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S. Gao

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    MA17 - Genetic Drivers (ID 409)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Biology/Pathology
    • Presentations: 1
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      MA17.05 - Evolutionary Trajectories of Molecular Progression in Different Subtypes of Primary Lung Adenocarcinomas (ID 5712)

      14:20 - 15:50  |  Author(s): S. Gao

      • Abstract
      • Presentation
      • Slides

      Morphological and genetic heterogeneity predict prognostics, impede continuous responses to systemic regimens and foster inevitable treatment failure. But how morphological and genetic features evolve in tumorigenesis still remains controversial.

      Single(n=1112) and multiple(n=91) primary adenocarcinoma patients receiving surgeries with specific prominent subtypes were screened. Six patients with mixed ground glass opacities and maximum cross-sections of primary tumors were randomly selected. Intra-tumoral regions with different subtypes and imaging densities related to relative distributions, were resected for target region sequencing and further molecular evolutionary analyses.

      Clinical data revealed certain preferences of driver gene mutations and discrepant survival benefits. Driver gene heterogeneity was higher in multiple primary lung cancers(51.7%, 15/29) than single ones(1.4%, 1/70). Copy number alterations implied more consistence within the same subtype and tended to be higher in lepidic subtype. Somatic nucleotide variants revealed highest homogeneity between different regions within the same tumor lesion. Sequencing data indicated larger fractions of geographically ubiquitous mutations than pathologically ones, and higher mutation frequencies of shared mutations in the lepidic than acinar subtype. Phylogenetic trees exhibited higher geographically private mutation burdens of lepidic than acinar region in lesions with mixed subtypes; while in lesions with the same subtype, the central region bore higher mutation burdens than in the periphery, implying a linear accumulation of genetic mutations. Functional analyses of private mutations verified that lepidic subtypes promoted intracellular organism and structure development, promoting growth and proliferation. Acinar subtypes lead to metabolic and signaling transduction pathway. Preferences of divergent pathway alterations delineated branched evolutions from low to higher grade subtypes. Figure 1

      We propose a model that the same morphological subtype evolves with a linear accumulation and mixed subtypes in branched evolutionary trajectories with preferences to pathway alterations. Couple with relatively geological distributions of different subtypes, tumor microenvironment might contribute more to genetic instability and thus tumor evolutions.

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