Author of

• 25916

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  MA24 - Genomic Evolution, KEAP 3 and More Non-Coding RNA (ID 928)

  • Event: WCLC 2018
  • Type: Mini Oral Abstract Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/26/2018, 10:30 - 12:00, Room 205 BD

  • 26180

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    MA24.02 - Genomic Alterations in Lung Adenocarcinoma Precursor Lesions (ID 13037)

    10:35 - 10:40  |  Author(s): Michael K. Asiedu
    • Abstract
    • Presentation
    • Slides

    Background
    

    Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are thought to be precursor lesions of invasive disease. Genomic alterations in these lesions have not been described.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Genomic analysis including whole genome and exome sequencing, and SNP array analysis were performed on 9 AIS and 18 MIA pathologically confirmed samples to identify single nucleotide variants (SNVs), structural variations and copy number variations. Mutation significance and signature analysis were determined by MutSig and NMF analyses. Pathway analysis was performed using ingenuity IPA.

    4c3880bb027f159e801041b1021e88e8 Result
    

    The range of mutation burden for AIS and MIA was 0.7 to 12/Mb with a median of 1.7/Mb. This compared to a mean of 7.2/Mb for invasive lung adenocarcinoma. Significantly mutated genes identified in AIS and MIA were ELAVL4, LIN37, XCL1, ELK3, RPS9, FBXO2, HLA-B and MYOG, which affected pathways regulating ESR1, ELAVL1 and TP53. Genes with recurrent mutations included MTPN, CDC27, GGT2, CTBP2, EGFR, NCOR1 and TGIF1 and implicated EGFR, MYC and MAPK1 pathways. Somatic mutations were characterized by C>T and T>C transition signature, whereas CNV analysis found high concentrations of copy number amplifications at 6p21.3 to 6p22.1, 8q24.12 to 8q24.3 and at 21q22.3. There were comparable structural variations in the AIS cases compared to MIA.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    In contrast to hypothesized models of tumor progression, AIS and MIA can harbor significant genomic alterations and tumor mutation burden. These observations challenge the notion of accumulating mutation burden during the progression to invasive disease. The finding of high mutation burden in some of these precursor lesions also suggests the intriguing concept of immunotherapeutic options for either treatment or chemoprevention.

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