Author of

• 15382

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  P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

  • Event: WCLC 2015
  • Type: Poster
  • Track: Biology, Pathology, and Molecular Testing
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)

  • 15445

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    P3.04-063 - The Mutational Landscape of Pulmonary Premalignancy in the Context of Lung Adenocarcinoma (ID 1614)

    09:30 - 09:30  |  Author(s): L. Tran
    • Abstract

    Background:
    While genomic alterations in lung cancer are being actively investigated, the early mutational events that occur within the pulmonary field of cancerization that subsequently drive early carcinogenesis are poorly understood. As a result, the clinical importance of premalignant lesions remains enigmatic. Epithelial cells in the field of lung injury can give rise to distinct premalignant lesions that may bear unique genetic aberrations. A subset of these lesions may progress to invasive cancer, however the mutational landscape that may predict progression has not been determined. In the present study we performed whole exome DNA sequencing to measure the incidence of somatic DNA alterations in matched sets of primary tumor, premalignant lesions and adjacent normal lung tissues.
    
    Methods:
    FFPE tissue blocks from 41 patients were obtained from the UCLA Lung Cancer SPORE Tissue Repository. The following regions were dissected from distal airways utilizing Laser Capture Microdissection: a) normal airway epithelial cells (1-3 regions), b) premalignant atypical adenomatous hyperplasia (AAH, 2-4 regions), c) adenocarcinoma in situ (AIS, 1-3 regions) and, d) adenocarcinoma (ADC, 1-3 regions). DNA was extracted and sequencing libraries were constructed followed by exome capture. Sequencing was performed on an Illumina HiSeq2000 with a mean coverage of ~50x per base.
    
    Results:
    Data analysis included analyses for germline and somatic variants, loss of heterozygosity and copy number alternations. Within each case, position-specific missense and nonsense mutations were compared. Different cases were compared for the mutations at a gene-specific level. Mutations found only in AAH lesions were defined as premalignant, in ADC as malignant, and in both AAH and ADC as progression-associated mutations. The analysis demonstrated that AAH lesions from the same patient often have different mutational profiles. We identified novel recurring progression-associated mutations in 33 genes, most of which have not been previously described as key drivers for lung cancer. Interestingly, recurring mutations were found in genes involved in calcium signaling and extracellular matrix/receptor interaction. The data was compared to the TCGA and COSMIC databases. Among affected proteins, only 3% overlapped with the COSMIC and approximately 6% with the TCGA database. Interestingly, all of the mutations overlapping with the COSMIC, were found to be common mutations in AAH. Furthermore, pathways affected by the mutated genes were identified utilizing Gene Ontology and pathways from the KEGG, Biocarta or Reactome databases. The observation that few genes mutated in both AAH and ADC are known as key drivers, indicates that: a) progression-associated mutations might facilitate malignant transformation by mutated key driver(s), or b) a combination of two or more progression-associated mutations that are not oncogenic alone, might drive malignant transformation. These hypotheses will be further tested by mapping progression- and malignant-associated genes in the context of pathways.
    
    Conclusion:
    Our data indicate that premalignant lesions from the same patient may have different mutational profiles. This inter-lesion heterogeneity suggests that a progression-associated mutational landscape could be defined in longitudinal studies of pulmonary premalignancy. These results could help identify targets for the development of targeted chemopreventive strategies for lung cancer. Supported by EDRN (U01CA152751-AS).