POLE mutations improve the prognosis of endometrial cancer via regulating cellular metabolism through AMF/AMFR signal transduction
POLE mutations improve the prognosis of endometrial cancer via regulating cellular metabolism through AMF/AMFR signal transduction
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POLE突变通过AMF/AMFR信号转导调节细胞代谢改善子宫内膜癌的预后
DOI：
10.1186/s12881-019-0936-2
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发表时间：
2019-12-21
影响因子：
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通讯作者：
Wan, Xiao-Ping
中科院分区：
文献类型：
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作者：
Li, Yiran;Bian, Yiding;Wan, Xiao-Ping
背景：子宫内膜肿瘤是女性常见的恶性肿瘤，近年来发病率和死亡率呈上升趋势。POLE编码负责前导链DNA复制的DNA聚合酶β。POLE的体细胞突变已经在许多癌症中得到承认，导致DNA错误的积累，导致超突变肿瘤。据报道，POLE核酸外切酶结构域的突变可改善子宫内膜癌的无进展生存期。然而，POLE突变与子宫内膜癌患者预后之间的潜在关系和潜在机制尚不清楚。方法：从TCGA数据库中获得全外显子组测序数据、RNA测序数据和临床信息，并用于本研究的分析。使用全外显子组测序数据分析详细的突变信息，并用OncoPlot显示突变基因。采用生存曲线和考克斯比例风险回归分析评价患者预后、临床特征与预后的关系。用edgeRR/Bioconductor软件包分析差异表达基因，然后用GSEA预排序工具进行基因集富集分析（Gene Set Enrichment Analysis，GSEA），估计基因的功能。表达值进行聚类，使用层次聚类与欧氏距离和沃德连锁的dendextend R package.Results：POLE突变状态被证明是一个独立的预后因素子宫内膜癌患者。体细胞POLE突变的患者预后良好。POLE突变调节糖酵解和细胞因子分泌，影响细胞代谢和免疫反应。自分泌运动因子（AMF）/PGI和AMFR/gp 78在POLE突变患者中表现出更高的表达水平。结论：POLE基因突变是子宫内膜癌发生的一个重要因素，导致AMF/PGI和AMFR/gp 78的高表达。提示综合考虑POLE突变、AMF/PGI和AMFR/gp 78的表达，可能为子宫内膜癌的治疗提供一种更为可行和有效的方法，并可能改善预后。
Background: The morbidity and mortality of endometrial tumors, a common type of malignant cancer in women, have increased in recent years. POLE encodes the DNA polymerase epsilon, which is responsible for the leading strand DNA replication. Somatic mutations of POLE have been acknowledged in numerous cancers, resulting in the accumulation of DNA errors, leading to ultra-mutated tumors. Mutations in the exonuclease domain of POLE have been reported to improve progression-free survival in endometrial cancer. However, the potential relationship and underlying mechanism between POLE mutations and the prognosis of endometrial cancer patients remains unclear.Methods: The whole exome sequencing data, RNA sequencing data, and clinical information were obtained from the TCGA database and employed for the analyses in this study. The detailed mutational information was analyzed using whole exome sequencing data and the mutated genes were shown with OncoPlot. The survival curves and cox proportional hazards regression analysis were used to accessed patient prognosis, the association of clinical characteristics and prognosis. Differentially expressed genes were analyzed by the edgeR R/Bioconductor package, then the GSEA Pre-ranked tool was used for Gene Set Enrichment Analysis (GSEA) to estimate the function of genes. Expression values were clustered using hierarchical clustering with Euclidean distance and ward linkage by the dendextend R package.Results: POLE mutational status was proven to be an independent prognostic factor for endometrial cancer patients. Patients with somatic POLE mutations presented a favorable prognosis. POLE mutations regulated glycolysis and cytokine secretion, affecting cell metabolism and immune response. Autocrine motility factor (AMF)/PGI and AMFR/gp78 exhibited higher expression levels in POLE mutant patients. The comprehensive high expressions of AMFR/gp78 and low expression of POLE were associated with the favorable prognosis of endometrial cancer patients.Conclusions: This study showed the POLE mutations a vital factor in endometrial cancer patients, leading to a higher expression of AMF/PGI and AMFR/gp78. These results suggested comprehensive consideration of the POLE mutations, expression of AMF/PGI and AMFR/gp78 may provide a more feasible and effective approach for the treatment of endometrial cancer, which might improve the prognosis.