Abstract
Abstract Background Malignant pleural mesothelioma (MPM) is a deadly disease with poor prognosis, few treatment options, and an increasing incidence worldwide. There is, therefore, a great need to identify new therapeutic targets and develop more effective therapies for patients with MPM. To better characterize the molecular changes occurring in MPM, we determined genetic and proteomic abnormalities in MPM cell lines and correlated them with those found in MPM tumor tissue specimens. Methods We performed SNP/copy number analysis using Affymetrix SNP 6.0 chips, messenger RNA (mRNA) analysis using Affymetrix U133 plus 2.0 chips, and Reverse Protein Phase Array (RPPA) analysis in 4 mesothelioma cell lines (H28, MSTO-211H, H2052 and H2452) along with the control normal cell line HCT-4012, for comparison. DNA copy number microarray data were analyzed using the Nexus 5.0 software (BioDiscovery Inc.), while mRNA expression array data were analyzed using the GeneSpring GX 11 software (Agilent technologies, Inc.). Additionally, we evaluated copy number gain (CNG) of the c-myc gene and expression of c-myc protein in the mesothelioma cell lines and control cell line by fluorescent in situ hybridization (FISH) and Western blot, respectively. Furthermore, we investigated CGN in MPM tumor tissue specimens by performing FISH using the c-myc probe on tissue microarrays (TMAs) containing 80 MPM samples from different histological subtypes (41 epithelioid, 27 biphasic, 12 sarcomatoid). Results DNA copy number analysis using the Affymetrix chip revealed CNG or amplification of the c-myc oncogenic locus in 3 out of 4 mesothelioma cell lines compared to the control HCT-4012 cell line. In concordance, the mRNA microarray data also showed increased number of transcripts from this locus; more importantly, the RPPA array data showed increased c-myc protein expression in these cell lines compared to control. These results were confirmed by FISH and Western blot analysis, which showed CNG or amplification at this locus and increased levels of the c-myc protein in the mesothelioma cell lines. FISH analysis of TMAs also revealed a relatively high frequency (21%) of CNG (≥4 copies in ≥70% of cells) for the c-myc locus in the MPM tumors. Interestingly, this amplification were seen in either epithelioid (10%) or biphasic (11%) histotype, and none were observed in the sarcomatoid cases. Similarly, within the biphasic cases, we observed that the amplification was present only in the epithelioid component, and not in the sarcomatoid component. Conclusion Our findings suggest that CNG of the c-myc locus is characteristic for MPM tumors of the epithelioid histotype or of the epitheloid component of biphasic histotype, and suggest that c-myc CNG could have a role in pathogenesis of this disease; however, further studies are needed to clarify the role of c-myc in MPM development and progression. Supported by grant US DoD W81XWH-07-1-0306. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4031. doi:10.1158/1538-7445.AM2011-4031
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