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.
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.
Cancer Genet. 2021 Nov;258-259:18-22. doi: 10.1016/j.cancergen.2021.06.004. Epub 2021 Jun 23.
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.
间变性淋巴瘤激酶 (ALK) 融合/重排在非小细胞肺癌 (NSCLC) 中作为致癌驱动突变。ALK 酪氨酸激酶抑制剂在 ALK 阳性 NSCLC 中具有抗肿瘤活性。虽然 EML4-ALK 融合在 NSCLC 中很常见，但同时存在另外一种 ALK 融合与 EML4-ALK 融合并不常见。在这里，我们介绍了一例肺腺癌，其存在两种 ALK 融合，一种新的 RMDN2-ALK 融合伴随着 EML4-ALK 融合，通过靶向下一代测序检测到。RMDN2-ALK 融合的基因组易位断点定位于 RMDN2 的内含子 2 和 ALK 的外显子 15，而 EML4-ALK 断点定位于 EML4 的内含子 13 和 ALK 的内含子 19。ALK 断裂分离 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 测序揭示了两种 ALK 融合。RMDN2 基因位于 2 号染色体的短臂上，位于 ALK 和 EML4 基因之间。完整的 ALK 激酶结构域与 RMDN2 融合。在多个染色体臂和 2 号染色体的短臂上发现了全基因组拷贝数变异，提示存在复杂的重排。进一步详细分析断点和拷贝数变异可能有助于阐明其在肺癌恶性肿瘤中的形成和发病机制。
