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A. Tan



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    OA 07 - Biomarker for Lung Cancer (ID 659)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      OA 07.06 - Innate Genetic Evolution of Lung Cancers and Spatial Heterogeneity: Analysis of Treatment-Naïve Lesions (ID 9102)

      15:45 - 17:30  |  Author(s): A. Tan

      • Abstract
      • Presentation
      • Slides

      Background:
      Cancers are composed of heterogeneous cell populations in terms of somatic mutations and dysregulated signaling pathways. We hypothesized that such heterogeneity, together with selection advantages conferred by distinct microenvironments, may contribute to tumor evolution and metastatic patterns.

      Method:
      We collected tumor specimens and non-cancer tissues from treatment-naïve autopsied patients to study the innate genetic evolution and spatial heterogeneity by RNA-sequencing. Our cohort consists of four NSCLC patients and one SCLC patient. Each patient had 5 – 9 primary and metastatic lesions, including metastases to lung, liver, colon (distant metastases), visceral or parietal pleura (pleural metastases), and intra- or extra-thoracic lymph nodes (lymph nodes metastases). Comprehensive data analyses were performed, including gene expression / pathway analyses and fusions / somatic variants detection.

      Result:
      Global unsupervised clustering analysis of expression data reveals that lesions from each patient clustered together, indicating that tumor cells themselves have greater effects on the gene expression signature than the microenvironment. Pathway analyses in individual patients revealed that the primary lesion is distinct from metastatic lesions in NSCLCs (Figure-left). For the SCLC patient, distant metastases and lymph node metastases clustered according to different parts of the primary tumor (Figure-right). Pathway analyses also revealed that cell-cycle, DNA replication, RNA polymerase, and spliceosome-related pathways are upregulated, while immune-related pathways are downregulated in all metastatic patterns compared with primary lesions. In particular, we observed that multiple immune-related pathways, related to NK cells and T-cells, were downregulated in pleural metastases. Detection of fusions / somatic variants identified the KIF5B-RET fusion as a founder mutation in a never-smoking adenocarcinoma patient. Notch signaling was upregulated, in this patient, in all metastatic lesions but not the primary site.Figure 1



      Conclusion:
      These data demonstrate the similarity and the heterogeneity between primary and metastatic lesions in lung cancer patients. In addition, we identified the correlation between tumor heterogeneity and metastatic patterns.

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