Zhang Bingdong, Li Yuerui, Yang Liu, Chen Yongbing
Department of Gastrointestinal Surgery & Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
Geriatric Cardiology Department of The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army of China General Hospital, Beijing, China.
Front Oncol. 2021 Sep 2;11:584213. doi: 10.3389/fonc.2021.584213. eCollection 2021.
Gastric adenocarcinoma is an important contributor to cancer mortality and morbidity. This study aimed to explore the prognostic value of mutation patterns in gastric adenocarcinoma.
We extracted somatic mutation data for 437 gastric adenocarcinoma samples from The Cancer Genome Atlas (TCGA) Stomach Adenocarcinoma (STAD) cohort. Kaplan-Meier survival in the R package maftools was used to analyze associations between mutations and survival. Multivariate Cox proportional model was used to establish risk formula. A four-gene-based risk score was developed to predict the overall survival of patients with gastric adenocarcinoma. We used the Tianjin cohort dataset with survival information to further evaluate the clinical value of this mutation signature.
Forty-five survival-related mutated genes were identified and verified, most of which were co-occurring in their mutation pattern and co-occurring with MLH3 and polymerase ϵ (POLE) mutations. Gastric adenocarcinoma samples with the 45 mutated genes had a significantly higher mutation count. Four-gene [UTRN, MUC16, coiled-coil domain-containing protein 178 (CCDC178), and HYDIN] mutation status was used to build a prognostic risk score that could be translated into the clinical setting. The association between the four-gene-based signature and overall survival remained statistically significant after controlling for age, sex, TNM stage, and POLE mutation status in the multivariate model [hazard ratio (HR), 1.88; 95% CI, 1.33-2.7; p < 0.001]. The prognostic significance of the four-gene-based risk score identified in TCGA cohort was validated in the Tianjin cohort.
A four-mutated gene risk formula was developed that correlated with the overall survival of patients with gastric adenocarcinoma using a multivariable Cox regression model. In two independent genomic datasets from TCGA and Tianjin cohorts, low risk scores were associated with higher tumor mutation loads and improved outcome in patients with gastric adenocarcinoma. This finding may have implications for prognostic prediction and therapeutic guidance for gastric adenocarcinoma.
胃腺癌是导致癌症死亡和发病的重要因素。本研究旨在探讨胃腺癌突变模式的预后价值。
我们从癌症基因组图谱（TCGA）胃腺癌（STAD）队列中提取了437例胃腺癌样本的体细胞突变数据。使用R包maftools中的Kaplan-Meier生存分析来分析突变与生存之间的关联。采用多变量Cox比例模型建立风险公式。开发了基于四个基因的风险评分来预测胃腺癌患者的总生存期。我们使用具有生存信息的天津队列数据集进一步评估这种突变特征的临床价值。
鉴定并验证了45个与生存相关的突变基因，其中大多数在其突变模式中同时出现，并与MLH3和聚合酶ε（POLE）突变同时出现。具有这45个突变基因的胃腺癌样本的突变计数显著更高。基于四个基因[UTRN、MUC16、含卷曲螺旋结构域蛋白178（CCDC178）和HYDIN]的突变状态构建了一个可转化为临床应用的预后风险评分。在多变量模型中控制年龄、性别、TNM分期和POLE突变状态后，基于四个基因的特征与总生存期之间的关联仍具有统计学意义[风险比（HR），1.88；95%置信区间，1.33 - 2.7；p < 0.001]。在天津队列中验证了在TCGA队列中鉴定的基于四个基因的风险评分的预后意义。
使用多变量Cox回归模型开发了一个与胃腺癌患者总生存期相关的四个突变基因风险公式。在来自TCGA和天津队列的两个独立基因组数据集中，低风险评分与胃腺癌患者较高的肿瘤突变负荷和更好的预后相关。这一发现可能对胃腺癌的预后预测和治疗指导具有重要意义。
