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

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

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.

Related collections

Most cited references 44

Record: found
Abstract: found
Article: not found

Molecular pathogenesis of malignant mesothelioma.

Yoshitaka Sekido (2013)

Malignant mesothelioma (MM) is an aggressive tumor arising primarily from the pleural or peritoneal cavities. It develops by asbestos exposure after a long latency, which is characterized by insidious growth and clinical presentation at an advanced stage of disease. MM is highly refractory to conventional therapies even with a combination of aggressive surgical intervention and multimodality strategies, with cure remaining elusive. Molecular genetic analysis has revealed several key genetic alterations, which are responsible for the development and progression of MM. The cyclin-dependent kinase inhibitor 2A/alternative reading frame (CDKN2A/ARF), neurofibromatosis type 2 (NF2) and BRCA1-associated protein-1 (BAP1) genes are the most frequently mutated tumor suppressor genes detected in MM cells; the alterations of the latter two are relatively characteristic of MM. Merlin, which is encoded by NF2, regulates multiple cell signaling cascades including the Hippo and mammalian target of rapamycin pathways, which regulate cell proliferation and growth. BAP1 is involved in histone modification and its inactivation induces the disturbance of global gene expression profiling. The discovery of a new familial cancer syndrome with germline mutation of BAP1 also indicates the importance of genetic factors in MM susceptibility. Meanwhile, although frequent expression and functional activations of oncogene products such as receptor tyrosine kinases are observed in MM cells, activating mutations of these genes are rare. With further comprehensive genome analyses, new genetic and epigenetic alterations in MM cells are expected to be revealed more precisely, and the new knowledge based on them will be applied for developing new diagnostic tools and new target therapies against MMs.

0 comments Cited 99 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: not found
Article: not found

Asbestos, asbestosis, and cancer, the Helsinki criteria for diagnosis and attribution 2014: recommendations.

Henrik Wolff, Tapio Vehmas, Panu Oksa … (2015)

0 comments Cited 78 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas.

Valerie Rusch, P Illei, Marc Ladanyi … (2003)

Homozygous deletions at chromosome region 9p21 targeting the CDKN2A gene have been reported as a common cytogenetic abnormality in mesothelioma. MTAP, a gene approximately 100-kb telomeric to CDKN2A, encodes methylthioadenosine phosphorylase, an enzyme essential in the salvage of cellular adenine and methionine, and its codeletion with CDKN2A has been reported in other tumors. The aim of this study was to define the prevalence of homozygous deletion of CDKN2A alone or in combination with MTAP in a large series of pleural mesothelioma. We used a fluorescent in situ hybridization assay for CDKN2A and MTAP on interphase nuclei in imprints of frozen tissue from 95 cases of pleural mesothelioma. Histologically, the cases were classified as epithelial (71), biphasic (19) and sarcomatous (5). In each experiment, a 9p21 locus specific probe and a chromosome 9 centromeric probe were used and fluorescent in situ hybridization signals for both probes were simultaneously recorded in at least 100 nuclei. Cases were considered homozygously deleted if both 9p21 signals were lost in at least 20% of nuclei. Overall, 70 cases (74%) had homozygous deletion of CDKN2A. MTAP was codeleted in 64 of these cases (91%). No case with MTAP deletion without CDKN2A deletion was identified. Homozygous loss of CDKN2A was seen in 49 of 71 epithelial (70%), 16 of 19 biphasic (89%), and 5 of 5 sarcomatous (100%) mesotheliomas. Homozygous deletion of CDKN2A is seen in the majority of pleural mesotheliomas, and MTAP is codeleted in most of these cases. Previous cell line studies have shown that loss of MTAP renders cells dependent on de novo synthesis of purine derivatives. Thus, the particularly high prevalence of MTAP codeletion in mesothelioma makes it an ideal candidate for trials of targeted therapy using inhibitors of de novo AMP synthesis (e.g., L-alanosine).

0 comments Cited 76 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Eeva Kettunen:

ORCID: http://orcid.org/0000-0001-5769-3010

+358-30-4742211 , eeva.kettunen@ttl.fi

Sauli Savukoski: sauli.savukoski@ttl.fi

Kaisa Salmenkivi: kaisa.salmenkivi@hus.fi

Tom Böhling: tom.bohling@helsinki.fi

Esa Vanhala: esa.vanhala@ttl.fi

Eeva Kuosma: eeva.kuosma@kolumbus.fi

Sisko Anttila: sisko.l.anttila@hus.fi

Henrik Wolff: henrik.wolff@ttl.fi

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 28 May 2019

Publication date PMC-release: 28 May 2019

Publication date Collection: 2019

Volume: 19

Electronic Location Identifier: 507

Affiliations

[1 ]ISNI 0000 0004 0410 5926, GRID grid.6975.d, Research and Service Centre for Occupational Safety, Finnish Institute of Occupational Health, PO Box 40, FI-00032 Työterveyslaitos, ; Helsinki, Finland

[2 ]Department of Pathology, University of Helsinki, and HUSLAB, Helsinki University Hospital, 00029 HUS, Helsinki, Finland

Author information

Eeva Kettunen http://orcid.org/0000-0001-5769-3010

Article

Publisher ID: 5652

DOI: 10.1186/s12885-019-5652-y

PMC ID: 6537412

SO-VID: 3d056ff3-7c67-40c1-8e3d-7e9010cdf915

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 9 November 2018

Date accepted : 29 April 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100005878, Terveyden Tutkimuksen Toimikunta;

Award ID: 115372

Award Recipient : Eeva Kettunen

Funded by: FundRef http://dx.doi.org/10.13039/501100009067, K. Albin Johanssons Stiftelse;

Funded by: FundRef http://dx.doi.org/10.13039/501100003128, Työsuojelurahasto;

Award ID: 109003

Award Recipient : Sisko Anttila

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: malignant pleural mesothelioma,cdkn2a,p16,tumor stroma,asbestos exposure

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: malignant pleural mesothelioma, cdkn2a, p16, tumor stroma, asbestos exposure

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

Read this article at

Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Karger: Oncology

Most cited references 44

Molecular pathogenesis of malignant mesothelioma.

Asbestos, asbestosis, and cancer, the Helsinki criteria for diagnosis and attribution 2014: recommendations.

Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas.

Author and article information

Contributors

Journal

Affiliations

Author information

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 282

Cited by 8

Most referenced authors 532