Molecular alterations at 9q33.1 and polyploidy in asbestos-related lung cancer

Our plain-English summary of Molecular alterations at 9q33.1 and polyploidy in asbestos-related lung cancer, by P. Nymark, E. Kettunen, M. Aavikko, et al (Clinical Cancer Research, 2009).

The study

• Authors: P. Nymark, E. Kettunen, M. Aavikko, S. Ruosaari, E. Kuosma, E. Vanhala, K. Salmenkivi, R. Pirinen, A. Karjalainen, S. Knuutila, H. Wikman, S. Anttila
• Journal: Clinical Cancer Research
• Published: 2009;15(2):468-75
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: Asbestos causes DNA damage and the fibers, together with tobacco smoke, have a synergistic effect on lung cancer risk. We recently identified 18 chromosomal regions that showed differences in DNA copy number between the lung tumors of asbestos-exposed and nonexposed patients. One of the previously identified asbestos-associated chromosomal regions at 9q was further analyzed for allelic imbalance and DNA copy number alterations (CNA) in the lung tumors of asbestos-exposed and nonexposed patients. In addition, the ploidy level of the tumors was studied.

Experimental Design: Allelic imbalance was analyzed at 9q31.3-34.3 with 15 microsatellite markers in 52 lung tumor samples from asbestos-exposed and nonexposed patients. CNA at 9q32-34.3 were characterized by fluorescent in situ hybridization (FISH) with six bacterial artificial chromosome probes in 95 lung tumors. The ploidy level was analyzed in 100 lung tumors with FISH using three to five centromere probes.

Results: Allelic imbalance at 9q31.3-q34.3 was found in all asbestos-exposed patient tumors (100%, 17 of 17) compared with 64% (14 of 22) in the nonexposed cases (P = 0.005). The most significant difference was detected at 9q33.1 (P = 0.002). FISH results showed that also CNA were more frequent at 9q33.1 in the three major histologic types of non-small-cell lung tumors of exposed patients, and the association showed a dose-dependent trend (P = 0.03). Furthermore, we detected more frequent polyploidy among the exposed (48%, 28 of 58) than among the nonexposed (29%, 12 of 42) patient tumors (P < 0.05).

Conclusions: These results provide a basis for the development of a method to identify asbestos-related lung cancer on a molecular level.

In plain English

This Finnish laboratory study compared genetic changes in lung tumors from patients classed as asbestos-exposed or nonexposed by the asbestos fiber count measured in their lung tissue. Exposed patients had at least 1 million fibers per gram of dry lung tissue. Nonexposed patients had 0.5 million or fewer. The authors examined one part of chromosome 9, called 9q. An imbalance between the two inherited copies of this region was found in all 17 exposed patients' tumors that could be evaluated for this comparison, compared with 14 of 22 evaluable tumors (64%) from nonexposed patients. At the smaller region 9q33.1 the figures were 11 of 15 (73%) versus 4 of 19 (21%). In the three main types of non-small-cell lung cancer, changes in the number of copies at 9q33.1 were seen in 15 of 37 (41%) exposed and 6 of 34 (18%) nonexposed patients' tumors. These changes were more frequent at higher fiber counts. Polyploidy (extra sets of chromosomes) was found in 28 of 58 exposed (48%) and 12 of 42 nonexposed (29%) tumors. The authors concluded these changes could be of clinical interest in diagnosing asbestos-related lung cancer.

