Malignant mesothelioma (MM) is frequent in individuals continuously exposed to carcinogenic mineral fibers such as asbestos and erionite, but it is very rare in those with limited or no exposure. Genetics influences susceptibility to MM, and we have recently demonstrated that carriers of germline BAP1 mutations have increased incidence of multiple cancer types, including MM. In some BAP1-mutation carrying families, MM accounts for more than 50% of deaths, and our central hypothesis is that this may be due to increased susceptibility to MM from exposure to modest amounts of asbestos that would normally not cause MM in the general population. The mechanism(s) by which mutated BAP1 causes MM pathogenesis is unknown. Our preliminary data show a previously uncharacterized BAP1 function in the cytoplasm, wherein BAP1 appears to regulate Ca2+ release from the endoplasmic reticulum and, in turn, apoptosis. Our preliminary data also show that monoallelic BAP1 loss increased susceptibility to low doses of asbestos, and that germline BAP1 mutation carriers have higher levels of serum HMGB1, a critical factor for MM development and progression. In addition, our preliminary investigations show that germline BAP1 mutation carriers with MM have significantly prolonged median survival (5 years) compared to sporadic MM (1 year). Therefore, we hypothesize that, on one hand, BAP1 mutation favors malignant transformation by inhibiting apoptosis and therefore increasing the percentage of cells that accumulate genetic damage, and that, on the other hand, BAP1 mutation may impair the aggressiveness of MM cells by either directly altering tumor cell growth or by affecting the tumor microenvironment. We further hypothesize that monitoring blood levels of HMGB1 in family members who carry BAP1 mutations may facilitate early detection of MM. To address the hypotheses, we will examine the following specific aims:
(Aim 1) To elucidate the novel cytoplasmic functions of BAP1 and determine whether BAP1 mutations increase resistance to apoptosis by modulating Ca2+ homeostasis.
(Aim 2) To determine whether BAP1 mutations increase susceptibility to MM upon exposure to low amounts of asbestos and elucidate why MM may be less aggressive in BAP1 mutation carriers.
(Aim 3) To determine whether HMGB1 is increased in individuals with germline BAP1 mutations. To elucidate the role of cytoplasmic BAP1 and its possible contribution to malignancy, we have assembled a unique cohort of families carrying germline BAP1 mutations and have access to unique models. We will elucidate the mechanisms and genetic alterations that lead to MM in BAP1 mutation carriers using a heterozygous BAP1 mouse model and derived cell cultures. Finally, we will evaluate whether HMGB1 can be used as a biomarker so as to improve our ability to monitor these high-risk individuals for early detection of MM, which will directly impact patients because detection of MM at the early stages of MM progression is strongly correlated to increased survival. These studies will also be relevant to the multiple malignancies associated with the BAP1 cancer syndrome.

Public Health Relevance

Germline BAP1 mutations are associated with high susceptibility to multiple tumor types, and mesothelioma (MM) may predominate upon exposure to low amounts of asbestos that does not normally cause disease. Moreover, there are no known biomarkers for asbestos exposure or for early detection of MM. The proposed studies will determine how BAP1 mutations increase susceptibility to MM and evaluate whether HMGB1 can be used as a biomarker for early detection of MM in this high-risk cohort.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Johnson, Ronald L
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University of Hawaii
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Affar, El Bachir; Carbone, Michele (2018) BAP1 regulates different mechanisms of cell death. Cell Death Dis 9:1151
Carbone, Michele; Amelio, Ivano; Affar, El Bachir et al. (2018) Consensus report of the 8 and 9th Weinman Symposia on Gene x Environment Interaction in carcinogenesis: novel opportunities for precision medicine. Cell Death Differ 25:1885-1904
Daou, Salima; Barbour, Haithem; Ahmed, Oumaima et al. (2018) Monoubiquitination of ASXLs controls the deubiquitinase activity of the tumor suppressor BAP1. Nat Commun 9:4385
Mao, Weimin; Zhang, Xing; Guo, Zhenying et al. (2017) Association of Asbestos Exposure With Malignant Mesothelioma Incidence in Eastern China. JAMA Oncol 3:562-564
Bononi, Angela; Giorgi, Carlotta; Patergnani, Simone et al. (2017) BAP1 regulates IP3R3-mediated Ca2+ flux to mitochondria suppressing cell transformation. Nature 546:549-553
Guo, Zhenying; Carbone, Michele; Zhang, Xing et al. (2017) Improving the Accuracy of Mesothelioma Diagnosis in China. J Thorac Oncol 12:714-723
Pellegrini, Laura; Xue, Jiaming; Larson, David et al. (2017) HMGB1 targeting by ethyl pyruvate suppresses malignant phenotype of human mesothelioma. Oncotarget 8:22649-22661
Chen, Zhongjian; Gaudino, Giovanni; Pass, Harvey I et al. (2017) Diagnostic and prognostic biomarkers for malignant mesothelioma: an update. Transl Lung Cancer Res 6:259-269
Bononi, Angela; Yang, Haining; Giorgi, Carlotta et al. (2017) Germline BAP1 mutations induce a Warburg effect. Cell Death Differ 24:1694-1704
Carbone, Michele; Yang, Haining (2017) Mesothelioma: recent highlights. Ann Transl Med 5:238

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