Abstract 1217: Chromosomal imbalances detected by microarray CGH in malignant pleural mesothelioma.
Authors: Jacques Raphael, Nicolas Dorvault, Cedric Orear, Bastien Job, Vincent Thomas de Montpreville, Francois Leroy-Ladurie, Philippe Girard, Pierre Validire, Gwenael Le Teuff, David Planchard
Journal: Cancer Research (2013)

Abstract Background CDKN2A (9p21 locus) and NF2 (22q locus) genes are inactivated in most Malignant Pleural Mesotheliomas (MPM). Few other recurrent molecular abnormalities have been described as well. A better understanding of the molecular pathways is needed to identify potential additional driver genes. We did an integrated analysis of chromosomal copy number variations from MPM specimens and cells lines. Patients and Methods In order to describe genomic profiles, we performed microarray Comparative Genomic Hybridization (CGH) (Agilent 400K). Analyses were carried out using genomic DNA samples extracted from 26 MPM primary tumours (frozen sections) and 5 MPM cell lines (Four ATCC cell lines and one cell line established in our laboratory from a pleural effusion). Subsequently the results were correlated with the baseline characteristics of the patients. Results The mean age of the patients was 60 years (30-81). The sex ratio (M/F) and the histologic epithelioid type were 1.6 and 69% respectively. Our results showed that MPM are characterized by a complex pattern of genetic changes where losses of genomic regions are more frequent than gains. Common losses (30-70%) were clustered at chromosomal regions: 1p36.13, 1p13.3, 1q21.3-1q24.2, 1p22.3-1p12 (41%) (NRAS gene), 1p36.33-1q21.2 (30%) (JUN gene) 3p22.1-3p14.2 (59%) (BAP1, RASSF1 genes), 4q13.2, 6p21.32, 6q14.1-6q27 (63%) (ROS1 gene), 7q36.1, 8p23.1, 9p24.1, 9p22.1-9p21 (52%) (CDKN2A gene), 10p11.1-10q26.3 (30%) (RET, PTEN genes), 11q25, 14q11.2, 14q32.33, 15q11.2, 15q14, 22q11.22-22q13.33 (63%) (NF2 gene). Common gains (30-50%) were located at chromosomal regions 1q44, 8p11.22, 11q11, 12p13.31, 15q11.2, 16p11, 20p13, 22q11.23, Xq22.2. The most common deletions (D) and amplifications (A) (&amp;gt;20%) defined as having a log2(ratio) ≤-1.0 and ≥1.0 respectively were located at chromosomal regions: 1p31.1 (A, D), 1q21, 1q24.2 (D), 6p21.32, 6q16.3, 6q27 (D), 7q22.1 (D), 8p11.22 (A), 9p21.3, 9q34.2 (D), 12p13.2 (D), 14q32.33 (D), 16q23.1, 16q22.1 (WWOX gene)(D), 20p13 (A, D), 22q11.23 (D). Higher frequency of genetic alterations was noted in cell lines than tumour specimens. Different patterns of genetic changes were observed according to gender, stage, histology, smoking history, asbestos exposure and performance status. Conclusion Our study confirmed the complexity pattern of genetic changes in MPM through high-resolution microarray CGH analysis. We found high number of chromosomal imbalances not yet well identified. Some correspond to known genes and others could be the areas of unknown genes involved in its development that we will try to identify thereafter. Moreover, identifying patient subgroups seems essential for having a more individualized therapy and personalized medicine in MPM (e.g. MOSCATO trial, ongoing in our cancer center). Citation Format: Jacques Raphael, Nicolas Dorvault, Cedric Orear, Bastien Job, Vincent Thomas de Montpreville, Francois Leroy-Ladurie, Philippe Girard, Pierre Validire, Gwenael Le Teuff, David Planchard. Chromosomal imbalances detected by microarray CGH in malignant pleural mesothelioma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1217. doi:10.1158/1538-7445.AM2013-1217