Research and Service Centre for Occupational Safety, Finnish Institute of Occupational Health, PO Box 40, FI-00032 Työterveyslaitos, Helsinki, Finland.
Department of Pathology, University of Helsinki, and HUSLAB, Helsinki University Hospital, 00029 HUS, Helsinki, Finland.
BMC Cancer. 2019 May 28;19(1):507. doi: 10.1186/s12885-019-5652-y.
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.
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.
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.
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.
CDKN2A 基因座缺失是多种恶性肿瘤发生的核心因素。在恶性胸膜间皮瘤（MPM）中，它是最常报道的基因组改变之一。MPM 与患者的石棉暴露密切相关。然而，CDKN2A 的状态以及相应的蛋白质 p16 在 MPM 患者石棉暴露中的表达情况知之甚少。先前已经表明，2p16、9q33.1 和 19p13 上的拷贝数改变与石棉暴露相关的肺癌中会累积，但它们在 MPM 中的状态尚不清楚。
我们使用荧光原位杂交（FISH）研究了 92 名 MPM 患者的 CDKN2A 基因拷贝数，其中 75 名患者已知石棉暴露状态。我们还通过 FISH 研究了 MPM 中 2p16、9q33.1 和 19p13 的拷贝数改变。
我们未能检测到 MPM 肿瘤细胞中 p16 表达与肺石棉纤维计数之间的关联。然而，高肺石棉纤维计数（> 100 万纤维/克 [f/g]）的 MPM 患者的基质 p16 免疫反应性明显高于低暴露（≤ 0.5 万 f/g）的 MPM 患者（51.4%比 16.7%；p = 0.035，卡方检验）。我们发现 MPM 肿瘤细胞中 CDKN2A 的异常拷贝数与高肺石棉纤维计数相关（p = 0.044，Fisher 精确检验，双侧）。与我们之前在石棉相关肺癌中的发现相反，尽管在这些区域观察到了不同拷贝数的单个病例，但 2p16、9q33 和 19p13 上的 DNA 拷贝数改变在 MPM 中并不常见。
我们发现有两个实例，基因座 CDKN2A 或其相应的蛋白质表达与高石棉暴露水平相关。这表明高肺石棉纤维计数的间皮瘤与低纤维计数的间皮瘤之间可能存在生物学差异。
