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 (χ2=6.647, P<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 (χ2=5.570, P<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 (P<0.05), and the 3-year RFFS and DFS in patients with AMPK pathway mutation were significantly lower than those in unmutated patients (χ2=4.553, P<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 P<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: 基因突变是导致肿瘤发生、发展的重要原因之一。本研究探讨磷脂酰肌醇3 激酶-蛋白激酶 B(phosphatidylinositol 3 kinase-protein kinase B，PI3K-Akt)、雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)、AMP依赖的蛋白激酶[adenosine 5'-monophosphate (AMP)-activated protein kinase，AMPK]信号通路与鼻咽癌患者疗效及预后的关系。方法: 选取中南大学湘雅医学院附属肿瘤医院/湖南省肿瘤医院头颈放疗二科31例初治中晚期鼻咽癌患者，采用基因测序平台Illumina NextSeq CN500检测治疗前鼻咽部活检组织中288个基因的全部外显子、38个基因的内含子、启动子或融合断点区域，对728个基因的编码区域进行目标区域捕获的高深度测序，并检测肿瘤基因4种变异类型，包括点突变、小片段的插入缺失、拷贝数变异和目前已知的融合基因。31例患者均接受以铂类为基础的诱导化学治疗联合同步放化疗，并对患者进行长期随访。结果: PI3K-Akt通路突变患者的3年区域无失败生存率(regional failure-free survival，RFFS)及无病生存率(disease-free survival，DFS)均显著低于未突变患者，差异有统计学意义(χ2=6.647，P<0.05)。mTOR通路突变患者的3年RFFS及DFS均显著低于未突变患者，差异有统计学意义(χ2=5.570，P<0.05)。AMPK通路未突变患者在治疗后3个月的完全缓解(complete response，CR)率显著高于突变的患者，差异有统计学意义(P<0.05)，AMPK通路突变患者的3年RFFS及DFS均显著低于未突变患者，差异有统计学意义(χ2=4.553，P<0.05)。PI3K-Akt/mTOR/AMPK信号通路突变和治疗前EB病毒DNA拷贝数是鼻咽癌患者3年RFFS和DFS的独立预后因素(均P<0.05)。结论: 存在PI3K-Akt/mTOR/AMPK信号通路基因突变的鼻咽癌患者预后较差，应用二代测序对PI3K-Akt/mTOR/AMPK驱动基因和信号通路的检测有望为鼻咽癌基础研究及靶向治疗提供新思路。.
Keywords: PI3K-Akt/mTOR/AMPK signaling pathway; efficacy; nasopharyngeal carcinoma; next-generation sequencing; prognosis.