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M.A. Archer

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    ORAL 14 - Biology 2 (ID 112)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      ORAL14.03 - Integrin Linked Kinase Pathway: A Potential Driver of Tumorigenesis of Malignant Pleural Mesothelioma (ID 2135)

      16:45 - 18:15  |  Author(s): M.A. Archer

      • Abstract
      • Slides

      Identifying driver mutations assists with understanding molecular aspects of cancer and development of novel drugs. The genetics of malignant pleural mesothelioma (MPM) has primarily been to date described in terms of deletions of specific chromosomal regions with CDKN2A and NF2 most commonly mutated, and more recently, evidence for a role of BAP1. The current work suggests that activation of the Integrin Linked Kinase (ILK) pathway may be oncogenic in a subset of MPM.

      Whole-genome sequencing was accomplished for 10 tumor and matched normal genomic DNA samples using a Complete Genomics platform. Tumor and normal genomes were sequenced to at least 30-fold haploid coverage, with corresponding diploid coverage of at least 99.5%. Selected candidates single nucleotide variations (SNVs) were further characterized using PCR and Sanger sequencing to identify tumor-specific single nucleotide mutations. Potential driver genes were investigated in 147 additional MPM cases by targeted resequencing. Levels of transcripts were examined in an available expression data set (Affymetrix® Human Gene 1.1 ST Array). Association of mutation status and gene expression to clinicopathologic variables was explored statistically.

      Among 146 single nucleotide variants (SNVs) mapping in amino acid coding regions of annotated exons and generating non-synonymous amino acid changes, 85 were confirmed to be tumor specific. Functional enrichments of genes affected by point mutations were performed utilizing Ingenuity Pathway Analysis to identify clusters of genes annotated in pathways potentially relevant to the biology of MPM. Mutations affecting genes involved in the Integrin Linked Kinase (ILK) pathway were the most significantly (p = 4.9e-5) enriched. Specifically, 5 of 10 sequenced MPM samples showed point mutations in at least one of 6 genes of this pathway (MYH9, MYH6, MYH10, PIK3C2A, RHOA, and TNFRSF1A). Re-sequencing analysis of 147 MPM tumors identified 40 SNVs in these genes among 31 MPM samples (21%). Thirty-five (88%) SNVs were present in both tumor and matching normal DNA samples. In 4 samples, tumor specific mutations were identified, 3 in MYH9 (1.4%) and 2 in RHOA (1.4%) both recently proposed as genes involved in tumorigenesis. Non-epithelioid tumors expressed significantly higher levels of MYH9 (p<0.001), RHOA (p<0.001), and MYH10 (p=0.001) compared to epithelioid tumors. RHOA was more highly expressed in men than women (p=0.001). The highest quartile of MYH9 and of RHOA expression was associated with higher gender-adjusted risk of death (HR=2.23 and HR=1.95, respectively) compared to the lower three quartiles (p<0.001) by multivariate analysis.

      Tumor specific mutations in MYH9 or RHOA were found in six of 157 (3.8%) MPM patients. Interestingly, both MYH9 (22q13.1) and RHOA (3p21.3) reside in two chromosomal regions frequently deleted in MPM. Additional analysis is in progress to investigate the role of ILK pathway activation in MPM. These observations suggest that a sub-class of MPM may respond to therapy targeting the ILK pathway.

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