Comparison of DNA copy number changes in malignant mesothelioma, adenocarcinoma and large-cell anaplastic carcinoma of the lung

Our plain-English summary of Comparison of DNA copy number changes in malignant mesothelioma, adenocarcinoma and large-cell anaplastic carcinoma of the lung, by A.M. Björkqvist, L. Tammilehto, S. Nordling, et al (British Journal of Cancer, 1998).

The study

• Authors: A.M. Björkqvist, L. Tammilehto, S. Nordling, M. Nurminen, S. Anttila, K. Mattson, S. Knuutila
• Journal: British Journal of Cancer
• Published: 1998;77(2):260-9
• Cited by: 82 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The differential diagnosis of mesothelioma, primary adenocarcinomas and pleural metastases frequently causes problems. We have used the comparative genomic hybridization (CGH) technique on 34 malignant mesotheliomas and 30 primary lung carcinomas (adenocarcinoma, including bronchoalveolar carcinoma and large-cell anaplastic carcinoma) to compare their copy number changes and to evaluate the use of CGH to distinguish between these two types of tumour. In mesothelioma, gains of genetic material occurred as frequently as losses, whereas gains predominated over losses in carcinoma. In mesothelioma, the most frequent changes were losses in 4q, 6q and 14q and gains in 15q and 7p, whereas gains in 8q, 1q, 7p, 5p and 6p were the most common changes in carcinoma. Amplification of KRAS2 was detected in two adenocarcinomas by Southern blot analysis. CGH showed gains in 12p in the same tumours. Statistically significant differences between the two types of tumour were detected in chromosomes X, 1, 2p, 4, 8q, 10q, 12p, 14q, 15q and 18q. When comparing the frequency of gains and losses between mesothelioma and lung carcinoma using discriminant analysis, the sensitivity of CGH to differentiate mesotheliomas from lung carcinomas was 81% and the specificity 77%. The differences in DNA copy number changes between the two types of tumour suggest that they are genetically different tumour entities. Although CGH cannot be used as a definitive discriminatory method, we were able to distinguish between mesothelioma and lung carcinoma in a large proportion of the abnormal cases.

In plain English

This Finnish laboratory study used comparative genomic hybridization (CGH) to compare DNA gains and losses across chromosomes in two tumour groups. These were 34 malignant mesotheliomas (33 pleural, one peritoneal) and 30 primary lung carcinomas (adenocarcinoma, bronchoalveolar and large-cell anaplastic carcinoma). Twenty-four mesothelioma patients had a history of asbestos exposure. This was listed case by case, but findings were not compared by exposure. DNA changes were found in 27 of 34 mesotheliomas, where gains occurred as often as losses. They were found in 26 of 30 carcinomas, where gains outnumbered losses 4.6 to 1. The groups differed significantly in changes on chromosomes X, 1, 2p, 4, 8q, 10q, 12p, 14q, 15q and 18q. Among the 53 tumours with detected changes, classification by combined gains and losses reached 81% sensitivity and 77% specificity, with a 21% error rate (26% on cross-validation). The authors concluded that the differences suggest genetically different tumour entities, but that CGH cannot definitively tell them apart. They noted the subgroups were too small for reliable prediction models and no second tumour series was available for testing.