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 tumor samples from asbestos-exposed and nonexposed patients, using fragment analysis (allelic imbalance) and fluorescence in situ hybridization (FISH) for copy number changes and ploidy
• Who was studied: Finnish Caucasian patients with histologically confirmed primary lung cancer, from two sample collections. The first was 59 fresh-frozen surgical samples from Helsinki University Central Hospital in the 1990s. The second was 80 formalin-fixed paraffin-embedded samples sent to the Finnish Institute of Occupational Health for fiber counting in 1990-2006. By fiber count, 77 samples were classed as exposed and 62 as nonexposed. Allelic imbalance was analyzed in 52 tumors (23 exposed, 29 nonexposed), locus-specific FISH in 95 tumors, and ploidy in 100 tumors. Nearly all patients were male.
• Exposure: Pulmonary asbestos fiber concentration measured by electron microscopy with energy dispersive spectrometry. Exposed meant 1 million fibers per gram of dry lung tissue or more. Nonexposed meant 0.5 million or fewer. Cases between 0.5 and 0.99 million were excluded. Fiber types were not reported.
• Main results:
  • Of the 23 exposed and 29 nonexposed tumors analyzed, those with more than six informative markers were evaluated for allelic imbalance across the whole 9q31.3-34.3 region. Imbalance was found in 100% (17 of 17) of evaluable exposed patients' tumors and 64% (14 of 22) of evaluable nonexposed patients' tumors (P = 0.005, Fisher's exact test).
  • At 9q33.1, allelic imbalance was found in 73% (11 of 15) of exposed and 21% (4 of 19) of nonexposed patients' tumors (P = 0.002).
  • Every individual marker showed more frequent allelic imbalance in exposed (42-90%) than nonexposed (10-65%) tumors. The difference was statistically significant only at the TC repeat marker (P = 0.01).
  • In the three major non-small-cell lung cancer types (adenocarcinoma, squamous cell carcinoma, large cell carcinoma), copy number alterations at 9q33.1 occurred in 41% (15 of 37) of exposed and 18% (6 of 34) of nonexposed patients' tumors (P = 0.03).
  • In these non-small-cell tumors, copy number alterations at 9q33.1 rose with fiber count. They were seen in 18% (6 of 34) of nonexposed tumors, 35% (8 of 23) at 1 to 9.9 million fibers/g, and 50% (7 of 14) at 10 million fibers/g or more (P = 0.03, trend test).
  • When small-cell lung cancer and rare tumor types were included, the trend was similar but not statistically significant (P = 0.10).
  • Polyploidy was found in 48% (28 of 58) of exposed and 29% (12 of 42) of nonexposed patients' tumors (P less than 0.05).
  • No dose-dependent trend was seen for polyploidy.
• The authors' conclusion: The authors concluded that allelic imbalance and copy number changes at 9q33.1, and polyploidy, could be of clinical interest in diagnosing asbestos-related lung cancer. They suggested these changes might be combined with other markers in a test to separate asbestos-related from non-asbestos-related lung cancer.
• Limitations the authors state:
  • Histologic tumor types were not tested separately because of the small number of samples.
  • Small numbers of rare non-small-cell and small-cell lung cancers led the authors to restrict the copy number analysis to the three major non-small-cell types as a group.
  • The authors noted that chromosome 9 appears vulnerable to damage in general, so the changes may not be specific to asbestos.

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, Synergistic Effect, Fluorescence In Situ Hybridization (FISH).

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)
• Accumulation of genomic alterations in 2p16, 9q33.1 and 19p13 in lung tumours of asbestos-exposed patients — P. Nymark, M. Aavikko, et al. (2013)
• Long crocidolite asbestos fibers cause polyploidy by sterically blocking cytokinesis — C.G. Jensen, L.C. Jensen, et al. (1996)
• Bringing together evolution on serpentine and polyploidy: spatiotemporal history of the diploid-tetraploid complex of Knautia arvensis (Dipsacaceae) — F. Kolář, T. Fér, et al. (2012)
• Identification of specific gene copy number changes in asbestos-related lung cancer — P. Nymark, H. Wikman, et al. (2006)
• Induction of micronuclei, hyperdiploidy and chromosomal breakage affecting the centric/pericentric regions of chromosomes 1 and 9 in human amniotic fluid cells after treatment with asbestos and ceramic fibers — E. Dopp, M. Schuler, et al. (1997)

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