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    P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P1.08-010 - Understanding the Genetic Landscape of Malignant Mesothelioma - A Comparison of Human and Murine Mesothelioma Cell Lines (ID 1641)

      09:30 - 17:00  |  Author(s): J. Pearson

      • Abstract
      • Slides

      Background:
      Malignant mesothelioma (MM) is predominantly caused by exposure to asbestos. Next generation sequencing is being used in MM to understand the nature of the genetic lesions that underlie the disease and to identify potential new therapeutic targets. MM has the unusual distinction of having a mouse homologue that largely replicates the human cancer. This provides an opportunity to use murine tumor sequence data to understand mesothelioma pathogenesis, examine asbestos mutational signatures and test potential treatment strategies predicted by the genetic landscape. We have undertaken exome sequencing of asbestos induced murine MM, and compared our findings with human MM.

      Methods:
      Whole exome sequencing (WES) was performed on the Ion Torrent Proton platform on 15 early passage MM cell lines developed from ascites induced following asbestos exposure and tumour development in three wild-type mouse strains (BALB/c, CBA and C57BL/6 strains). Wild type germline murine normal samples were sequenced concurrently. Somatic single nucleotide variants (SNVs) were identified using publicly available algorithms with a subset being validated using Sanger sequencing. Copy number variation was analysed using GISTIC. Mutation signatures were identified using the Somatic Signatures algorithm in R.

      Results:
      There were on average 760 SNV identified in mouse MM cell lines (range 212-2234) equivalent to a median of approximately 9 mutations per Mb. There were significantly more SNV detected in the BALB/c strain than the CBA and C57Bl/6 strains. As previously observed there was a tendency for chromosome deletion rather than amplification in MM. Deletions in chromosome 4 in the region of p16 were common. Non-synonymous mutations accounted for 60-80% of all exonic mutations. C>T and G>A transitions were more prevalent than other mutation types across all tumours. Mutation signature analysis showed a higher rate of C>A, C>G and C>T mutations in specific dinucleotide contexts, which was mirrored in the human MM tumours.

      Conclusion:
      Genetic analysis of murine models of MM enables the identification of candidate mutational changes that can help inform about changes in human tumors. These models also provide excellent opportunities for pre-clinical proof-of-principle therapeutic studies of the use of sequence information in clinical trials.

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