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

Our plain-English summary of CDKN2A copy number and p16 expression in malignant pleural mesothelioma in relation to asbestos exposure, by E. Kettunen, S. Savukoski, K. Salmenkivi, et al (BMC Cancer, 2019).

The study

• Authors: E. Kettunen, S. Savukoski, K. Salmenkivi, T. Böhling, E. Vanhala, E. Kuosma, S. Anttila, H. Wolff
• Journal: BMC Cancer
• Published: 2019;19(1):507
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study examined stored tumor tissue from 92 Caucasian patients with malignant pleural mesothelioma from Finnish hospitals. For 75, lung asbestos fibers had been counted by electron microscopy; fiber types were not named. Patients were grouped as high exposure (over 1 million fibers per gram of dry lung) or low exposure (0.5 million or less). The authors studied a gene region, CDKN2A, and its protein, p16. In tumor cells, p16 staining was not associated with fiber count. Stromal (supporting) cells were assessed only in non-sarcomatoid tumors; p16 staining was found there in 19 of 37 high-exposure patients (51.4%) versus 2 of 12 low-exposure patients (16.7%; p = 0.035). An abnormal CDKN2A copy number was found in 84% of 63 tumors overall. It was more common in high-exposure (34 of 36, 94%) than low-exposure tumors (10 of 14, 71%; p = 0.044). Changes at three other DNA regions earlier linked to asbestos in lung cancer were not frequent. The authors noted small case numbers. They concluded that mesotheliomas with high and low lung fiber counts may differ biologically.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of archived tumor tissue (tissue microarrays), using fluorescence in situ hybridization (FISH) for DNA copy number and immunohistochemistry for p16 protein, compared across lung asbestos fiber count groups
• Who was studied: 92 Caucasian patients with malignant pleural mesothelioma (epithelioid, sarcomatoid or biphasic), with tissue originally collected as diagnostic specimens in Central Hospitals in Finland. Lung fiber counts were available for 75 patients (Table 1: 53 high, 22 low). Seven non-mesothelioma tumors served as quality controls. Dates are not given.
• Exposure: Pulmonary asbestos fiber counts (fibers longer than 1 micrometre) measured by electron microscopy on autopsy lung tissue. Fiber types are not specified. High exposure was over 1 million fibers per gram dry lung (1.0 million or more in the tables), very high was 5 million or more, and low was 0.5 million or less. Eight cases between 0.5 and 1 million were excluded.
• Main results:
  • In mesothelioma tumor cells, p16 staining was not associated with lung asbestos fiber count (positive in 8 of 42, 19%, in the high group vs 5 of 15, 33%, in the low group; p = 0.453).
  • p16 staining in stromal cells was more frequent in the high-exposure group (19 of 37 evaluable patients, 51.4%) than in the low-exposure group (2 of 12, 16.7%; p = 0.035, Chi-Square). Sarcomatoid tumors were not evaluated for stromal staining.
  • Stromal p16 positivity was more frequent in the very-high-exposure group (5 million or more fibers per gram; 14 of 24, 58%) than in the low-exposure group (2 of 12, 17%; p = 0.018).
  • Staining in stroma but not in tumor cells was seen in 15 (39.5%) high-exposure patients vs 1 (8.3%) low-exposure patient (p = 0.048, Fisher exact test).
  • Of 63 tumors scored by FISH, 84% had an abnormal CDKN2A copy number. The most common abnormality was homozygous deletion, in 65%.
  • Abnormal CDKN2A copy number was associated with high lung fiber count: 34 of 36 (94%) in the high group vs 10 of 14 (71%) in the low group (p = 0.044, Fisher's Exact test, two-tailed).
  • The association was strongest in epithelioid mesothelioma: 31 of 32 (97%) high-exposure vs 4 of 7 (57%) low-exposure tumors abnormal (p = 0.014).
  • DNA copy number changes at 2p16, 9q33 and 19p13 were not frequent in mesothelioma, although the high-exposure group showed wider ranges of copy number than the low-exposure group.
• The authors' conclusion: The authors concluded that, because CDKN2A copy number and stromal p16 staining were associated with high asbestos exposure, there may be biological differences between mesotheliomas with high and low lung fiber counts.
• Limitations the authors state:
  • The match between CDKN2A abnormality and p16 staining in the low-exposure group rested on small case numbers.
  • The FISH probe also covered the MTAP and CDKN2B genes, while the antibody detected only p16. The authors said this could explain some lack of correlation between the two tests.
  • Few tumors had a normal CDKN2A copy number, which limited statistical comparison.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: CDKN2A, Pleural Mesothelioma, Asbestos Exposure, Lung Cancer, Fluorescence In Situ Hybridization (FISH), Immunohistochemistry, Fibers Per Gram, Mesothelioma.

Related studies

• Correlation of methylthioadenosine phosphorylase (MTAP) protein expression with MTAP and CDKN2A copy number in malignant pleural mesothelioma — D.B. Chapel, A.M. Dubuc, et al. (2021)
• BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas — N. Leblay, F. Leprêtre, et al. (2017)
• CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival — A.M. Krasinskas, D.L. Bartlett, et al. (2010)
• DNA copy number loss and allelic imbalance at 2p16 in lung cancer associated with asbestos exposure — E. Kettunen, M. Aavikko, et al. (2009)
• Genome-wide analysis of abdominal and pleural malignant mesothelioma with DNA arrays reveals both common and distinct regions of copy number alteration — A.C. Borczuk, J. Pei, et al. (2016)
• Genomic copy number alterations in 33 malignant peritoneal mesothelioma analyzed by comparative genomic hybridization array — P. Chirac, D. Maillet, et al. (2016)

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