Author of

• 12736

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  P3.14 - Poster Session 3 - Mesothelioma (ID 197)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Mesothelioma
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12747

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    P3.14-011 - Genomic profiling of Epithelial Malignant Pleural Mesothelioma (MPM) using Massively Parallel Sequencing. (ID 2855)

    09:30 - 09:30  |  Author(s): A. Khattri
    • Abstract

    Background
    Development of targeted therapies in malignant pleural mesothelioma has been limited due to the incomplete understanding of genetic aberrations occurring in this disease. We determined mutational and copy number (CN) events in a comprehensive fashion in 12 patients with epithelial malignant pleural mesothelioma in order to identify characteristic genetic aberrations and new potential treatment targets.

    Methods
    Fresh frozen tumor (≥70% tumor content) and matched normal tissue from 12 patients with treatment-naïve epithelial malignant pleural mesothelioma were evaluated using targeted, massively parallel sequencing (Illumina HiSeq) for 580 cancer-relevant genes using hybrid capture target enrichment and an established bioinformatics analysis pipeline. CN analysis was performed using sequencing data (CONTRA) and validated on the NanoString nCounter. Mutations were modeled bioinformatically using the CHASM oncogenic driver prediction algorithm and reviewed for prior occurrence in COSMIC and evidence supporting usefulness as a treatment target.

    Results
    Loss of CDKN2A was the most common genetic event occurring in 80% of samples. INPP4B and TRAF6 were lost in 20-30% of tumors. No loss of PTEN was observed in any sample. Two BAP1 small frameshift deletions were observed. Copy number aberrations, in particular amplifications, were rare. The only gene with modest increase in copy number was MET (median CN=2.8). We identified multiple somatic missense mutations including: two APC mutations (K1245E, G2502D; both predicted to be damaging), one TSC1 (K587A) and one TSC2 (P952A, predicted driver) mutation, one KIT mutation (L799F; predicted driver), one JAK2 (P953A; predicted driver), as well as single mutations in NF1 (G849R), EPHA1 (P697S), EPHA4 (T532I), and mTOR (L2208P), all of which had driver character. Specific mutations have not been reported in COSMIC. No canonical PI3K or MAPK pathway aberrations were identified.

    Conclusion
    We identified several novel and known mutations and copy number events in epithelial malignant pleural mesothelioma: deletions in CDKN2A and INPP4B were the most common copy number events. Frameshift deletions in BAP1 were identified. Overall few copy number events were observed. Potentially targetable aberrations include missense mutations in NF1, JAK2, EPHA1, TSC2, mTOR and KIT, which are predicted to have driver character and additional experimental validation is indicated. Additional tumor and cell line samples are being processed and will be available at the time of presentation.