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Risk of Low-Level Exposure to Radiation-Biological Basis
Published in Lawrence T. Dauer, Bae P. Chu, Pat B. Zanzonico, Dose, Benefit, and Risk in Medical Imaging, 2018
Tatjana Paunesku, Gayle E. Woloschak
The great majority of mechanistic low-dose radiation studies point to different aspects of p53 protein activity (although this could be a research bias of investigators studying p53 to the exclusion of other proteins that could be equally important). This tumor suppressor gene is indeed important in the development of cancer as well as senescence, apoptotic cell death, and teratogenesis. Nevertheless, it is still probable that its predominant recurrence in discussions on low-dose radiation effects comes from the fact that mouse animal models with altered p53 function contributed so much data to this field. It is therefore advisable to generate and explore other transgenic models as well, exploring low-dose radiation in mice heterozygous for other tumor-suppressor genes. Simplifying the genetic landscape through the use of knock-out mutations is a long-accepted tool in mechanistic biology; however, data interpretation remains labor intensive even under such circumstances. For example, another tumor-suppressor gene, BRCA1 associated protein (BAP1), is a ubiquitin carboxy (C)-terminal hydrolase critical for DNA double-strand break repair by homologous recombination [84]; this protein is necessary for G1-S checkpoint transition and its absence increases radiosensitivity [85]. Animals heterozygous for BAP1 spontaneously develop different types of cancer [86]; in most cases, cancer cells demonstrate loss of heterozygosity, suggesting that BAP1 is a tumor-suppressor gene that could “…offer key insights into the contribution of carcinogen exposure to enhanced cancer susceptibility.” Interestingly, the most recent paper on BAP1 has shown that BAP1 is also a regulator of apoptosis [87]; thus, it may be that it is (at least in part) the increased survival of cells with chromosomal abnormalities that contributes to the apparent DNA damage load in these cells.
Malignant pleural mesothelioma: Presentation of a case report
Published in Egyptian Journal of Basic and Applied Sciences, 2018
Munir Ahmad, Muhammad Omer Aamir, Khurram Minhas, Khwaja Ajmal, Iftikhar Ahmad
Asbestos exposure presumably remains the major factor that modulates the pathogenesis of MPM [13], particularly in older patients while younger patients have been reported to exhibit higher susceptibility of non-asbestos related MPM [14,15] . However, there was no history of asbestos exposure in our 56-year-old patient. Alternatively, it is likely that genetic predisposition may increase the risk of MPM manifestation. Indeed, the risk of MPM development has been previously linked with mutations in the germline BRCA1 associated protein-1 (BAP1) [16[17]–18] . Our patient did not cooperated to carry out a comprehensive study of genetic susceptibility. Nevertheless, we found that the two most sensitive markers of MPM (i.e., calretinin and cytokeratin 5/6) were positive on IHC [6,7] . Overall, it appears that the diagnosis of MPM can be difficult and requires knowledge of the clinical presentation of the disease.
Pleural mesothelioma and lung cancer: the role of asbestos exposure and genetic variants in selected iron metabolism and inflammation genes
Published in Journal of Toxicology and Environmental Health, Part A, 2019
F. Celsi, S. Crovella, R. R. Moura, M. Schneider, F. Vita, L. Finotto, G. Zabucchi, P. Zacchi, V. Borelli
Recently, a screening of a cohort of mesothelioma patients with a family history of cancer showed the presence of BAP1 (BRCA associated protein 1) mutations in a minority of patients (Ohar et al. 2016), a result further confirmed by two whole-genome investigations accomplished in different geographic areas (Betti et al. 2017; Bueno et al. 2016). Mutations in the tumor suppressor gene BAP1 (truncation, deletions, somatic variants including large deletions, and/or chromosomal loss) associated with different types of cancer, including MPM, reviewed in Betti et al. (2019), and LC (Carbone et al. 2013), supporting the concept that a common mutation might trigger diverse malignancies. BAP1 plays an important role in chromatin modulation, transcriptional regulation, cell proliferation, DNA repair, cell death, and glucidic metabolism. Interestingly, Zhang et al. (2018) reported that cells with reduced BAP1 activity also display impaired ferroptosis, providing a possible link between Fe and BAP1 pathways in the development of asbestos-related malignancies. Many other genes were identified as involved in predisposition to MPM, which are predominantly involved in DNA repair (Betti et al. 2019). These findings suggest that the contribution of the BAP1 failure (and also that of the other genes) may follow the damage initiated by other pathways triggered by asbestos, such as those Fe-mediated. It is likely that it is the synergic (rare) combination of these pathways to determine the predisposition. External pollutants, such as asbestos and cigarette smoke, increase Fe loads in the lungs (Ghio et al. 2008; Pascolo et al. 2016), induce oxidative stress and inflammation, tipping the point toward cancer development. In this context, alterations of genes involved in Fe-metabolism might either elevate or decrease the toxicity of this metal thus possibly either inducing or protecting from the neoplastic transformation.