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W.S. Kim



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    MA05 - Innovative Techniques in Pulmonology and the Impact on Lung Cancer (ID 378)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Pulmonology
    • Presentations: 1
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      MA05.05 - Genomic Profiles of Lung Cancer Associated with Idiopathic Pulmonary Fibrosis (ID 5842)

      16:30 - 16:36  |  Author(s): W.S. Kim

      • Abstract
      • Presentation
      • Slides

      Background:
      Idiopathic pulmonary fibrosis (IPF) is associated with an increased risk of lung cancer (LC) independent of the effect of cigarette smoking. The prognosis of IPF-associated LC (IPF-LC) is known to be worse than the lone IPF or LC mainly due to the complications accompanying LC treatment with no established or standardized consensus. However, despite recent progress in the understanding of pathogenesis and the treatment of LC in general population based on the advances in molecular genomics, the pathogenesis or molecular profiles of IPF-LC has been largely unknown to date.

      Methods:
      We assessed genomic profiles of IPF-LC using targeted exome-sequencing (OncoPanel version 2) in 35 matched tumor/normal pairs surgically resected between 2004 and 2014. Germline and somatic variant calling were performed using GATK HaplotypeCaller and MuTect with GATK SomaticIndelocator, respectively. Copy number analysis was conducted using CNVkit with focal events determined by GISTIC 2.0, and pathway analysis (KEGG) using DAVID.

      Results:
      Germline mutations in TERT (rs2736100,n=33) and CDKN1A (rs2395655,n=27) linked with IPF risk were detected in most samples. A total of 410 somatic mutations were identified with an average of 11.7 per tumor including 69 synonymous, 177 missense, 17 nonsense, 1 nonstop, 11 splice-site mutations, and 135 small coding indels. Spectra of the somatic mutations revealed predominant C→T transitions despite extensive smoking histories across most study subjects, suggesting more associations with APOBEC3B-related mutagenesis in the process of IPF-LC development, rather than smoking. TP53 (22/35,62.9%) and BRAF (6/35,17.1%) genes were found significantly mutated in IPF-LC. Recurrent focal amplifications in 3 chromosomal loci (3q26.33, 7q31.2, and 12q14.3), and 9p21.3 deletion were identified, and genes associated with JAK-STAT signaling pathway were significantly amplified in IPF-LC (P=0.012).

      Conclusion:
      IPF-LC is genetically characterized by the presence of somatic mutations reflecting viral and immune-related mutagenic processes in the background of specific germline mutations, and is associated with potentially targetable alterations such as BRAF mutations.

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