Primary and Metastatic Cutaneous Melanomas Express ALK Through Alternative Transcriptional Initiation.
Primary and Metastatic Cutaneous Melanomas Express ALK Through Alternative Transcriptional Initiation.
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DOI：
10.1097/pas.0000000000000611
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Wiesner T
中科院分区：
文献类型：
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作者：
Busam KJ;Vilain RE;Lum T;Busam JA;Hollmann TJ;Saw RP;Coit DC;Scolyer RA;Wiesner T
在黑色素瘤中已经发现了一些常见的驱动基因突变，但其他遗传或表观遗传异常也可能在黑色素瘤的发病机制中发挥作用，并提供潜在的治疗靶点。例如，间变性淋巴瘤激酶(ALK)的易位被报道在痰样黑素细胞肿瘤中导致激酶融合蛋白，从而导致免疫组织化学可检测到ALK的表达。在这项研究中，我们试图确定ALK是否也在非痰液性原发和转移性皮肤黑色素瘤中表达。对600例患者的603例黑色素瘤(原发灶303例，转移瘤300例)进行了碱性磷酸酶免疫组织化学(IHC)染色。ALK IHC在7例原发肿瘤和9例转移瘤中均有表达。7例原发肿瘤中5例和9例转移灶中6例肿瘤细胞碱性磷酸酶免疫反应阳性。在另外两个原发灶和三个转移灶中，只有不到一半的肿瘤细胞呈阳性染色。在BRAF或NRAS突变的存在或不存在时，ALK阳性。与之前对ALK阳性的Spitz肿瘤的观察相反，ALK阳性的黑色素瘤中没有一例有易位。相反，ALK阳性的黑色素瘤主要表达最近描述的ALK亚型ALKATI，它缺乏野生型ALK的胞外和跨膜结构域，主要由细胞内酪氨酸激酶结构域组成，起源于ALK基因内的另一个转录起始(ATI)位点。这一发现具有临床意义，因为有ALK表达的转移性黑色素瘤患者可能从ALK激酶抑制剂的治疗中受益。
A number of common driver mutations have been identified in melanoma, but other genetic or epigenetic aberrations are also likely to play a role in the pathogenesis of melanoma and present potential therapeutic targets. Translocations of the anaplastic lymphoma kinase (ALK), for example, have been reported in spitzoid melanocytic neoplasms leading to kinase-fusion proteins that result in immunohistochemically detectable ALK expression. In this study, we sought to determine whether ALK was also expressed in non-spitzoid primary and metastatic cutaneous melanomas. ALK immunohistochemistry (IHC) was performed on 603 melanomas (303 primary and 300 metastatic tumors) from 600 patients. ALK IHC expression was identified in 7 primary and 9 metastatic tumors. In 5 of 7 primary tumors and in 6 of 9 metastatic lesions, the majority of tumor cells were immunoreactive for ALK. In the other two primary and three metastatic lesions, positive staining was identified in less than half of the tumor cells. ALK-positivity was found in the presence or absence of BRAF or NRAS mutations. In contrast to prior observations with ALK-positive Spitz tumors, none of the ALK-positive melanomas harbored a translocation. Instead, the ALK-positive melanomas predominantly expressed the recently described ALK isoform, ALKATI, which lacks the extracellular and transmembrane domains of wild-type ALK, consists primarily of the intracellular tyrosine kinase domain, and originates from an alternative transcriptional initiation (ATI) site within the ALK gene. The findings are clinically relevant as patients with metastatic melanoma who have ALK expression may potentially benefit from treatment with ALK kinase inhibitors.