Establishment and validation of a novel autophagy-related gene signature for patients with breast cancer
Establishment and validation of a novel autophagy-related gene signature for patients with breast cancer
复制标题
乳腺癌患者新型自噬相关基因特征的建立和验证
DOI：
10.1016/j.gene.2020.144974
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发表时间：
2020-12-15
期刊：
影响因子：
3.5
通讯作者：
Zhu, Wei
中科院分区：
文献类型：
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作者：
Du, Jun-Xian;Chen, Cong;Zhu, Wei
背景：大量证据表明自噬在乳腺癌的生物学过程中起重要作用。本研究旨在基于高通量测序数据集构建和评估一种新的自噬相关基因标签作为乳腺癌患者的潜在预后因子和治疗靶点。分析从人类自噬数据库获得的自噬相关基因和从癌症基因组图谱（TCGA）获得的高测序数据，以鉴定肿瘤和正常组织之间的差异表达基因（DEG）。通过GO和KEGG分析探讨DEG的潜在生物学和病理学功能。单因素考克斯回归分析筛选自噬相关的预后基因。随后使用Alkaike信息准则（AIC）和多变量考克斯回归模型进行逐步模型选择以构建自噬相关基因签名。然后，根据自噬相关基因签名确定的风险评分，将患者分为高风险组和低风险组。采用多因素考克斯回归模型和分层分析来确定该基因标签在整个队列和各个亚组中的预后价值。分别采用t检验和方差分析比较连续变量（5个预后基因和风险评分）在二分类组和多分类组中的表达差异。通过Kaplan-Meier分析、对数秩检验和受试者工作特征（ROC）曲线下面积（AUC）验证基于GSE 20685和GSE 21653数据集的自噬相关基因特征的准确性和精确性。GO和KEGG分析提示自噬相关DEG可能参与乳腺癌的发生、发展和耐药。然后，我们确定了五个自噬相关基因（EIF 4 EBP 1，ATG 4A，BAG 1，MAP 1 LC 3A和SERPINA 1），这些基因对乳腺癌有显著的预后价值。构建自噬相关基因签名，并根据患者的风险评分将其分为高风险组和低风险组。高危组患者的总生存期（OS）和无复发生存期（RFS）均短于低危组（OS：HR = 1.620，95%CI：1.345-1.950; P < 0.001; RFS：HR = 1.487，95%CI：1.248-1.771，P < 0.001）。自噬相关基因标签在分层亚组中具有显著的预后价值，特别是在晚期乳腺癌亚组（T3-4; N2-3; III-IV期）中。其预后价值在两个GEO验证数据集中得到进一步证实（GSE 20685：P = 6.795e-03; GSE 21653：P = 1.383e-03）。结论：我们建立并证实了一种新的自噬相关基因标签，该基因标签对乳腺癌患者尤其是晚期乳腺癌患者具有独立的生存预后价值。本研究为乳腺癌自噬相关基因的分子机制研究提供了新的思路。
Background: There exists considerable evidence conforming that autophagy may play an important role in the biological process of breast cancer. This study aimed to construct and evaluate a novel autophagy-related gene signature as a potential prognostic factor and therapeutic target in breast cancer patients based on high-throughput sequencing datasets.Materials & methods: Autophagy-related genes obtained from the Human Autophagy Database and high-sequencing data obtained from The Cancer Genome Atlas (TCGA) were analyzed to identify differential expressed genes (DEGs) between tumor and normal tissues. Then GO and KEGG analysis were performed to explore potential biological and pathological functions of DEGs. Autophagy-related prognostic genes were identified by univariate COX regression analysis. Subsequently stepwise model selection using the Alkaike information criterion (AIC) and multivariate COX regression model was performed to construct autophagy-related gene signature. Then patients were divided into high- and low-risk groups based on the risk score identified by the autophagy-related gene signature. Multivariate COX regression model and stratification analysis were used to specify the prognostic value of this gene signature in whole cohort and various subgroups. T-test and ANOVA analysis were used to compare the expression differences of continuous variables (5 prognostic genes and risk score) in binary and multiple category groups respectively. Kaplan-Meier analysis, log-rank tests and the area under receiver operating characteristic (ROC) curve (AUC) were conducted to validate the accuracy and precise of the autophagy-related gene signature based on GSE20685 and GSE21653 datasets.Results: We profiled autophagy-related DEGs in normal and breast tumor tissues. GO and KEGG analysis indicated that autophagy-related DEGs might participate in breast cancer occurrence, development and drug resistance. Then we identified five autophagy-related genes (EIF4EBP1, ATG4A, BAG1, MAP1LC3A and SERPINA1) that had significantly prognostic values for breast cancer. Autophagy-related gene signature was constructed and patients were divided into highand lowrisk groups based on their risk score. Patients in the high-risk group tended to have shorter overall survival (OS) and relapse-free survival (RFS) times than those in the low-risk group (OS: HR = 1.620, 95%CIs: 1.345-1.950; P < 0.001; RFS: HR = 1.487, 95%CIs: 1.248-1.771, P < 0.001). Autophagy-related gene signature had significant prognostic value in stratified subgroups especially in advanced breast cancer subgroups (T3-4; N2-3; stage III-IV). Its prognostic value was further confirmed in two GEO validation datasets (GSE20685: P = 6.795e-03; GSE21653: P = 1.383e-03). Finally, association analysis between clinicopathological factors and gene signature showed the risk score was higher in patients with ER/PR negative, higher clinical stage or T stage (P < 0.01).Conclusion: We established and confirmed a novel autophagy-related gene signature for patients with breast cancer that had independent survival prognostic value especially in advanced breast cancer subgroups. Our research might promote the molecular mechanism study of autophagy-related genes in breast cancer.