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

Eeva Kettunen,Eeva Kuosma,Sisko Anttila,Sauli Savukoski,Kaisa Salmenkivi,Tom Böhling,Esa Vanhala,Henrik Wolff

doi:10.1186/s12885-019-5652-y

Abstract

BackgroundDeletion 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.MethodsWe 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.ResultsWe 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.ConclusionsWe 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.

Highlights

Deletion of the CDKN2A locus is centrally involved in the development of several malignancies
As we have earlier shown in lung cancer asbestos exposure-related accumulation of copy number alterations in 2p16, 9q33.1 and 19p13 [29, 30], we studied the same loci in malignant pleural mesothelioma (MPM)
DNA copy numbers were evaluated in genomic regions 2p16, 9q33.1, and 19p13 that earlier in lung cancer have been found with accumulating changes that associated with asbestos exposure [29]

Summary

Introduction

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. 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. Malignant pleural mesothelioma (MPM) is a rare but deadly tumor type that is strongly associated with patients’ asbestos exposure [2]. In MPM, deletion of CDKN2A is the most frequently detected chromosomal change and the most common cause for p16 protein inactivation (reviewed in [8]). Other genomic alterations (or their protein products) common in MPM such as in BAP1 (BRCA1 associated protein 1), MTAP (methylthioadenosine phosphorylase) and NF2 (neurofibromin 2) have been studied to find out the most valuable marker combinations for differential diagnosis in MPM [25]

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Conclusion