ADAM28: a potential oncogene involved in asbestos-related lung adenocarcinomas

Our plain-English summary of ADAM28: a potential oncogene involved in asbestos-related lung adenocarcinomas, by C.M. Wright, J.E. Larsen, N.K. Hayward, et al (Genes, Chromosomes & Cancer, 2010).

The study

• Authors: C.M. Wright, J.E. Larsen, N.K. Hayward, M.U. Martins, M.E. Tan, M.R. Davidson, S.M. Savarimuthu, R.E. McLachlan, L.H. Passmore, M.N. Windsor, B.E. Clarke, E.E. Duhig, I.A. Yang, R.V. Bowman, K.M. Fong
• Journal: Genes, Chromosomes & Cancer
• Published: 2010;49(8):688-98
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Asbestos-related lung cancer accounts for 4-12% of all lung cancers worldwide. Since putative mechanisms of carcinogenesis differ between asbestos and tobacco induced lung cancers, tumors induced by the two agents may be genetically distinct. To identify gene expression biomarkers associated with asbestos-related lung tumorigenicity we performed gene expression array analysis on tumors of 36 patients with primary lung adenocarcinoma, comparing 12 patients with lung asbestos body counts above levels associated with urban dwelling (ARLC-AC: asbestos-related lung cancer-adenocarcinoma) with 24 patients with no asbestos bodies (NARLC-AC: non-asbestos related lung cancer-adenocarcinoma). Genes differentially expressed between ARLC-AC and NARLC-AC were identified on fold change and P value, and then prioritized using gene ontology. Candidates included ZNRF3, ADAM28, PPP1CA, IRF6, RAB3D, and PRDX1. Expression of these six genes was technically and biologically replicated by qRT-PCR in the training set and biologically validated in three independent test sets. ADAM28, encoding a disintegrin and metalloproteinase domain protein that interacts with integrins, was consistently upregulated in ARLC across all four datasets. Further studies are being designed to investigate the possible role of this gene in asbestos lung tumorigenicity, its potential utility as a marker of asbestos related lung cancer for purposes of causal attribution, and its potential as a treatment target for lung cancers arising in asbestos exposed persons.

In plain English

This laboratory study, from The Prince Charles Hospital in Queensland, Australia, compared gene activity in lung adenocarcinoma tumors from 36 patients. Twelve had 20 or more asbestos bodies per gram wet weight of lung tissue (classed as moderately exposed) and 24 had none. Using gene expression microarrays, the authors found 89 probes that differed between the groups at P less than 0.001, where 20 would be expected by chance. They chose six candidate genes and rechecked them with a second method (qRT-PCR), and four held up. They then checked the candidates in three further datasets: 58 more adenocarcinomas from their own tumor bank, 28 lung tumors from an earlier study by Wikman and colleagues, and published data on cell lines exposed to crocidolite. Only ADAM28 was consistently more active in the asbestos-related groups across all datasets. The authors concluded that ADAM28 is a potential asbestos-related cancer biomarker. They said further experiments are needed to confirm whether the change is due to asbestos independent of tobacco smoke, since most asbestos-exposed patients had also smoked.

