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A. Napolitano



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    MS04 - Mesothelioma Genetics and Novel Targets (ID 21)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Mesothelioma
    • Presentations: 1
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      MS04.1 - BAP1 Gene Mutation and Mesothelioma Pathogenesis (ID 471)

      14:00 - 15:30  |  Author(s): A. Napolitano

      • Abstract
      • Presentation
      • Slides

      Abstract
      Malignant mesothelioma (MM) is a lethal cancer whose pathogenesis results from complex interactions between host genetics and environmental carcinogens, such as asbestos and erionite fibers. Recently, BAP1 (BRCA associated protein 1) has been identified as a novel MM tumor suppressor gene. BAP1 is located at the 3p21, a region frequently deleted in MM, and encodes for a deubiquitinase enzyme known to target histones and other proteins. Originally discovered as a BRCA1 interacting protein, BAP1 appears to exert its anti-tumor activities mainly in a BRCA-independent manner, through its association in multi-protein complexes with diverse functions. For example, when associated to the Polycomb protein ASXL1, BAP1 is important for the regulation of the cell epigenome, via modulation of histone H2A ubiquitination and thus chromatin accessibility. In complex with other proteins (e.g. HCF-1, OGT, and YY1), BAP1 is also important in the transcriptional regulation of several genes and in the stability of target proteins such as PGC-1α. Recent reports also suggest a possible involvement of BAP1 in DNA repair pathways. However, the relevance of BAP1 to the biology of normal and cancer cells remains largely unexplained, in fact manipulation of BAP1 in cancer cells has often yielded unexpected or even contradictory results. For example, silencing of BAP1 in MM and uveal melanoma cell lines resulted in reduced cell growth (Bott et al; Matatall et al). We discovered that germline BAP1 mutations cause a novel cancer syndrome characterized by a significant excess of both pleural and peritoneal MM, uveal and cutaneous melanoma and possibly other tumors. In the same study, we reported that 22% sporadic MM tumors harbored somatic BAP1 mutations (Testa et al). In a separate study using 53 primary pleural MM collected in the USA, 42% of tumors harbored either BAP1 loss, BAP1 somatic mutations (detected in 23% of the samples), or both. Moreover, another 25% of tumors showed no BAP1 staining by immunohistochemistry (IHC) despite apparently normal BAP1 status, raising the possibility of post-translational deregulation of BAP1 in a subset of cases. In this MM cohort, there was a significant association between BAP1 status and patients’ age (66.7 years in mutant BAP1 compared to 58.6 years in wild-type BAP1), but there was no significant correlation with other variables such as sex, overall survival, histological subtype or asbestos exposure (Bott et al). In a recent meeting, using a bigger sample size, the same group confirmed that somatic BAP1 mutations occur in about 20% of pleural MM. They reported that the only clinical variable significantly different among those with and without BAP1 mutations was smoking (former or current), with BAP1 mutations more prevalent among smokers (75% vs. 42%). A Japanese study reported BAP1 gene alterations (either deletions or sequence-level mutations) in 61% of their 23 MM samples (Yoshikawa et al). Their data, but not those reported by Bott et al, also suggested an association between BAP1 mutations and the epithelioid histological MM subtype. Whether this discrepancy results from the different methodologies in sample preparation and detection of BAP1 mutations or it is an intrinsic difference between the two populations (e.g. due to ethnicity) has still to be determined. A third recent study, with a separate cohort of 52 pleural MM, reported absence of BAP1 IHC staining in 60% of pleural MM, confirming previous results (Arzt et al). The Authors also confirmed the absence of a correlation between BAP1 expression and asbestos exposure, and suggested that expression of BAP1 in tumor samples is inversely correlated to survival. The discovery of BAP1 germline and somatic mutations has renewed after decades the interest in MM genetics. Because germline BAP1 mutations predispose to multiple cancers and because BAP1 loss of heterozygosity is frequent in different tumor types, BAP1 would appear to act as a classical tumor suppressor. However, this definition is unsatisfactory because manipulation in vitro of BAP1 expression has often given unexpected and paradoxical results, complicating our understanding of its mechanisms of action. BAP1 absence (due to genetic, genomic, epigenomic or post-translational causes) was reported in about 60% of pleural MM. No studies so far have thoroughly investigated BAP1 expression in MMs arising from other sites. BAP1 expression is not associated to asbestos exposure, suggesting that its role in MM pathogenesis may be independent from the known asbestos-related pathways. Other clinicopathological associations are at this moment too weak to be conclusive, possibly due to limited tumor sample sizes, methodological differences in the studies or finally ethical differences of the analyzed populations. It appears, but remains unproven, that patients with germline BAP1 mutations have less aggressive MMs compared to sporadic MMs in which BAP1 mutations do not appear to influence prognosis. More experiments are urgently required to see whether BAP1 expression could be use in diagnostic, prognostic, or therapeutic settings. In fact, defining a therapeutically accessible synthetic lethal target in the setting of BAP1 loss could eventually benefit the approximately 40-60% of patients with BAP1 negative MMs. Even more speculatively, the same synthetic lethal target could be studied as chemoprevention drug targets in individuals with germline BAP1 mutations. The impact of this work obviously extends to other cancers with BAP1 mutations.

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    P1.22 - Poster Session 1 - Epidemiology, Etiology (ID 166)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P1.22-012 - Continuous exposure to chrysotile asbestos can cause transformation of human mesothelial cells via HMGB1 and TNF-α signaling. (ID 3478)

      09:30 - 16:30  |  Author(s): A. Napolitano

      • Abstract

      Background
      Background: Malignant mesothelioma is strongly associated with asbestos exposure. Among asbestos fibers, crocidolite is considered the most and chrysotile the least oncogenic. Chrysotile accounts for >90% of asbestos used worldwide but its capacity to induce malignant mesothelioma is still controversial.

      Methods
      Methods: Human mesothelial cells were exposed to crocidolite or chrysotile for a period of 48hr or 5 weeks, either in the presence of TNF–α or human macrophages in a co-culture system mimicking the process of recruitment and activation of inflammatory cells to sites of fiber deposition, which leads to the carcinogenesis of mesothelioma. Functional studies, as well as whole-genome wide expression profiling were performed to compare the molecular mechanisms and the carcinogenic potential of chrysotile and crocidolite.

      Results
      Results: We found that chrysotile and crocidolite exposures have similar effects on human mesothelial cells. Morphological and molecular alterations suggestive of epithelial-mesenchymal transition, such as E–cadherin down-regulation and β–catenin phosphorylation followed by nuclear translocation, were induced by chrysotile and crocidolite. Gene expression profiling data detected High-Mobility Group Box-1 protein (HMGB1) as a key regulator of the transcriptional alterations induced by both chrysotile and crocidolite. Crocidolite and chrysotile induced differential expression of 57 out of 28,869 genes interrogated by oligo-nucleotide microarrays and 13 were HMGB1 targeted genes. Crocidolite-induced gene alterations were sustained, while chrysotile effects returned to background levels in five weeks. Similarly, HMGB1 release in vivo progressively increased for 10 or more weeks following crocidolite exposure, while returned to background levels eight weeks from chrysotile exposure.

      Conclusion
      Conclusion: Our results show that chrysotile has the capacity to induce, in HM, molecular changes associated to MM development similar to those induced by crocidolite, but these changes are short lasting. The data suggest that HMGB1 and TNF–α are key mediators of these processes for both crocidolite and chrysotile. However a continuous administration of chrysotile was required for inducing sustained HMGB1 levels. These data support the hypothesis that the different bio-persistence of the two asbestos fibers influences their biological activities.