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Zhifang Liu



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    P53 - Tumor Biology and Systems Biology - Basic and Translational Science - Misc. Topics (ID 213)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P53.09 - Molecular Alterations of KIT Oncogene in a Large Cohort of Chinese Pan-Lung Cancer Patients (ID 2007)

      00:00 - 00:00  |  Presenting Author(s): Zhifang Liu

      • Abstract
      • Slides

      Introduction

      KIT was identified as a proto-oncogene mutated or up-regulated in different types of cancers. However, it is unlikely that KIT inhibitors will be effective for lung cancer patients. Analysis of activating KIT mutations in lung cancer will be helpful to explain the above issue. Furthermore, previous studies showed that an activating KIT mutation could induce crizotinib resistance in ROS1-positive lung cancer. To assess the probability of tyrosine kinase inhibitors (TKIs) resistance induced by activating KIT mutations, we explored co-occurring activating alterations of KIT with other tyrosine kinase genes in a large cohort of Chinese lung cancer patients.

      Methods

      A total of 14429 Chines patients with all types of pathologically confirmed lung cancers were enrolled from January 2017 to November 2019. The mutation profiles of KIT and other genes were detected by next-generation sequencing.

      Results

      In our cohort, 836 patients with lung cancer (5.79%) were identified as having at least one genomic alteration of KIT. The most frequent mutation was R19C (0.49%), followed by M541L (0.35%), D975N (0.24%), and T84M (0.19%). However, the clinical significance of those mutations is unknown. Next, activating KIT mutations were analyzed. Surprisingly, our results showed that activating KIT mutations (including V559D, V560D, K642E, V654A, T670I, D816V/Y/F/H, D820E/V, N822Y/K, and so on), which were identified in other cancer types, were very rare in lung cancer. The frequency of activating KIT mutations is 0.243% (35/14429). Our results also showed that activating KIT mutations do not co-occur with clinically relevant alterations of ROS1, RET, NTRK, and MET. Only one patient had co-occurring alteration of KIT with ALK fusion. This suggested that crizotinib resistance induced by activating KIT mutation was an uncommon event. Furthermore,about 11.4% (4/35) of patients had co-occurring activating mutations of KIT and EGFR. Now we are studying whether KIT activating mutations affects EGFR-TKIs therapy.

      Conclusion

      Although 5.79% of Chinese lung cancer patients harbored KIT mutations, only 0.243% had activating mutations. This suggested that targeting KIT might show clinical benefit in several cases and immunohistochemistry staining might not a good method for patient selection in imatinib clinical trials in lung cancers. Meanwhile, further investigation is required to determine whether KIT activating mutations can induce resistance to EGFR-TKIs therapy.

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    P88 - Targeted Therapy - Clinically Focused - ROS1 (ID 265)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P88.05 - A Recommended one-step Targeted Sequencing Technology for Identification of a Dual CD74-ROS1 in NSCLC (ID 3630)

      00:00 - 00:00  |  Author(s): Zhifang Liu

      • Abstract
      • Slides

      Introduction

      ROS1 rearrangements define a distinct molecular subtype of non-small-cell lung cancer (approximately 2% of NSCLC), which can be effectively treated with a tyrosine kinase inhibitor (TKI) targeting ROS1/MET/ALK rearrangements such as crizotinib. The coexistence of two variants of ROS1 fusion has been described, however, dual-ROS1 fusions detected simultaneously in one patient with NSCLC is still rare. Herein we present a dual CD74-ROS1 (CD74-E6 and ROS1-E32/34) fusions in a patient with lung adenocarcinoma using one-step targeted sequencing technology who responded well to crizotinib.

      Methods

      We retrospectively reviewed genomic profiles of 180 NSCLC patients using a targeted panel across 51 cancer-related genes . A dual ROS1 fusions: CD74-ROS1 (C6:R32, 21.64%) and CD74-ROS1 (C6:R34, 28.24%) was identified in this cohort and the break-apart FISH analysis showed clear separation of green (5’) and red (3’) signals corresponding to the ROS1 gene. 51 genes panel is based on the one-step targeted sequencing technology, which can achieve high coverage depth at relatively low cost for its amplicon-based protocol. To validate the reliability of this dual fusions detected, the hybridization capture-based assay and paired-end RNA sequencing were performed. The hybridization capture-based assay detected neither of the dual fusions using a targeted DNA panel which included ROS1 and CD74 genes for the fusions. The average distinct coverage of this sample is 1565× and the total mapping reads are 141892 for ROS1 intron31-35 region in hybridization capture-based assay. Both CD74-ROS1 (C6:R32) and CD74-ROS1 (C6:R34) were observed in RNAseq assay using Collibri stranded RNA-Seq kit and VAHTS® Universal V6 kit.

      Results

      Based on reliable results, especially coverage reads number of CD74-ROS1 (C6:R32) and CD74-ROS1 (C6:R34), this finding may be due to the alternative splicing of ROS1 RNA. RNA splicing plays an essential role in the process of gene regulation, which allows for the exon composition of spliced mRNA to vary significantly[4]. However, because of lack of DNA sequence of the fusion gene, we can be unable to determine whether one of the dual-ROS1 fusion is a resulting variant from different genomic rearrangement or just a splice variant in mRNA of CD74-ROS1. In addition, the break-apart FISH is the most commonly used diagnostic method for detecting ROS1 fusion genes to date. However, FISH can’t identify the coexistence of divergent variants of fusion genes.

      Conclusion

      For this dual ROS1 fusion pattern, one-step targeted sequencing technology may be a more efficient diagnostic method than FISH, the hybridization capture-based assay and RNA-Seq. Our results are also given demonstrated the one-step targeted sequencing technology is as a potential effective tool for dual fusions detection. Although ROS1 gene fusion is found in about 1-2% of NSCLC, data on dual ROS1 fusions remain scarce because of the low occurrence rate. The mechanism of this phenomenon and the possible difference in response to ROS1 inhibitors and the clinical behavior of patients with dual-ROS1 fusions has yet to be investigated.

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