Overexpression of a set of genes in mesothelioma versus parietal pleura may explain its chemo- and radio-resistance.

13506 Background: Malignant mesothelioma is a tumour highly resistant to most conventional chemotherapy and radiation. Little is known about the molecular basis for mesothelioma therapy resistance. Differential gene expression of mesothelioma versus normal pleura could elucidate some issues related to resistance and lead to discovery of new therapeutic targets.,Needle biopsies from five patients with mesothelioma were obtained and snap-frozen in liquid nitrogen. Normal visceral and parietal pleura were obtained by Video Assisted Thoracoscopy from six cancer-free patients with spontaneous pneumothorax, anatomically dissected and snap-frozen in liquid nitrogen. Adjacent tissue was formalin-fixed and Hematoxylin-Eosin- Safran (HES) stained for analysis of cell types. RNA was extracted and analyzed with the Affymetrix Human Genome U133 Plus 2.0 Chip oligoarray of 39 000 genes. Principal Component Analysis was used to discover tissue with similar gene expression patterns and differentially expressed genes were identified by a modified T -test. KEGG Pathways and biological processes gene ontology (GO) terms that were overrepresented among the differentially expressed genes were identified. Cell specific expression of proteins encoded by some of the overexpressed genes was detected by immunohistochemistry.,Six mesothelioma samples and ten normal (seven parietal and three visceral) samples were analyzed. Parietal, visceral pleura and mesothelioma had distinct expression profiles. When parietal pleura and tumor were compared, several key genes encoding proteins known to confer chemo- resistance (e.g. TOP1, TOP2A, TYMS, BIRC5/Survivin, TUBB and 12 proteasome genes) and radio-resistance by several DNA-repair and DNA- damage checkpoint genes (e.g. BRCA2, FANCA, FANCD2, RAD51) were overexpressed in tumour.,Mesothelioma resistance to therapy is reflected in the gene profile where many known genes related to chemo-and radio-resistance are significantly over- expressed. Specific suppression of some selected genes or gene products could lead to increased anti-tumour effect of conventional chemo- and/or radiotherapy. No significant financial relationships to disclose.