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.

非小细胞肺癌 (NSCLC) 中的间变性淋巴瘤激酶 ( ALK ) 融合/重排充当致癌驱动突变。ALK酪氨酸激酶抑制剂在ALK阳性 NSCLC 中具有抗肿瘤活性。尽管EML4-ALK融合在 NSCLC 中很常见，但额外的ALK融合与EML4-ALK融合的同时存在并不常见。在这里，我们提出了一种具有两种ALK融合的肺腺癌，一种新型的RMDN2-ALK融合伴随着EML4-ALK融合，通过靶向下一代测序分析检测到。RMDN2-ALK的基因组易位断点融合被定位到RMDN2 的内含子 2和ALK 的外显子 15 ，并且EML4-ALK断点被定位到EML4 的内含子 13和ALK 的内含子 19 。ALK分离 FISH 检测到多个ALK重排，基因融合面板 (NanoString) 测试证实了EML4-ALK融合，RNA 测序显示两个ALK融合。所述RMDN2基因定位于染色体之间2的短臂ALK和EML4基因。与RMDN2融合的完整ALK激酶结构域. 在多个染色体臂和 2 号染色体的短臂中发现了全基因组拷贝数变异，表明存在复杂的重排。对断点和拷贝数变异的进一步详细分析可能会阐明它们在肺部恶性肿瘤中的形成和发病机制。