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V. Varadan

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    ORAL 22 - Moving Beyond a Smoking Related-Cancer to the Young, Never-smokers and Inherited Disease (ID 117)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL22.06 - Whole Exome Sequencing to Profile the Genomic Landscapes of Young Patients (pts) Diagnosed with Non-Small Cell Lung Cancer (NSCLC) (ID 3073)

      10:45 - 12:15  |  Author(s): V. Varadan

      • Abstract
      • Slides

      The incidence of NSCLC in pts 45 years of age or younger is ~2% of total cases, with annual newly diagnosed cases reaching 4,500 in the United States alone. Majority of these pts are diagnosed at an advanced stage with poor outcomes. Although several specific genomic alterations have been identified in young NSCLC pts particularly in light-/never smokers, e.g. EGFR mutations, the overarching underlying causative mechanisms in the pathogenesis and progression in these young pts remain largely unknown, and likely are different from older pts. The objective of this study is to examine the genomic landscapes of NSCLC in young pts through comprehensive whole exomic survey with the objective to arrive at novel predictive and prognostic genomic biomarkers and therapeutic opportunities in young NSCLC pts.

      We initially identified a cohort of 20 pts (40% male) diagnosed with NSCLC at an age of ≤45, who underwent surgical resection for the primary tumors or metastatic lesions at Cleveland Clinic from 2000-2012. Matching genomic DNA from FFPE lung tumor samples and paired-normal lung tissue/peripheral blood was subjected to whole exome sequencing using Illumina HiSeq 2000 platform. Exome variant calling was performed using GATK and/or SOAPsnp algorithms to identify somatic mutations in individual tumors. Pathway and protein-protein interaction (PPI) network analysis on mutant genes was performed using KEGG/NCI-PID databases and HotNet suite, respectively. Second cohort of young NSCLC tumor cases (n=50) were identified from the Sun Yat-sen University Cancer Center and genomic analysis is underway.

      Majority of the tumors from the first cohort had adenocarcinoma (n=12) or squamous cell (n=4) histology. Six (6) pts were never-smokers, while the others had a median 30 pack-year cigarette smoking history. A significantly higher mutation burden was found in smokers (Median, 3.47/Mb) compared to never-smokers (Median, 0.76/Mb). We also found that the G:C→T:A transversions were more common in smokers, and C:G→T:A transitions more common among never-smokers. Key driver cancer genes such as TP53 (50%) and KRAS (17%) harbored mutations exclusively in smokers, whereas EGFR mutations (14%) were observed specifically in never-smokers. Interestingly, global pathway/PPI analysis of the mutant genes revealed distinct sub-networks associated with cell adhesion and epithelial mesenchymal transition (EMT) processes with a 7-fold enrichment in mutation frequency in these young pts when compared to their overall frequencies in the COSMIC/TCGA lung cancer dataset.

      Our study nominated novel candidate genes/pathways especially relating to cell adhesions and EMT processes, that potentially play a key role in early-onset NSCLC. Further analysis and validation of our findings could improve our understanding of lung cancer pathogenesis and eventually lead to precision therapies to benefit younger NSCLC pts.

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