title: Cartography of Pathway Signal Perturbations Identifies Distinct Molecular Pathomechanisms in Malignant and Chronic Lung Diseases.
abstract: Lung diseases are described by a wide variety of developmental mechanisms and clinical manifestations. Accurate classification and diagnosis of lung diseases are the bases for development of effective treatments. While extensive studies are conducted toward characterization of various lung diseases at molecular level, no systematic approach has been developed so far. Here we have applied a methodology for pathway-centered mining of high throughput gene expression data to describe a wide range of lung diseases in the light of shared and specific pathway activity profiles. We have applied an algorithm combining a Pathway Signal Flow (PSF) algorithm for estimation of pathway activity deregulation states in lung diseases and malignancies, and a Self Organizing Maps algorithm for classification and clustering of the pathway activity profiles. The analysis results allowed clearly distinguish between cancer and non-cancer lung diseases. Lung cancers were characterized by pathways implicated in cell proliferation, metabolism, while non-malignant lung diseases were characterized by deregulations in pathways involved in immune/inflammatory response and fibrotic tissue remodeling. In contrast to lung malignancies, chronic lung diseases had relatively heterogeneous pathway deregulation profiles. We identified three groups of interstitial lung diseases and showed that the development of characteristic pathological processes, such as fibrosis, can be initiated by deregulations in different signaling pathways. In conclusion, this paper describes the pathobiology of lung diseases from systems viewpoint using pathway centered high-dimensional data mining approach. Our results contribute largely to current understanding of pathological events in lung cancers and non-malignant lung diseases. Moreover, this paper provides new insight into molecular mechanisms of a number of interstitial lung diseases that have been studied to a lesser extent.
authors.affiliation: Group of Bioinformatics, Institute of Molecular Biology, National Academy of SciencesYerevan, Armenia; College of Science and Engineering, American University of ArmeniaYerevan, Armenia.
authors.forename: Arsen
authors.initials: A
authors.lastname: Arakelyan
authors.affiliation: Group of Bioinformatics, Institute of Molecular Biology, National Academy of SciencesYerevan, Armenia; College of Science and Engineering, American University of ArmeniaYerevan, Armenia.
authors.forename: Lilit
authors.initials: L
authors.lastname: Nersisyan
authors.affiliation: Laboratory of Immunogenomics, Department of Pathological Physiology, Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacky University Olomouc Olomouc, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Petrek
authors.affiliation: Interdisciplinary Centre for Bioinformatics, University of Leipzig Leipzig, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Löffler-Wirth
authors.affiliation: Interdisciplinary Centre for Bioinformatics, University of Leipzig Leipzig, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Binder
keywords: biological pathways; chronic lung diseases; high-throughput gene expression; lung cancers; pathway signal flow; self-organizing maps