Abstract 4679: Novel pathway mutations in malignant mesothelioma revealed by high-throughput DNA and RNA sequencing

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Abstract Background: Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. Because MM is usually diagnosed at an advanced stage and is largely unresponsive to conventional therapy, it is necessary to identify the signal pathways driving MM and to develop therapeutics specifically targeting these pathways. Materials and Methods: We carried out RNA sequencing of 12 MM cell lines and 4 clinical samples and exome sequencing of 6 MM cells using a so-called next-generation sequencer. We further performed pathway-targeted genome sequencing of 23 paired samples of MM tumor and normal tissue. Results: We identified 15 novel fusion genes by RNA sequencing and confirmed them by conventional Sanger sequencing and FISH analyses. We showed that the novel gene was included in both LOH and a fusion gene, and the gene which was critical tumor-suppressor roles caused two hit and was down-regulated. The gene has been identified as a central player of the emerging signaling pathway. We further identified the accumulation of mutations in 35% of the MMs by pathway-targeted genome sequencing. Conclusions: We indicated the need for the discovering molecular targets in the novel pathway in MMs. Our findings provide novel insights into the pathogenesis of MM and unequivocally demonstrate the power of sequencing technologies in cancer research. Citation Format: Akihiko Miyanaga, Mari Masuda, Koji Tsuta, Yuka Nakamura, Hisao Asamura, Akihiko Gemma, Tesshi Yamada. Novel pathway mutations in malignant mesothelioma revealed by high-throughput DNA and RNA sequencing. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4679. doi:10.1158/1538-7445.AM2014-4679