Concomitance of a novel RMDN2-ALK fusion and an EML4-ALK fusion in a lung adenocarcinoma

  • Author Footnotes
    1 The authors contributed equally to this work.
    Liqun Jiang
    Footnotes
    1 The authors contributed equally to this work.
    Affiliations
    Johns Hopkins Genomics, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD 21205, United States

    Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
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  • Author Footnotes
    1 The authors contributed equally to this work.
    Suping Chen
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    1 The authors contributed equally to this work.
    Affiliations
    Johns Hopkins Genomics, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD 21205, United States

    Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
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  • Victoria Stinnett
    Affiliations
    Clinical Cytogenetics Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States

    Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
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  • Lisa Haley
    Affiliations
    Johns Hopkins Genomics, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD 21205, United States

    Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
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  • Laura Morsberger
    Affiliations
    Johns Hopkins Genomics, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD 21205, United States

    Clinical Cytogenetics Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States

    Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
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  • Alison Shane
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    Clinical Cytogenetics Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States

    Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
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  • Melanie Hardy
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    Clinical Cytogenetics Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States

    Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
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  • Kirstin Smith
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    Johns Hopkins Genomics, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD 21205, United States

    Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
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  • Christopher D. Gocke
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    Johns Hopkins Genomics, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD 21205, United States

    Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
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  • Author Footnotes
    1 The authors contributed equally to this work.
    Ming-Tseh Lin
    Footnotes
    1 The authors contributed equally to this work.
    Affiliations
    Johns Hopkins Genomics, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD 21205, United States

    Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
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  • Author Footnotes
    1 The authors contributed equally to this work.
    Ying S. Zou
    Correspondence
    Corresponding author: Johns Hopkins Genomics, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD 21205, United States.
    Footnotes
    1 The authors contributed equally to this work.
    Affiliations
    Johns Hopkins Genomics, Johns Hopkins University School of Medicine, 1812 Ashland Ave., Suite 221, Baltimore, MD 21205, United States

    Clinical Cytogenetics Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States

    Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
    Search for articles by this author
  • Author Footnotes
    1 The authors contributed equally to this work.

      Highlights

      • A novel RMDN2-ALK fusion was identified in a lung adenocarcinoma.
      • ALK rearranged with two different genes located on chromosome 2.
      • RMDN2-ALK and EML4-ALK fusions coexisted in the same lung cancer.
      • The RMDN2 gene locates between ALK and EML4 genes.
      • Both RMDN2-ALK and EML4-ALK fusions contain the intact ALK kinase domain.

      Abstract

      The anaplastic lymphoma kinase (ALK) fusions/rearrangements in non-small cell lung cancer (NSCLC) act as oncogenic driver mutations. ALK tyrosine kinase inhibitors have anti-tumor activities in ALK-positive NSCLC. Although the EML4-ALK fusion is common in NSCLC, concomitance of an additional ALK fusion together with an EML4-ALK fusion is not common. Here, we present a lung adenocarcinoma with two ALK fusions, a novel RMDN2-ALK fusion accompanied by an EML4-ALK fusion, detected by a targeted next generation sequencing assay. The genomic translocation breakpoints of the RMDN2-ALK fusion were mapped to intron 2 for RMDN2 and exon 15 for ALK, and EML4-ALK breakpoints were mapped to intron 13 for EML4 and intron 19 for ALK. ALK break-apart FISH detected multiple ALK rearrangements, a gene fusion panel (NanoString) test confirmed the EML4-ALK fusion, and RNA-sequencing revealed two ALK fusions. The RMDN2 gene locates at the short arm of chromosome 2 between ALK and EML4 genes. The intact ALK kinase domain fused to RMDN2. Genome-wide copy number variants were found in multiple chromosome arms and the short arm of chromosome 2, suggestive of complex rearrangements. Further detailed analyses of breakpoints and copy number variants may shed light on mechanisms of their formation and pathogenesis in lung malignancies.

      Keywords

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