PI3K-Akt/mTOR/AMPK 信号通路基因突变与鼻咽癌疗效及预后的关系。
Relationship of PI3K-Akt/mTOR/AMPK signaling pathway genetic mutation with efficacy and prognosis in nasopharyngeal carcinoma.
机构信息
Second Department of Head and Neck Radiotherapy, Hunan Cancer Hospital; Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, China.
出版信息
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2022 Feb 28;47(2):165-173. doi: 10.11817/j.issn.1672-7347.2022.200821.
OBJECTIVES
Genetic mutation is one of the important causes for tumor genesis and development, but genetic mutation in nasopharyngeal carcinoma (NPC) has rarely been reported. This study explored the role of phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt), mammalian target of rapamycin (mTOR), and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway in the efficacy and prognosis in patients with NPC.
METHODS
A total of 31 patients with advanced NPC, who came from the Affiliated Cancer Hospital of Xiangya School of Medicine of Central South University/Hunan Provincial Cancer Hospital, were enrolled. All of the exons of 288 genes, introns of 38 genes and promoters or fusion breakpoint regions from the nasopharyngeal biopsy tissues before treatment were detected by the gene sequencing platform Illumina NextSeq CN500. The coding regions of 728 genes were carried out a high-depth sequencing of target region capture, and the 4 variant types of tumor genes (including point mutations, insertion deletions of small fragments, copy number variations, and currently known fusion genes) were detected. All of 31 patients received platinum-based induction chemotherapy combined with concurrent chemoradiotherapy and were followed up for a long time.
RESULTS
The 3-year regional failure-free survival (RFFS) and disease-free survival (DFS) in patients with PI3K-Akt pathway mutation were significantly lower than those in unmutated patients (χ=6.647, <0.05). The 3-year RFFS and DFS in patients with mTOR pathway mutations were significantly lower than those in unmutated patients, and there was significant difference (χ=5.570, <0.05). The rate of complete response (CR) in patients with unmutated AMPK pathway was significantly higher than that in patients with mutation at 3 months after treatment (<0.05), and the 3-year RFFS and DFS in patients with AMPK pathway mutation were significantly lower than those in unmutated patients (χ=4.553, <0.05). PI3K-Akt/mTOR/AMPK signaling pathway mutations and pre-treatment EB virus DNA copy numbers were independent prognostic factors for 3-year RFFS and DFS in patients with NPC (both <0.05).
CONCLUSIONS
The NPC patients with PI3K-Akt/mTOR/AMPK signaling pathway mutation have poor prognosis, and the detection of PI3K-Akt, mTOR, AMPK driver genes and signaling pathways by next-generation sequencing is expected to provide new idea for basic research and targeted therapy of NPC.
目的
基因突变是肿瘤发生和发展的重要原因之一，但鼻咽癌（NPC）的基因突变很少有报道。本研究探讨了磷脂酰肌醇 3 激酶-蛋白激酶 B（PI3K-Akt）、哺乳动物雷帕霉素靶蛋白（mTOR）和腺苷 5'-单磷酸（AMP）激活的蛋白激酶（AMPK）信号通路在 NPC 患者疗效和预后中的作用。
方法
本研究共纳入 31 例来自中南大学湘雅医学院附属肿瘤医院/湖南省肿瘤医院的晚期 NPC 患者。采用基因测序平台 Illumina NextSeq CN500 检测治疗前鼻咽活检组织中 288 个基因的外显子、38 个基因的内含子以及启动子或融合断点区域，对 728 个基因的编码区进行靶向区域捕获的高深度测序，检测肿瘤基因的 4 种变异类型（包括点突变、小片段插入缺失、拷贝数变异和目前已知的融合基因）。所有 31 例患者均接受铂类诱导化疗联合同期放化疗，并进行长期随访。
结果
PI3K-Akt 通路突变患者的 3 年区域无失败生存率（RFFS）和无疾病生存率（DFS）明显低于未突变患者（χ=6.647，<0.05）。mTOR 通路突变患者的 3 年 RFFS 和 DFS 明显低于未突变患者，差异有统计学意义（χ=5.570，<0.05）。治疗 3 个月时，未突变 AMPK 通路患者的完全缓解（CR）率明显高于突变患者（<0.05），且 AMPK 通路突变患者的 3 年 RFFS 和 DFS 明显低于未突变患者（χ=4.553，<0.05）。PI3K-Akt/mTOR/AMPK 信号通路突变和治疗前 EBV-DNA 拷贝数是 NPC 患者 3 年 RFFS 和 DFS 的独立预后因素（均<0.05）。
结论
NPC 患者存在 PI3K-Akt/mTOR/AMPK 信号通路突变，预后不良，通过下一代测序检测 PI3K-Akt、mTOR、AMPK 驱动基因及其信号通路，有望为 NPC 的基础研究和靶向治疗提供新的思路。
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