DNA copy number loss and allelic imbalance at 2p16 in lung cancer associated with asbestos exposure

Our plain-English summary of DNA copy number loss and allelic imbalance at 2p16 in lung cancer associated with asbestos exposure, by E. Kettunen, M. Aavikko, P. Nymark, et al (British Journal of Cancer, 2009).

The study

• Authors: E. Kettunen, M. Aavikko, P. Nymark, S. Ruosaari, H. Wikman, E. Vanhala, K. Salmenkivi, R. Pirinen, A. Karjalainen, E. Kuosma, S. Anttila
• Journal: British Journal of Cancer
• Published: 2009;100(8):1336-42
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Five to seven percent of lung tumours are estimated to occur because of occupational asbestos exposure. Using cDNA microarrays, we have earlier detected asbestos exposure-related genomic regions in lung cancer. The region at 2p was one of those that differed most between asbestos-exposed and non-exposed patients. Now, we evaluated genomic alterations at 2p22.1-p16.1 as a possible marker for asbestos exposure. Lung tumours from 205 patients with pulmonary asbestos fibre counts from 0 to 570 million fibres per gram of dry lung, were studied by fluorescence in situ hybridisation (FISH) for DNA copy number alterations (CNA). The prevalence of loss at 2p16, shown by three different FISH probes, was significantly increased in lung tumours of asbestos-exposed patients compared with non-exposed (P=0.05). In addition, a low copy number loss at 2p16 associated significantly with high-level asbestos exposure (P=0.02). Furthermore, 27 of the tumours were studied for allelic imbalances (AI) at 2p22.1-p16.1 using 14 microsatellite markers and also AI at 2p16 was related to asbestos exposure (P=0.003). Our results suggest that alterations at 2p16 combined with other markers could be useful in diagnosing asbestos-related lung cancer.

In plain English

This Finnish laboratory study examined chromosome 2 in lung tumours from 205 lung cancer patients. Each patient's lung asbestos fibre count had been measured by electron microscopy. Patients with at least 1.0 million fibres per gram of dry lung counted as asbestos-exposed, those with at least 5 million as highly exposed, and those with 0.5 million or fewer as non-exposed. Using three DNA probes, the authors found DNA loss at a region called 2p16 more common in exposed patients' tumours. No probe showed loss in 32 of 41 (78%) highly exposed patients' tumours, 24 of 29 (83%) from patients with 1 to under 5 million fibres per gram, and 65 of 71 (91%) non-exposed patients' tumours (P = 0.05, both exposed groups versus non-exposed). In 27 tumours, allelic imbalance at 2p16 was also more frequent in exposed patients (P = 0.003). Gains of DNA at 2p21 were common regardless of exposure. The authors concluded that the 2p16 changes, combined with other markers, may help diagnose asbestos-associated lung tumours. They noted small subgroup numbers and that sensitivity could not be estimated.

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 genetic study of lung tumour tissue comparing asbestos-exposed and non-exposed patients, using fluorescence in situ hybridisation (FISH) for DNA copy number changes and microsatellite fragment analysis for allelic imbalance
• Who was studied: 205 lung cancer patients in Finland. 81 had fresh-frozen tumour samples from surgery during 1990–1996 at Helsinki University Central Hospital. 124 had formalin-fixed paraffin-embedded samples from various Finnish hospitals. Most were male (119 of 124 and 73 of 81). A subgroup of 27 patients (13 exposed, 14 non-exposed) was studied for allelic imbalance.
• Exposure: Asbestos fibre counts in lung tissue measured by electron microscopy with energy dispersive spectrometry. Exposed meant at least 1.0 million fibres per gram of dry lung, highly exposed at least 5 million, and non-exposed 0.5 million or fewer. The median count among exposed patients was 6.6 million per gram (range 1.0–570 million). The article does not report fibre types for the patients.
• Main results:
  • With the RP11-703K23 probe at 2p16.3, losses (compared with no change) were significantly associated with asbestos exposure (P = 0.03), and more so among highly exposed patients (P = 0.02). Losses with this probe occurred in 6 of 41 (15%) highly exposed patients' tumours, 2 of 29 (7%) tumours from patients with 1 to under 5 million fibres per gram, and 1 of 64 (2%) non-exposed patients' tumours.
  • With the three 2p16 probes combined, no probe showed loss in 32 of 41 (78%) highly exposed patients' tumours, 24 of 29 (83%) tumours from patients with 1 to under 5 million fibres per gram, and 65 of 71 (91%) non-exposed patients' tumours. P = 0.05 for the highly exposed and exposed groups together versus non-exposed; P = 0.04 for highly exposed versus non-exposed.
  • The authors estimated that the specificity of 2p16 copy number losses for detecting asbestos-related lung tumours would be 93%. They stated that sensitivity could not be estimated.
  • In the 27 tumours studied for allelic imbalance on 2p, imbalance was on average more frequent in exposed patients' tumours (52%) than in non-exposed patients' tumours (32%). At marker D2S123 it occurred in 63% of exposed and 0% of non-exposed patients' tumours (P = 0.08). Imbalance at 2p16, scored using five markers together, was significantly more frequent in exposed patients (P = 0.003).
  • Low copy number gains at 2p21 were frequent regardless of exposure status. No significant association with asbestos was found for gains.
• The authors' conclusion: The authors concluded that copy number loss and allelic imbalance at 2p16.3–p16.2 are associated with asbestos exposure in lung tumours, while low-level gains at 2p21 are common in lung cancer in general. They suggested that alterations at 2p16, combined with other markers such as alterations at 19p13 and 9q33.1, could be useful in diagnosing asbestos-related lung cancer.
• Limitations the authors state:
  • Case numbers in each histological tumour type were small. Only squamous cell carcinoma showed significant P-values in the subgroup comparisons.
  • Sensitivity could not be estimated, because it is not known which cancers in the exposed group were caused by asbestos.
  • Because cells overlapped, fewer than 100 cells could be counted in some specimens: 50–100 cells in 19% of tissue microarray specimens, and 30–50 cells in 12% of tissue microarray and 35% of biopsy specimens.

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: Lung Cancer, Asbestos Exposure, Fluorescence In Situ Hybridization (FISH).

Related studies

• 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)
• Accumulation of genomic alterations in 2p16, 9q33.1 and 19p13 in lung tumours of asbestos-exposed patients — P. Nymark, M. Aavikko, et al. (2013)
• Comparison of DNA copy number changes in malignant mesothelioma, adenocarcinoma and large-cell anaplastic carcinoma of the lung — A.M. Björkqvist, L. Tammilehto, et al. (1998)
• Identification of specific gene copy number changes in asbestos-related lung cancer — P. Nymark, H. Wikman, et al. (2006)
• DNA copy number changes in familial malignant mesothelioma — V. Ascoli, Y. Aalto, et al. (2001)
• Molecular alterations at 9q33.1 and polyploidy in asbestos-related lung cancer — P. Nymark, E. Kettunen, et al. (2009)

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