Lung Cancer Malignant pleural mesothelioma: Genome-wide expression

Malignant pleural mesothelioma is an asbestos-related multi-resistant tumour with increasing incidence worldwide. Well-characterized snap-frozen normal parietal, visceral pleura and mesothelioma samples were analysed with Affymetrix Human Genome U133 Plus 2.0 GeneChip oligoarray of 38 500 genes. We discovered a close relation between gene profile and resistance towards topoisomerase poisons, alkylating agents, antitubulines, antifolates, platinum compounds and radiation therapy. Target genes of chemo- (e.g. TOP2A, BIRC5/Survivin and proteasome) and radiotherapy (e.g. BRCA2, FANCA, FANCD2, CCNB1 and RAD50) were significantly overexpressed. The Fanconi anemia/BRCA2 pathway, responsible for homologous recombination DNA repair appears as a key pathway in both chemo- and radio-resistance of mesothelioma. Leukocyte trans-endothelial migration gene down-regulation could partly explain resistance against immunological therapies. Gene expression features found in other resistant cancer types related to DNA repair and replication are shared by mesothelioma and could represent general features of tumour resistance. Targeted suppression of some of those key genes and pathways combined with chemotherapy or radiation could improve the outcome of mesothelioma therapy. We propose CHEK1, RAD21, FANCD2 and RAN as new co-targets for mesothelioma treatment. The pro-angiogenic AGGF1 mRNA and protein was highly overexpressed in all tumours and may serve as a target for anti-angiogenic treatment. Overexpression of NQO1 may render mesothelioma sensitive to the novel compound betaLapachone. © 2009 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Median survival of malignant mesothelioma is currently 12 months [1], an aggressive tumour derived from cells of the pleura, peritoneum or tunica vaginalis testis, where pleural location accounts for about 70% of the cases [2]. Epithelial subtype is an important positive prognostic factor in contrast to the sarcomatous and mixed subtypes. It is among the most chemo- and radio-resistant malignant tumours [3] and no curative treatment is available, but occasionally good responders and long-term survivors are seen. Pemetrexed, a multi-folate inhibitor combined with cisplatin is the only treatment that has shown increased median survival in a Phase III study, from 9.3 to 12.1 months [4]. Studies unraveling the biology of mesothelioma and identifying novel molecular targets for treatment are thus urgently warranted. We ∗ Corresponding author. Tel.: +47 73900650. E-mail address: oluf.roe@stolav.no (O.D. Røe). recently did genome-wide expression analysis of human pleural mesothelioma versus normal parietal pleura samples that portraits the aggressive and resistant biology of mesothelioma (Røe et al., in preparation). Here we focus on genes and pathways with signifi- cant differential expression from the same material, that could be related to the drug and irradiation resistance of pleural mesothelioma and propose some future targets. 2. Materials and methods 2.1. Mesothelioma and control patients Patients diagnosed between 2003 and 2005 were included after obtaining informed written consent. Diagnostic biopsies and material for gene expression were taken from adjacent locations with needles by Computer Tomography and/or ultrasound guidance. Diagnostic samples were formalin-fixed and paraffin-embedded. Material for gene expression analysis was snap-frozen in liquid nitrogen within two minutes. Biopsies of morphologically normal