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  P35 - Pathology - Genomics (ID 105)

  • Event: WCLC 2020
  • Type: Posters
  • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall

  • 34736

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    P35.27 - Next Generation Sequencing Reveals the Genetic Landscape of JAK Family in Chinese Lung Cancer Patients (ID 2150)

    00:00 - 00:00  |  Presenting Author(s): Lin Gui
    • Abstract
    • Slides

    Introduction
    

    Gain-of-function mutations of JAK genes are the main molecular pathogenesis of hematologic malignancies, such as myeloproliferative neoplasm (MPN), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) and adult acute lymphocytic leukemia (ALL). Some studies have shown that the constitutive activation of JAK pathway is related to EGFR-TKI resistance in lung cancer patients, but the genomic mutational status of JAK gene family in lung cancer remains unclear.

    Methods
    

    Totally 14429 patients with lung cancer in China were studied retrospectively; then we analyzed the mutation patterns of JAK family and EGFR gene in tumor tissues and/or liquid biopsy samples of these patients through high-throughput sequencing technology.

    Results
    

    The mutation frequencies of JAK family genes JAK1, JAK2, and JAK3 in Chinese patients with lung cancer were 0.55% (79/14429), 5.27% (760/14429), and 1.67% (241/14429), respectively. Among them, the most common mutations in JAK1 were N339K (5 patients), H183Q (4 patients) and H1072Q (3 patients); the mutations in JAK3 include I688F (19 patients) and A573V (11 patients). Interestingly, the most frequent hotspot mutation of JAK2 gene in lung cancer patients was V617F (87 patients), in line with blood tumors such as MPN. Others were L892Q (19 patients), H848Q (14 patients) and F148I (13 patients). However, in lung cancer, JAK2 mutations mainly occurred in exon 5. It is inconsistent with the locations of JAK2 mutations in blood tumors, which happen largely in exon 12 and exon 16.

    Studies have found that activation of the JAK pathway can lead to drug resistance in patients with lung cancer who are sensitive to EGFR-TKI, erlotinib. Our analysis found that the frequencies of JAK1 and JAK2 mutations with co-occurring erlotinib-sensitive EGFR common mutations (L858R, exon19 deletion, etc.) were 0.15% (22/14429) and 1.17% (169/14429), respectively. Among them, the proportion of EGFR L858R was the highest (0.10% in JAK1, 0.69% in JAK2). These patients with co-occurring mutations may be resistant to EGFR-TKI such as erlotinib.

    In addition, other studies found that JAK inhibitors can overcome EGFR-TKI resistance caused by EGFR T790M mutation. Forty-eight patients appeared common EGFR-TKI sensitive mutations, T790M mutations, and JAKs mutations simultaneously (EGFR co-mutated with JAK1 in 2 patients, with JAK2 in 41 patients, and with JAK3 in 5 patients). Thus, 0.3% lung cancer patients with acquired resistance to EGFR inhibitors may benefit from the combined therapy of JAK inhibitors and EGFR-TKIs.

    Conclusion
    

    Genomic studies on lung cancer patients in China have found that activation of the JAK signaling pathway is an important molecular biological feature of lung cancer. Gain-of-function mutations of JAKs in lung cancer patients, who harbor epidermal growth factor receptor-activating mutation, may lead to drug resistance to EGFR-TKI. Targeting inhibition of JAK and EGFR may be a new treatment in lung cancer patients with EGFR-TKIs resistance.

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