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 comparing DNA copy number changes in tumour specimens using comparative genomic hybridization (CGH), with Southern blot analysis of the KRAS2 gene and statistical (discriminant) analysis to test whether CGH can distinguish the tumour types
• Who was studied: 34 malignant mesotheliomas from patients treated at Helsinki University Central Hospital (5 fibromatous, 19 epithelial, 10 mixed; 33 pleural, 1 peritoneal) and 30 primary lung carcinomas (10 adenocarcinomas, 10 bronchoalveolar and 10 large-cell anaplastic carcinomas) from the files of the Department of Pathology, University of Helsinki. No study dates are given.
• Exposure: Asbestos exposure history was recorded for the mesothelioma patients only. Twenty-four had a history of asbestos exposure, 9 were not aware of any exposure, and exposure was not known for 1. Table 1 lists each mesothelioma patient's exposure status alongside that tumour's CGH findings, but the authors did not compare findings between exposed and unexposed patients. No fiber types, jobs or doses are given.
• Main results:
  • Mesothelioma: 27 of the 34 tumours showed DNA copy number changes, and gains occurred as frequently as losses.
  • Lung carcinoma: changes were found in 26 of the 30 tumours, and gains outnumbered losses by a ratio of 4.6:1.
  • In mesothelioma, the most common change was loss of DNA in the long arm of chromosomes 4 and 6, in 10 of 27 (37%) informative tumours.
  • In mesothelioma, the most frequent gain was in the long arm of chromosome 15 (q23-qter), in 9 of 27 (33%) informative cases.
  • In lung carcinoma, the most frequent change was a gain in the long arm of chromosome 8 (q23-qter), in 17 of 26 (65%) informative tumours.
  • Statistically significant differences between mesothelioma and lung carcinoma were seen in chromosomes X, 1, 2p, 4, 8q, 10q, 12p, 14q, 15q and 18q.
  • Gains in 15q were found in 30% of mesotheliomas and 4% of lung carcinomas (risk ratio 7.7, 95% CI 1.4-46.7).
  • Gains in 8q were found in 19% of mesotheliomas and 65% of lung carcinomas (risk ratio 0.28, 95% CI 0.12-0.61).
  • Differences in the overall number of gains and losses between mesothelioma and lung carcinoma were not statistically significant.
  • Linear discriminant analysis sorted the 53 informative tumours into six histological subgroups, with an overall misclassification rate of 47%.
  • Quadratic discriminant analysis misclassified 3 of 27 mesotheliomas and 9 of 26 lung carcinomas (sensitivity 89%, specificity 63%).
  • In the 53 informative tumours (27 mesotheliomas, 26 lung carcinomas), combining gains and losses in both chromosome arms gave an overall error rate of 21%, with 81% sensitivity and 77% specificity. On cross-validation, the error rate was 26%.
  • Within mesothelioma, a gain in 15q was more common in epithelial tumours (n = 14) than in the combined fibromatous and mixed group (n = 13) (risk ratio 6.5, 95% CI 1.3-39.3).
  • Southern blot analysis detected KRAS2 amplification in 2 of the 7 tumours with a 12p gain, both regular adenocarcinomas (3.7- and 8.2-fold). The analysis failed in the other five because of poor DNA quality.
• The authors' conclusion: The authors concluded that the differences in DNA copy number changes suggest mesothelioma and lung carcinoma are genetically different tumour entities. They added that CGH cannot be used as a definitive way to tell them apart, although it distinguished the two in 77% of the abnormal cases.
• Limitations the authors state:
  • The subgroups of classified tumours were too small to form reliable predictor models; there were only five fibromatous mesotheliomas.
  • There was no separate series of tumours for external validation of the model.
  • The size rule for the number of predictors was not met when four predictors were used to discriminate mesothelioma from lung carcinoma.
  • The normality assumption of discriminant analysis is not always valid in practice.
  • CGH cannot detect balanced translocations, inversions, small deletions or polyploidization.
  • CGH reveals only changes present in at least 50% of cells, so changes in a small proportion of cells are missed.
  • Losses in 9p may have been missed because of genetic variation within tumours.

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: Malignant Mesothelioma, Adenocarcinoma, Carcinoma, Differential Diagnosis, Mesothelioma.

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• DNA copy number loss and allelic imbalance at 2p16 in lung cancer associated with asbestos exposure — E. Kettunen, M. Aavikko, et al. (2009)
• 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)
• Gene expression profiling and gene copy-number changes in malignant mesothelioma cell lines — C. Zanazzi, R. Hersmus, et al. (2007)
• p40 is the best marker for diagnosing pulmonary squamous cell carcinoma: comparison with p63, cytokeratin 5/6, desmocollin-3, and sox2 — T. Tatsumori, K. Tsuta, et al. (2014)
• 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)

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