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 gene expression study comparing lung tumors from patients with and without asbestos bodies in the lung (microarray analysis), with candidate genes rechecked by qRT-PCR and tested in three independent datasets, one of which was asbestos-exposed cell line data
• Who was studied: Training set of 36 patients with primary lung adenocarcinoma at The Prince Charles Hospital, Queensland, Australia: 12 with 20 or more asbestos bodies per gram wet weight of lung (asbestos-related) and 24 with 0. Test sets: 58 further adenocarcinomas from the same tumor bank (28 asbestos-related, 30 not); 28 lung tumors of mixed types from the Wikman study (14 heavily exposed, 14 not); and three cell lines from the Nymark study. Study dates were not given.
• Exposure: Asbestos burden measured as asbestos bodies per gram wet weight of lung tissue by bleach digestion. The cut-off was 20, a level the authors cite as typical of urban dwellers without occupational exposure. Fiber type was not specified for the patients. In the cell line dataset, cells were exposed to crocidolite for 1 to 168 hours.
• Main results:
  • In the 36-patient training set, 89 probes differed between asbestos-related and non-asbestos tumors at P less than 0.001, where 20 would be expected by chance. Most were more active in the asbestos-related tumors.
  • Selecting genes with at least a 1.5-fold difference left 20 genes. Six with known function (ADAM28, PPP1CA, RAB3D, IRF6, ZNRF3, PRDX1) were taken forward.
  • On recheck by qRT-PCR in the training set, four of six candidates were replicated, all more active in asbestos-related tumors: PRDX1 (microarray fold change 1.73, qRT-PCR 1.39), ADAM28 (2.26; 1.65), PPP1CA (1.53; 1.73) and ZNRF3 (1.99; 1.13).
  • In the independent test set of 58 adenocarcinomas (28 asbestos-related, 30 not), higher expression of PRDX1 and ADAM28 was confirmed. The article prints fold changes of 3.18 for PRDX1 and 1.25 for ADAM28.
  • In the Wikman dataset of 28 lung cancers, ADAM28 (fold change 1.38), RAB3D (1.25) and IRF6 (1.43) were more active in exposed cases. PRDX1 (1.00) and PPP1CA (0.99) were not.
  • In the Nymark cell line data (cells exposed to crocidolite), ADAM28 was consistently more active. ZNRF3, PPP1CA, RAB3D and IRF6 showed no consistent increase.
  • Pathway analysis found biological processes over-represented in asbestos-related tumors, including immune response and NF-kappaB-related processes.
  • In the training set, smoking pack-years were lower in the asbestos-related group (mean 35.8) than the non-asbestos group (mean 55.3), a difference of borderline significance (P = 0.052).
• The authors' conclusion: The authors concluded that ADAM28 is a potential asbestos-related cancer biomarker, consistently more active across their own and independent datasets. They added that the ADAM28 changes could be due to asbestos exposure independent of tobacco smoke, but that additional experiments are needed to confirm this.
• Limitations the authors state:
  • Potential for false-positive findings (Type I errors).
  • The training set was small (36 patients), which risks overfitting.
  • The only public comparison dataset (Wikman) was small, mixed tumor types, and used different methods to assess asbestos exposure.
  • Most asbestos-exposed lung cancer patients also smoked, and it is not known whether tobacco alone would also raise ADAM28.
  • The cell line experiments involved short-term exposure, which may not mimic long-term exposure with long latency.
  • It was not confirmed that protein levels match the gene activity (mRNA) changes.
  • No data were available to tell whether ADAM28 changes occur early, in pre-cancerous tissue.

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 Adenocarcinoma, Lung Cancer, Carcinogenesis, Biomarker, Asbestos Body Formation, Adenocarcinoma, Asbestos Bodies, Attribution.

Related studies

• MS4A1 dysregulation in asbestos-related lung squamous cell carcinoma is due to CD20 stromal lymphocyte expression — C.M. Wright, S.M. Savarimuthu Francis, et al. (2012)
• Lung asbestos content in lungs resected for primary lung cancer — C.M. Wright, R.V. Bowman, et al. (2008)
• CD24: a potential new marker in differentiating malignant mesothelioma from pulmonary adenocarcinoma — D.J. Pinato, P. Nya, et al. (2013)
• Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling — G.J. Gordon, G.N. Rockwell, et al. (2005)
• Identification of DAB2 and Intelectin-1 as Novel Positive Immunohistochemical Markers of Epithelioid Mesothelioma by Transcriptome Microarray Analysis for Its Differentiation From Pulmonary Adenocarcinoma — M. Kuraoka, V.J. Amatya, et al. (2017)
• Circulating microRNAs found dysregulated in ex-exposed asbestos workers and pleural mesothelioma patients as potential new biomarkers — I. Bononi, M. Comar, et al. (2016)

Browse more research in Genes, Chromosomes & Cancer, or return to medical research.