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

Abstract

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.

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

“…Aberrant copy number alterations in CDKN2A and p16 arm identified with sequencing approaches were confirmed in other studies through fluorescent in-situ hybridization (FISH) and IHC and they were associated with higher asbestos fiber exposure (140).…”

CDKN2A Determines Mesothelioma Cell Fate to EZH2 Inhibition

“…Another common genetic alteration in MPM is the homozygous deletion of the 9p21 locus, within a cluster of genes that includes CDKN2A (cyclin-dependent kinase inhibitor 2A) encoding p16 ink4a (10,23,24). Heterozygous deletion of CDKN2A is also commonly observed, sometimes at higher levels than homozygous deletion, however, few reports have addressed its role in MPM (25)(26)(27).…”

Prognostic Value of Ki67 Percentage, WT-1 Expression and p16/CDKN2A Deletion in Diffuse Malignant Peritoneal Mesothelioma: A Single-Centre Cohort Study

“…Some works reported that deletion and asbestos exposure were not associated [30][31][32]. Instead, more recently, some authors suggested a different biology of the tumour in patients with or without asbestos exposure [24,33]. As no conclusive results have been obtained, this topic remains an important point warranting in-depth investigation.…”

“…The CDKN2A alteration is quite frequent in MM [24]. The loss of p16 protein may be due to homozygous deletion, promoter methylation or point mutations.…”