Zhao Liqin, Zhang Jieyun, Qu Xiaofei, Yang Ya'nan, Gong Zhe, Yang Yue, Wu Zhenhua, Guo Weijian
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
Onco Targets Ther. 2020 May 5;13:3809-3821. doi: 10.2147/OTT.S247757. eCollection 2020.
Gene mutations play important roles in tumour metastasis, which significantly affect the prognosis of gastric cancer (GC) patients. This study aimed to compare lymph node (LN) metastasis of GCs with different microsatellite instability (MSI) statuses and explore the effect of mutations on GC LN metastasis.
The association between clinicopathologic characteristics and MSI status or mutational status was analysed based on a GC dataset from The Cancer Genome Atlas (TCGA). The association of mutations with MSI status was assessed. Whole-exome sequencing data of 157 GCs from Chinese patients at Fudan University Shanghai Cancer Center were used to validate the association of mutated and MSI status. Survival plots were obtained from the KMPlot and cBioPortal databases. The roles of ACVR2A and its common mutants in GC cell migration and proliferation were assayed in vitro.
LN metastasis was significantly decreased in MSI-H GCs compared with microsatellite instability-low or microsatellite stable (MSI-L/MSS) GCs (=0.016). As the most frequently mutated gene in MSI-H GCs, mutated was significantly associated with MSI-H (<0.001) and a higher mutation frequency (<0.001). Additionally, a tendency toward decreased LN metastasis was observed in GCs with mutated , although the value was not statistically significant (=0.052). Higher expression of predicted a poor prognosis, but patients with mutations had slightly better disease-free survival. Two polyadenine microsatellite loci in the coding region were hotspot mutation sites. In vitro experiments demonstrated that wild-type ACVR2A promoted GC cell migration probably via the Snail/Slug-EMT pathway, while ACVR2A truncated mutants lost this function.
MSI-H GCs had lower LN metastasis partially due to mutations. Mutated was significantly associated with MSI-H in GC, making it a potential biomarker that could be useful in choosing candidates for immunotherapy.
基因突变在肿瘤转移中起重要作用，这对胃癌（GC）患者的预后有显著影响。本研究旨在比较不同微卫星不稳定性（MSI）状态的GCs的淋巴结（LN）转移情况，并探讨[具体基因]突变对GC LN转移的影响。
基于来自癌症基因组图谱（TCGA）的GC数据集，分析临床病理特征与MSI状态或[具体基因]突变状态之间的关联。评估[具体基因]突变与MSI状态的相关性。使用复旦大学附属肿瘤医院157例中国GC患者的全外显子测序数据来验证[具体基因]突变与MSI状态的相关性。生存曲线来自KMPlot和cBioPortal数据库。在体外检测ACVR2A及其常见突变体在GC细胞迁移和增殖中的作用。
与微卫星不稳定性低或微卫星稳定（MSI-L/MSS）的GCs相比，MSI-H的GCs的LN转移显著减少（P=0.016）。作为MSI-H的GCs中最常突变的基因，[具体基因]突变与MSI-H显著相关（P<0.001）且突变频率更高（P<0.001）。此外，在[具体基因]突变的GCs中观察到LN转移有减少的趋势，尽管P值无统计学意义（P=0.052）。[具体基因]的高表达预示预后不良，但[具体基因]突变的患者无病生存期稍好。[具体基因]编码区的两个多聚腺苷微卫星位点是热点突变位点。体外实验表明，野生型ACVR2A可能通过Snail/Slug-EMT途径促进GC细胞迁移，而ACVR2A截短突变体失去了该功能。
MSI-H的GCs的LN转移较低，部分原因是[具体基因]突变。[具体基因]突变在GC中与MSI-H显著相关，使其成为一种潜在的生物标志物，可用于选择免疫治疗的候选者。
