Author of

• 30292

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  EP1.01 - Advanced NSCLC (ID 150)

  • Event: WCLC 2019
  • Type: E-Poster Viewing in the Exhibit Hall
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall

  • 30298

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    EP1.01-06 - Loss of Heterozygosity of Oncogene ERBB2 with an Activating Mutation Was Identified as Driver Eventin Leptomeningeal Metastasis of NSCLC (ID 1184)

    08:00 - 18:00  |  Author(s): Min Shi
    • Abstract

    Background
    

    Due to limited access to leptomeningeal lesions, cerebrospinal fluid (CSF) may be the most representative liquid biopsy to get genomic information from leptomeningeal metastases (LM) in non-small-cell lung cancer (NSCLC). Loss of heterozygosity (LOH) is a common genetic event during cancer tumorigenesis. LOH of tumor suppressor gene in which loss-of-function occurs on alternative allele serves as “second hit” and leads to loss of the remaining functional allele. LOH of tumor suppressor gene, such as TP53,in CSF had been reported for its associated with EGFR-TKI resistance in LM. Here, through CSF derived liquid biopsy, we report a LOH of oncogene ERBB2 in LM of NSCLC patient. To the best of our knowledge, this is the first report of LOH of oncogene, no matter in a primary or metastatic tumor.

    Method
    

    Three CSF biopsies and matched peripheral blood were collected within 6 months from one NSCLC patient with LM. Cell-free DNA (cfDNA) was extracted, and somatic mutations were examined using a designed lung cancer panel of 180 genes. SCNAs were further identified through 2x whole genome sequencing (WGS). Genomic alternations identified in all three matched biopsies were included in the subsequent analysis.

    Result
    

    A rare oncogene ERBB2 activating mutation (V659E) was identified in CSF but not in plasma. V659E lies within the transmembrane domain and results in constitutive activation of Src and Akt signaling. Extreme high variants allele fraction (96.8%) of ERBB2 V659E in CSF implied the LOH of ERBB2 in LM. SNPs heterozygosity analysis and low pass WGS were further carried out and confirmed the LOH of entire chromosome 17, but not limited to ERBB2 region. Furthermore, A consecutive an amplification was observed on the remaining copy of chromosome 17q, on which the activated oncogene ERBB2 located. The amplification, following ERBB2 LOH with a concomitant activating mutation, may enhance constitutively active ERBB2 expression and drive the evolution of LM. Besides, there were two more unique mutations in CSF, TP53 T256fs (45.31%) and JAK3 R582Q (32.85%). Relatively Low variants allele fraction indicated that they were subclonal mutation occurring after ERBB2 activating mutation and LOH of chromosome 17.

    Conclusion
    

    We first reported an oncogene ERBB2 LOH in CSF from one NSCLC patient with LM. Based on phylogeny inference, the ERBB2 activating mutation and LOH of chromosome 17 were likely to be the earliest driver event.