title: Gene expression profiling and gene copy-number changes in malignant mesothelioma cell lines.
abstract: Malignant mesothelioma (MM) is an asbestos-induced tumor that acquires aneuploid DNA content during the tumorigenic process. We used instable MM cell lines as an in vitro model to study the impact of DNA copy-number changes on gene expression profiling, in the course of their chromosomal redistribution process. Two MM cell lines, PMR-MM2 (early passages of in vitro culture) and PMR-MM7 (both early and late passages of in vitro culture), were cytogenetically characterized. Genomic gains and losses were precisely defined using microarray-based comparative genomic hybridization (array-CGH), and minimal overlapping analysis led to the identification of the common unbalanced genomic regions. Using the U133Plus 2.0 Affymetrix gene chip array, we analyzed PMR-MM7 early and late passages for genome-wide gene expression, and correlated the differentially expressed genes with copy-number changes. The presence of a high number of genetic imbalances occurring from early to late culture steps reflected the tendency of MM cells toward genomic instability. The selection of specific chromosomal abnormalities observed during subsequent cultures demonstrated the spontaneous evolution of the cancer cells in an in vitro environment. MM cell lines were characterized by copy-number changes associated with the TP53 apoptotic pathway already present at the first steps of in vitro culture. Prolonged culture led to acquisition of additional chromosomal copy-number changes associated with dysregulation of genes involved in cell adhesion, regulation of mitotic cell cycle, signal transduction, carbohydrate metabolism, motor activity, glycosaminoglycan biosynthesis, protein binding activity, lipid transport, ATP synthesis, and methyltransferase activity.
authors.affiliation: Department of Pathology, Erasmus Medical Center, Daniel den Hoed Cancer Center, Josephine Nefkens Institute, Rotterdam, The Netherlands.
authors.forename: Claudia
authors.initials: C
authors.lastname: Zanazzi
authors.forename: Remko
authors.initials: R
authors.lastname: Hersmus
authors.forename: Imke M
authors.initials: IM
authors.lastname: Veltman
authors.forename: Ad J M
authors.initials: AJ
authors.lastname: Gillis
authors.forename: Ellen
authors.initials: E
authors.lastname: van Drunen
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.forename: Joost P J J
authors.initials: JP
authors.lastname: Hegmans
authors.forename: Marielle
authors.initials: M
authors.lastname: Verweij
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.forename: J Wolter
authors.initials: JW
authors.lastname: Oosterhuis
authors.forename: Leendert H J
authors.initials: LH
authors.lastname: Looijenga
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002877:Chromosomes, Human / Q000235:genetics*; D018628:Gene Dosage / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods*; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008654:Mesothelioma / Q000235:genetics* / Q000378:metabolism; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D032681:Spectral Karyotyping; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53