Gene expression and copy number profiling suggests the importance of allelic imbalance in 19p in asbestos-associated lung cancer

Our plain-English summary of Gene expression and copy number profiling suggests the importance of allelic imbalance in 19p in asbestos-associated lung cancer, by H. Wikman, S. Ruosaari, P. Nymark, et al (Oncogene, 2007).

The study

• Authors: H. Wikman, S. Ruosaari, P. Nymark, V.K. Sarhadi, J. Saharinen, E. Vanhala, A. Karjalainen, J. Hollmén, S. Knuutila, S. Anttila
• Journal: Oncogene
• Published: 2007;26(32):4730-7
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Asbestos is a pulmonary carcinogen known to give rise to DNA and chromosomal damage, but the exact carcinogenic mechanisms are still largely unknown. In this study, gene expression arrays were performed on lung tumor samples from 14 heavily asbestos-exposed and 14 non-exposed patients matched for other characteristics. Using a two-step statistical analysis, 47 genes were revealed that could differentiate the tumors of asbestos-exposed from those of non-exposed patients. To identify asbestos-associated regions with DNA copy number and expressional changes, the gene expression data were combined with comparative genomic hybridization microarray data. As a result, a combinatory profile of DNA copy number aberrations and expressional changes significantly associated with asbestos exposure was obtained. Asbestos-related areas were detected in 2p21-p16.3, 3p21.31, 5q35.2-q35.3, 16p13.3, 19p13.3-p13.1 and 22q12.3-q13.1. The most prominent of these, 19p13, was further characterized by microsatellite analysis in 62 patients for the differences in allelic imbalance (AI) between the two groups of lung tumors. 79% of the exposed and 45% of the non-exposed patients (P=0.008) were found to be carriers of AI in their lung tumors. In the exposed group, AI in 19p was prevalent regardless of the histological tumor type. In adenocarcinomas, AI in 19p appeared to occur independently of the asbestos exposure.

In plain English

This Finnish laboratory study compared lung tumors of asbestos-exposed and non-exposed patients. Exposure was judged from work history and lung fiber counts; fiber types are not named. In tumors from 14 heavily exposed and 14 non-exposed men, the activity of 47 genes sorted the tumors by exposure group. Adding copy-number data from their earlier study, the authors found six differing chromosome regions, the largest on chromosome 19p. They then tested 19p for allelic imbalance in tumors from 62 men. Imbalance was found in 26 of 33 heavily or moderately exposed patients (79%) and 13 of 29 non-exposed (45%), P = 0.008. In adenocarcinomas the rates were similar: 9 of 13 exposed (69%) versus 8 of 12 non-exposed (67%). In all other tumor types pooled, they were 17 of 20 (85%) versus 5 of 17 (29%). The authors concluded that tumors of asbestos-exposed patients have a distinct gene expression profile, with regions such as 19p significantly associated with exposure. They noted a high chance of false positives with thousands of genes and few patients, and that small groups limited subtype comparisons.

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) study comparing lung tumors from asbestos-exposed and non-exposed patients. It used gene expression microarrays, combined them with comparative genomic hybridization (CGH) array data from the authors' earlier study, and followed up with microsatellite analysis for allelic imbalance on chromosome 19p.
• Who was studied: Finnish Caucasian patients with histologically confirmed primary lung cancer and no previous malignancies. The gene expression analysis covered 14 heavily asbestos-exposed and 14 non-exposed male patients, matched for other characteristics. The microsatellite analysis covered 62 male patients: 25 heavily exposed, 8 moderately exposed and 29 non-exposed. The article does not give dates.
• Exposure: Asbestos exposure, with no fiber type specified. It was estimated by work-history interview and by asbestos fiber concentration in lung tissue. Heavy exposure meant a definite or probable occupational exposure history plus more than 5 million fibers per gram of dry lung tissue. Moderate exposure meant 1 to 5 million fibers per gram. Non-exposed meant that neither the history nor the fiber count indicated exposure.
• Main results:
  • In the 28 tumors studied by gene expression arrays, a set of 47 genes classified the tumors according to the patients' asbestos-exposure status.
  • Combining gene expression with DNA copy-number data identified six chromosome regions with exposure-related changes at both levels.
  • The largest region, 19p13.3 to p13.1, showed loss and downregulation of genes in tumors of exposed patients and gain in tumors of non-exposed patients.
  • Allelic imbalance on 19p was found in about 80% (20/25) of heavily exposed patients' tumors and 45% (13/29) of non-exposed patients' tumors (P = 0.0045).
  • Allelic imbalance on 19p was found in 75% (6/8) of moderately exposed patients' tumors.
  • With heavily and moderately exposed patients combined, allelic imbalance on 19p was found in 26/33 (79%) of exposed and 13/29 (45%) of non-exposed patients (P = 0.008, permutation test).
  • In adenocarcinomas, allelic imbalance was found in 9/13 (69%) of exposed and 8/12 (67%) of non-exposed patients (P = 1.0).
  • In all tumor types other than adenocarcinoma, pooled together, allelic imbalance was found in 17/20 (85%) of exposed and 5/17 (29%) of non-exposed patients (P = 0.0004). The individual non-adenocarcinoma types were too few for separate statistical analysis.
  • For 11 of the 19 individual microsatellite markers, the frequency of alterations was significantly higher in tumors of asbestos-exposed patients than in tumors of non-exposed patients.
  • Microsatellite instability was found in 10% (3/29) of non-exposed patients. Because instability was seen among moderately exposed and non-exposed patients, the authors judged it not to be a major factor in asbestos-related cancer.
• The authors' conclusion: The authors concluded that lung carcinomas of asbestos-exposed patients have a distinct gene expression profile, with certain chromosomal regions such as 19p significantly associated with the exposure.
• Limitations the authors state:
  • Analyzing thousands of genes in few patients gives a big chance of false-positive results. The authors correlated the expression data with CGH data to address this.
  • Microsatellite analysis cannot distinguish allelic gain from loss, so the authors state that the association of 19p with asbestos exposure may be underestimated.
  • Group sizes were too small for a more thorough comparison between lung cancer subtypes.

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, Carcinogenic, Asbestos Exposure, Adenocarcinoma.

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)
• Gene expression profiling and gene copy-number changes in malignant mesothelioma cell lines — C. Zanazzi, R. Hersmus, et al. (2007)
• Identification of specific gene copy number changes in asbestos-related lung cancer — P. Nymark, H. Wikman, et al. (2006)
• 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)
• Copy number gains on 5p15, 6p11-q11, 7p12, and 8q24 are rare in sputum cells of individuals at high risk of lung cancer — E. Kettunen, K. Salmenkivi, et al. (2006)

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