Malignant Mesothelioma: Molecular Markers

Kettunen, Eeva; Knuutila, Sakari; Sarhadi, Virinder

doi:10.1007/978-3-030-30766-0_18

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“…Asbestos exposure causes mechanical and oxidative DNA damage and is linked to genomic alterations [1, 2]. In mouse studies, MM formation through asbestos exposure has shown a significant role of alterations in Cdkn2a/Arf [37] and deletion of CDKN2A is the most frequently detected chromosomal change in human MPM [8]. Fiber-induced CDKN2A disruption has also been observed in a study in which mesothelioma was induced in mice by instillation of either asbestos fibers or long-fiber carbon nanotube (CNTs) into the pleural cavities [38].…”

Section: Discussionmentioning

confidence: 99%

“…Up to 80–90% of MPM in men is estimated to be associated with asbestos exposure [7]. In MPM, deletion of CDKN2A is the most frequently detected chromosomal change and the most common cause for p16 protein inactivation (reviewed in [8]). Hypermethylation of CDKN2A as a cause of loss of p16 expression in MPM has been reported in a minority of cases [9, 10].…”

Section: Introductionmentioning

confidence: 99%

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CDKN2A copy number and p16 expression in malignant pleural mesothelioma in relation to asbestos exposure

et al. 2019

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Background Deletion of the CDKN2A locus is centrally involved in the development of several malignancies. In malignant pleural mesothelioma (MPM), it is one of the most frequently reported genomic alteration. MPM is strongly associated with a patients’ asbestos exposure. However, the status of CDKN2A and the expression of the corresponding protein, p16, in relation to MPM patient’s asbestos exposure is poorly known. Copy number alterations in 2p16, 9q33.1 and 19p13 have earlier been shown to accumulate in lung cancer in relation to asbestos exposure but their status in MPM is unclear. Methods We studied DNA copy numbers for CDKN2A using fluorescence in situ hybridization (FISH) and p16 expression by immunohistochemistry (IHC) in 92 MPM patients, 75 of which with known asbestos exposure status. We also studied, in MPM, copy number alterations in 2p16, 9q33.1 and 19p13 by FISH. Results We were unable to detect an association between p16 expression and pulmonary asbestos fiber count in MPM tumor cells. However, significantly more MPM patients with high pulmonary asbestos fiber count (> 1 million fibers per gram [f/g]) had stromal p16 immunoreactivity than MPM of patients with low exposure (≤ 0.5 million f/g) (51.4% vs 16.7%; p = 0.035, Chi-Square). We found that an abnormal copy number of CDKN2A in MPM tumor cells associated with a high pulmonary asbestos fiber count ( p = 0.044, Fisher’s Exact test, two-tailed). In contrast to our earlier findings in asbestos associated lung cancer, DNA copy number changes in 2p16, 9q33 and 19p13 were not frequent in MPM although single cases with variable copy numbers on those regions were seen. Conclusions We found two instances where the gene locus CDKN2A or its corresponding protein expression, is associated with high asbestos exposure levels. This suggests that there may be biological differences between the mesotheliomas with high pulmonary asbestos fiber count and those with low fiber count. Electronic supplementary material The online version of this article (10.1186/s12885-019-5652-y) contains supplementary material, which is available to authorized users.

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