Pathway analysis suggests novel biological processes, molecular functions and cellular components for asbestos-related lung carcinogenesis
Authors: Tuija Hienonen-Kempas, Salla Ruosaari, Harriet Wikman, Virinder Sarhadi, Anne Puustinen, Jaakko Hollmen, Juha Saharinen, Sakari Knuutila, Sisko Anttila
Journal: Cancer Research (2007)

4992   Exposure to asbestos fibers is associated with several non-malignant and malignant diseases of the lung and pleura, e.g., asbestosis, malignant mesothelioma and lung cancer. Although asbestos use is forbidden or under strict control in most countries nowadays, the extensive past use and the long latency period between exposure and disease make asbestos-associated malignancies a continuous major health problem worldwide in the upcoming decades. Studies on asbestos-induced lung cancer have disclosed the role of, e.g., reactive oxygen/nitrogen species as well as NF-κB and MAPK signalling cascades. However, the exact molecular mechanisms are still to be characterized. We have previously demonstrated specific gene copy number changes in lung carcinomas of asbestos-exposed patients. To gain further insight into the asbestos-induced alterations we have now measured gene expression levels on normal lung and tumor tissue samples from 14 asbestos-exposed and 14 non-exposed lung cancer patients using Affymetrix HU133A GeneChips. The patient groups were fit to match the following features: sex, smoking history as well as histological type and stage of the tumor. The gene expression data was analyzed for differentially regulated pathways using gene annotation data on the Gene Ontology Database. Statistical analysis via permutation tests were performed to identify biological processes, molecular functions or cellular components that would differentiate the exposed patients at normal and/or tumor tissue levels. This approach allowed us to obtain a more comprehensive view on the underlying molecular events than would have been gathered by examining expression differences of individual genes alone. Furthermore, while a single gene might not show a significant difference between the exposed and non-exposed, the difference might still be enough to indicate a whole pathway as differentially regulated when considered together with other genes annotated to the same pathway. Using this approach, we were able to identify up- and down-regulated pathways both in normal and tumour tissue of asbestos-exposed patients. Some of the findings, such as upregulation of NF-κB cascade and downregulation of DNA repair, have already previously been presented in the literature. Other findings, such as downregulation of spliceosome complex or upregulation of nucleosome assembly and olfactory receptor activity have not been described before and therefore represent attractive candidates for future research. This is the first comprehensive pathway analysis on lung carcinomas and corresponding normal tissue samples from asbestos-exposed and non-exposed lung cancer patients. Our study indicates that there are distinct differences between the two groups of patients and ongoing research will provide further insight into some of the most intriguing pathway findings.