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MC Aubry



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

      10:35 - 10:40  |  Author(s): MC Aubry

      • 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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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-12 - EGFR Therapy in ASCL1 Positive Lung Adenocarcinoma (ID 14211)

      16:45 - 18:00  |  Author(s): MC Aubry

      • Abstract

      Background

      Greater than 40% of lung adenocarcinomas (LUAD) contain no known driver mutations from point mutation or structural variance analysis. Recently, we discovered that 15-20% of LUAD have abnormally high levels of ASCL1, a key regulator of neuroendocrine differentiation in the lung. ASCL1 in these tumors orchestrates the expression of a network of genes that affect the behavior of tumors and their microenvironments and provide opportunities for treatment that has largely been understudied. The goal of this study was to explore potential therapeutic options in these tumors.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Bioinformatics analyses used public and internally generated expression data from LUAD. In vitro co-immunoprecipitation and cytotoxicity assays were used to determine the interaction between proteins and the sensitivity to EGFR blockers gefitinib and lapatinib. These drugs were also tested in patient derived xenograft (PDX) models from cisplatin resistant brain met LUAD with (A+AD) and without (A-AD) ASCL1 expression.

      4c3880bb027f159e801041b1021e88e8 Result

      Our data demonstrated that ASCL1 acts upstream of RET and promotes chronic over-expression of the oncogene in A+AD. In vitro experiments revealed a strong interactions between wild type EGFR and RET in A+AD which rendered these tumors vulnerable to treatment by EGFR blockers. Furthermore, while EGFR inhibitors blocked tumor growth in the A+AD PDX model, they were completely ineffective in the A-AD PDX model. EGFR therapy also markedly changed key regulators of the tumor microenvironment in favor of anti-tumor immunity. Analysis of TCGA data identified some overlap between A+AD and other LUAD subtypes, such as KRAS or EGFR mutant tumors. Further meta-analysis in a compendium of microarray data in stage-1 LUAD from multiple institutions demonstrated that high expression of wild type RET was significantly associated with a poor overall survival. Furthermore, high expression of EGFR (or its ligand TGFA) and RET imparted an aggressive phenotype in A+AD with overall survival similar to small cell lung cancer. Notably, EGFR, TGFA, and RET did not have any prognostic value in A-AD.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our data provide strong evidence that patients with A+AD may benefit from a multipronged treatment strategy that include EGFR therapy even in the absence of mutations in EGFR.

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