Accumulation of genomic alterations in 2p16, 9q33.1 and 19p13 in lung tumours of asbestos-exposed patients

Our plain-English summary of Accumulation of genomic alterations in 2p16, 9q33.1 and 19p13 in lung tumours of asbestos-exposed patients, by P. Nymark, M. Aavikko, J. Mäkilä, et al (Molecular Oncology, 2013).

The study

• Authors: P. Nymark, M. Aavikko, J. Mäkilä, S. Ruosaari, T. Hienonen-Kempas, H. Wikman, K. Salmenkivi, R. Pirinen, A. Karjalainen, E. Vanhala, E. Kuosma, S. Anttila, E. Kettunen
• Journal: Molecular Oncology
• Published: 2013;7(1):29-40
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

We have previously demonstrated an association between genomic alterations in 19p13, 2p16, and 9q33.1 and asbestos exposure in patients' lung tumours. This study detected allelic imbalance (AI) in these regions in asbestos-exposed lung cancer (LC) patients' histologically normal pulmonary epithelium. We extended the analyses of tumour tissue to cover a large LC patient cohort and studied DNA copy number alteration (CNA) and AI in 19p13, 2p16, and 9q33.1 for the first time in combination. We found both CNA and AI in ≥2/3 of the regions to be significantly and dose-dependently (P < 0.001) associated with pulmonary asbestos fibre count. Twenty percent of the exposed patients' LC showed CNA in ≥2/3 of the regions, whereas none of the non-exposed patients' LC showed CNA in more than one region. AI was evident in 89% of the exposed and in only 26% of the non-exposed patients' LC. The genomic alterations in 19p13, 2p16, and 9q33.1 in compilation identified asbestos-exposed patients' lung tumours better than each of the regions alone. These alterations form the basis for the development of a combinatorial molecular assay that could be used to identify asbestos-related LC.

Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

In plain English

This Finnish laboratory study compared DNA changes in three chromosome regions (2p16, 9q33.1, 19p13) in lung tumours of asbestos-exposed and non-exposed patients. The 225 patients were grouped by lung-tissue asbestos fibre count: exposed (126; at least 1.0 million fibres per gram of dry lung) or non-exposed (99; 0.5 million or fewer). Two changes were tested: allelic imbalance (an imbalance between the two copies of a DNA region) and copy number alteration. Allelic imbalance in at least two regions appeared in 17 of 19 exposed and 5 of 19 non-exposed patients' tumours. Copy number alteration, here DNA loss at 2p16 or 19p13 and loss or gain at 9q33.1, appeared in at least two regions in 11 of 55 exposed and none of 45 non-exposed patients' tumours. Counting either change, the affected share rose with fibre count, from 5 of 48 non-exposed to 14 of 23 at 10 million fibres per gram or more. Smoking history was unavailable for most patients, so results were not adjusted for it. The authors concluded that asbestos-related lung cancer may be identifiable at a molecular level.

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 molecular genetic study comparing lung tumours, and in a subset the adjacent histologically normal airway lining, of asbestos-exposed and non-exposed lung cancer patients. The tests were allelic imbalance by fragment analysis and DNA copy number by fluorescence in situ hybridization (FISH).
• Who was studied: Primary lung tumours from 225 Finnish caucasian patients (216 males, 9 females): 126 asbestos-exposed and 99 non-exposed. There were two collections. The first was 64 patients operated on at Helsinki University Central Hospital in 1990 to 1996. The second was 161 patients whose lung tissue had been sent to the Finnish Institute of Occupational Health in 1990 to 2006 for fibre counts. Normal bronchial and bronchiolar epithelium was studied in 25 patients (12 exposed, 13 non-exposed).
• Exposure: Asbestos fibres counted in lung tissue by scanning electron microscopy. The groups were:
• non-exposed: 0.5 million fibres per gram of dry lung or fewer
• exposed: at least 1.0 million
• highly exposed: at least 5.0 million
• very highly exposed: at least 10.0 million

In the paraffin-embedded specimens, amphiboles were found in all but one case and chrysotile in five percent of cases. Samples with counts between 0.5 and 1 million fibres per gram were not collected.

• Main results:
  • Allelic imbalance in at least two of the three regions was found in 17 of 19 (89%) exposed patients' tumours and 5 of 19 (26%) non-exposed patients' tumours (P less than 0.001).
  • Allelic imbalance in at least two of the three regions was seen in all 12 (100%) very highly exposed patients' tumours (10 million fibres per gram or more) and in 5 of 7 (71%) exposed patients' tumours (1 to 9.99 million fibres per gram).
  • Copy number alteration was counted as DNA loss at 2p16 or 19p13, and as loss or gain at 9q33.1. Such alteration in at least two of the three regions was found in 11 of 55 (20%) exposed patients' tumours and in none of 45 non-exposed patients' tumours (P less than 0.001).
  • Copy number alteration in at least two regions increased with fibre count (trend P less than 0.01):
• highly exposed patients' tumours (5 million fibres per gram or more): 7 of 33 (21%)
• exposed patients' samples: 4 of 22 (18%)
• non-exposed patients' samples: 0 of 45
  • Tumours with either allelic imbalance or copy number alteration in at least two regions rose with fibre count (trend P less than 0.001):
• non-exposed: 5 of 48 (10%)
• exposed: 5 of 23 (22%)
• highly exposed: 7 of 17 (41%)
• very highly exposed: 14 of 23 (61%)
  • Looking at one region at a time across all lung cancer types, DNA loss in 19p13 was significantly associated with asbestos exposure (P = 0.01). Loss in 2p16 and copy number alteration in 9q33.1 were not.
  • Allelic imbalance was detected in histologically normal bronchial and bronchiolar epithelium of the 25 patients studied. In this epithelium material, it was not significantly associated with asbestos exposure.
• The authors' conclusion: The authors concluded that the combined alterations in 19p13, 2p16 and 9q33.1 identified asbestos-exposed patients' lung tumours better than any single region. They concluded that it may be possible to identify asbestos-related lung cancer at a molecular level, and that the findings could form the basis of a combined molecular test.
• Limitations the authors state:
  • Smoking status was missing for the second tumour group (161 patients), so no multivariate analysis was done.
  • Fibre types were not considered in the analysis because too few samples contained chrysotile to be tested.
  • Histological subgroups were relatively small.
  • It is not known how many tumours in the exposed group were truly asbestos-related, so sensitivity values could only be estimated.

Topics

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

Medical terms in this study, explained in our Lexicon: Asbestos Exposure, Lung Cancer, Epithelium.

Related studies

• DNA copy number loss and allelic imbalance at 2p16 in lung cancer associated with asbestos exposure — E. Kettunen, M. Aavikko, et al. (2009)
• Molecular alterations at 9q33.1 and polyploidy in asbestos-related lung cancer — P. Nymark, E. Kettunen, et al. (2009)
• Gene expression and copy number profiling suggests the importance of allelic imbalance in 19p in asbestos-associated lung cancer — H. Wikman, S. Ruosaari, et al. (2007)
• Genomic copy number alterations in 33 malignant peritoneal mesothelioma analyzed by comparative genomic hybridization array — P. Chirac, D. Maillet, et al. (2016)
• Aberrations of chromosome 19 in asbestos-associated lung cancer and in asbestos-induced micronuclei of bronchial epithelial cells in vitro — S.T. Ruosaari, P.E. Nymark, et al. (2008)
• Translocation (2;3)(p21;p26) as the sole anomaly in a benign localized fibrous mesothelioma — F. Mertens, R. Willén, et al. (1996)

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