Ozaki Mami, Ikushima Hiroaki, Suzuki Masaki, Yokoyama Akira, Fukuda Kensuke, Watanabe Kousuke, Shinozaki-Ushiku Aya, Kato Motohiro, Ushiku Tetsuo, Aburatani Hiroyuki, Oda Katsutoshi, Kage Hidenori
Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Thorac Cancer. 2025 Aug;16(15):e70146. doi: 10.1111/1759-7714.70146.
ALK fusions are well-established oncogenic drivers in lung cancer, typically resulting in ALK activation through dimerization mediated by partner proteins. However, alternative mechanisms of ALK activation have also been reported. We herein report an 80-year-old man with metastatic lung adenocarcinoma, who initially tested negative for ALK rearrangement using a polymerase chain reaction-based assay. RNA-based hybrid capture targeted sequencing later identified an EML4-ALK fusion transcript in which EML4 exon 15 and ALK intron 19 were fused. This resulted in a stop codon being retained in the unspliced ALK intron 19, preventing fusion protein translation. However, immunohistochemistry revealed overexpression of ALK, suggesting the existence of alternative translation initiation sites in exon 20 or downstream. The patient showed a marked response to alectinib therapy. This case underscores the importance of using multiple methods to detect actionable gene fusions and to ensure appropriate targeted therapy selection.
ALK融合是肺癌中已明确的致癌驱动因素，通常通过伴侣蛋白介导的二聚化导致ALK激活。然而，也有报道称存在ALK激活的其他机制。我们在此报告一名80岁的转移性肺腺癌男性患者，其最初使用基于聚合酶链反应的检测方法检测ALK重排为阴性。基于RNA的杂交捕获靶向测序后来鉴定出一种EML4-ALK融合转录本，其中EML4外显子15和ALK内含子19融合。这导致一个终止密码子保留在未剪接的ALK内含子19中，阻止了融合蛋白的翻译。然而，免疫组织化学显示ALK过表达，提示外显子20或下游存在替代翻译起始位点。该患者对阿来替尼治疗表现出显著反应。该病例强调了使用多种方法检测可操作基因融合并确保选择适当靶向治疗的重要性。
