diagnosis of epithelioid-type MM. (Cancer Sci 2012; 103: 868-874) M alignant mesothelioma (MM) is an asbestos-related malignancy that arises primarily from surface serosal cells of pleural, peritoneal, and pericardial cavities. Although the use of asbestos has decreased in Western countries and Japan, the incidence of MM is expected to increase over the next few decades because of the long latency period (20-40 years) of this malignancy.(1) Although the prognosis of MM is generally poor, epithelioid-type MM has been reported to be associated with better prognosis than non-epithelioid types of MM.(2) Multiple modality approaches involving surgery with radiation, chemotherapy, or immunotherapy have generated favorable outcomes, particularly for patients with epithelioid-type MM.(3)

Our data suggest that the VEGF serum concentration could be a useful marker for screening MPM among asbestos-exposed individuals and as a prognostic factor.

Our data suggest that the pleural effusion VEGF concentration could be useful as an aid for the diagnosis of MPM and as a prognostic factor.

2Corresponding author's email: ctabata@hyo-med.ac.jp Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin associated with asbestos Rationale: exposure. MPM has a limited response to conventional chemotherapy and radiotherapy so early diagnosis of MPM is very important. Vascular endothelial growth factor (VEGF), a potent mitogen for the vascular endothelium, is also known to be an autocrine growth factor for MPM. Here, we investigated the pleural effusion VEGF levels in patients with MPM and compared them to those of a population with a non-malignant pleuritis or lung cancer involving malignant pleural effusion.The pleural effusion VEGF concentrations were measured in 46 MPM patients and 45 individuals with non-MPM individuals (25 Methods: individuals with non-malignant pleural effusions, and 20 individuals with lung cancer involving malignant pleural effusion).We demonstrated that patients with MPM had significantly higher pleural effusion VEGF levels than a population with Results: non-malignant pleuritis or lung cancer involving malignant pleural effusion, and the patients with advanced stage MPM showed higher levels of VEGF than the early stage MPM patients. The difference in overall survival between the groups with pleural effusion VEGF levels lower and higher than the assumed cutoff of 2000 pg/ml was significant.Our data suggest that the pleural effusion VEGF concentration could be useful as an aid for the diagnosis of MPM and as a Conclusions: prognostic factor. This abstract is funded by: None Am J Respir Crit Care Med 183;2011:A4810 Internet address: www.atsjournals.org Online Abstracts Issue

The data suggest that the pleural effusion mesothelin concentration could be useful as an aid for the diagnosis of MPM.