Departments of *Pathology, §Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, Korea; †Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea; ‡Laboratory of Cancer Genomics and Molecular Pathology, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea; ‖Pfizer Oncology, San Diego, California; ¶Pathology Project for Molecular Targets of the Cancer Institute/Division of Pathology of the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan; and #Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea.
J Thorac Oncol. 2014 Mar;9(3):419-22. doi: 10.1097/JTO.0000000000000061.
The most common mechanism underlying overexpression and activation of anaplastic lymphoma kinase (ALK) in non-small-cell lung carcinoma could be attributed to the formation of a fusion protein. To date, five fusion partners of ALK have been reported, namely, echinoderm microtubule associated protein like 4, tropomyosin-related kinase-fused gene, kinesin family member 5B, kinesin light chain 1, and protein tyrosine phosphatase, nonreceptor type 3.
In this article, we report a novel fusion gene huntingtin interacting protein 1 (HIP1)-ALK, which is conjoined between the huntingtin-interacting protein 1 gene HIP1 and ALK. Reverse-transcriptase polymerase chain reaction and immunohistochemical analysis were used to detect this fusion gene's transcript and protein expression, respectively. We had amplified the full-length cDNA sequence of this novel fusion gene by using 5'-rapid amplification of cDNA ends. The causative genomic translocation t(2;7)(p23;q11.23) for generating this novel fusion gene was verified by using genomic sequencing.
The examined adenocarcinoma showed predominant acinar pattern, and ALK immunostaining was localized to the cytoplasm, with intense staining in the submembrane region. In break-apart, fluorescence in situ hybridization analysis for ALK, split of the 5' and 3' probe signals, and isolated 3' signals were observed. Reverse-transcriptase polymerase chain reaction revealed that the tumor harbored a novel fusion transcript in which exon 21 of HIP1 was fused to exon 20 of ALK in-frame.
The novel fusion gene and its protein HIP1-ALK harboring epsin N-terminal homology, coiled-coil, juxtamembrane, and kinase domains, which could play a role in carcinogenesis, could become diagnostic and therapeutic target of the lung adenocarcinoma and deserve a further study in the future.
非小细胞肺癌中，间变性淋巴瘤激酶（ALK）过表达和激活的最常见机制可归因于融合蛋白的形成。迄今为止，已经报道了 ALK 的五个融合伴侣，即类星体微管相关蛋白 4、原肌球蛋白相关激酶融合基因、驱动蛋白家族成员 5B、驱动蛋白轻链 1 和蛋白酪氨酸磷酸酶非受体型 3。
本文报道了一种新的融合基因——亨廷顿相互作用蛋白 1（HIP1）-ALK，它是由亨廷顿相互作用蛋白 1 基因 HIP1 和 ALK 拼接而成。采用逆转录-聚合酶链反应和免疫组织化学分析分别检测该融合基因的转录本和蛋白表达。我们使用 5'-快速扩增 cDNA 末端法扩增了该新型融合基因的全长 cDNA 序列。通过基因组测序证实了导致该新型融合基因产生的致病基因组易位 t(2;7)(p23;q11.23)。
所检查的腺癌主要表现为腺泡模式，ALK 免疫染色定位于细胞质，亚膜区染色强烈。在分离，ALK 的荧光原位杂交分析中，观察到 5'和 3'探针信号的分离和孤立的 3'信号。逆转录-聚合酶链反应显示肿瘤中存在一种新型融合转录本，其中 HIP1 的外显子 21 与 ALK 的外显子 20 融合，形成框架内融合。
新型融合基因及其蛋白 HIP1-ALK 具有 Epsin N 端同源性、卷曲螺旋、跨膜区和激酶结构域，可能在肿瘤发生中发挥作用，可成为肺腺癌的诊断和治疗靶点，值得进一步研究。
