铜死亡相关基因PDHA1与乳腺癌的预后关系及列线图的构建
作者:
通讯作者:
作者单位:

湖南师范大学附属第一医院/湖南省人民医院 乳甲外科,湖南 长沙 410005

作者简介:

杨秋怡,湖南师范大学附属第一医院/湖南省人民医院硕士研究生,主要从事乳腺及甲状腺疾病方面的研究。

基金项目:

湖南省自然科学基金资助项目(2022JJ30335);湖南师范大学附属第一医院/湖南省人民医院博士基金资助项目(BSJJ202107)。


Relationship between cuproptosis related gene PDHA1 and prognosis of breast cancer and its nomogram construction
Author:
Affiliation:

Department of Breast and Thyroid Surgery, the First Affiliated Hospital of Hunan Normal University/Hunan Provincial People's Hospital, Changsha 410005, China

Fund Project:

  • 摘要
  • |
  • 图/表
  • |
  • 访问统计
  • |
  • 参考文献
  • |
  • 相似文献
  • |
  • 引证文献
  • |
  • 资源附件
  • |
  • 音频文件
  • |
  • 视频文件
    摘要:

    背景与目的 丙酮酸脱氢酶E1组分α亚基(PDHA1)是丙酮酸脱氢酶复合物的关键调控位点,发挥着连接糖酵解和三羧酸循环的重要作用,对癌症代谢转变具有重要意义。最新研究发现了一种新的细胞死亡方式,即铜死亡。PDHA1是铜死亡的相关基因,参与铜死亡过程的调控。本研究旨在利用生物信息学方法探讨PDHA1与乳腺癌预后的关系并建立预后相关的列线图模型。方法 运用TCGA、TIMER、UALCAN、HPA、STRING、Gene MANIA、Kaplan-Meier、GEPIA、GeneCards等多个数据库对PDHA1在乳腺癌中的临床病理特征关系、表达情况、蛋白互相作用网络、基因-基因互作网络、预后价值、基因集富集分析等进行分析,并使用R语言构建列线图模型。结果 PDHA1表达水平与乳腺癌T分期(P<0.001)、病理分期(P=0.031)、人种(P<0.001)、组织学类型(P<0.001)、PR状态(P<0.001)、ER状态(P<0.001)、PAM50亚型(P<0.001)有关。TCGA数据库结果显示,乳腺癌组织PDHA1 mRNA的表达水平明显低于正常乳腺组织(P<0.001),UALCAN数据库结果显示,PDHA1蛋白在乳腺癌中低表达(P<0.001),HPA数据库进一步验证了该结果。PPI蛋白互作网络显示有15个与PDHA1相关的互作蛋白。基因-基因互作关系网络图得到20个PDHA1相关的互作基因。PDHA1高表达组患者的总生存期(HR=1.26,95% CI=1.02~1.54,P=0.029)、无复发生存期(HR=1.18,95% CI=1.05~1.32,P=0.005 1)、进展后生存期(HR=1.41,95% CI=1.07~1.86,P=0.015)、无转移生存期(HR=1.29,95% CI=1.1~1.52,P=0.002 3)均低于PDHA1低表达组。GSEA结果表明PDHA1共表达基因在乳腺癌中主要参与S期、三羧酸循环等通路。从GeneCards中找到10种与PDHA1表达相关的化合物。将PDHA1表达、年龄、放疗、N分期和M分期纳入构建列线图,校准图显示列线图预测和实际观察之间有极好的一致性。结论 PDHA1高表达乳腺癌患者预后较PDHA1低表达患者差。PDHA1表达水平是影响乳腺癌患者预后的相关因素。基于PDHA1表达的列线图模型对于乳腺癌患者预后的评估有一定的价值。

    Abstract:

    Background and Aims The α subunit of pyruvate dehydrogenase E1 component (PDHA1) is the key regulatory site of pyruvate dehydrogenase complex, playing an important role in connecting glycolysis and tricarboxylic acid cycle, and it is of great significance for the metabolic transformation of cancers. The latest research has found a new cell death mechanism, namely cuproptosis. PDHA1 is a gene related to cuproptosis and participates in the regulation of its process. The purpose of this study was to explore the relationship between PDHA1 and the prognosis of breast cancer by using bioinformatics methods and establish a nomogram model related to the prognosis.Methods The clinicopathologic relationship, expression, protein-protein interaction network, gene-gene interaction network, prognostic value, gene set enrichment of PDHA1 in breast cancer were analyzed by using the TCGA, TIMER, UALCAN, HPA, STRING, Gene MANIA, Kaplan-Meier, GEPIA, GeneCards and other databases. The nomogram model was constructed with R language.Results PDHA1 expression was associated with breast cancer T Stage (P<0.001), pathologic stage (P=0.031), race (P<0.001), histological type (P<0.001), PR status (P<0.001), ER status (P<0.001), and PAM50 subtype (P<0.001). TCGA database results showed that the expression level of PDHA1 mRNA in breast cancer tissues was significantly lower than that in normal breast tissues (P<0.001), while UALCAN database results showed that PDHA1 protein was lowly expressed in breast cancer (P<0.001), which was further verified by HPA database. The PPI protein-protein interaction network revealed 15 PDHA1-related interaction proteins. Twenty PDHA1-related interacting genes were obtained from the gene-gene interaction network diagram. Patients in the PDHA1 high-expression group had lower overall survival (HR=1.26, 95% CI=1.02-1.54, P=0.029), relapse-free survival (HR=1.18, 95% CI=1.05-1.32, P=0.005 1), post-progression survival (HR=1.41, 95% CI=1.07-1.86, P=0.015), and metastasis-free survival (HR=1.29, 95% CI=1.1-1.52, P=0.002 3). GSEA results showed that PDHA1 co-expressed genes were mainly involved in the S stage and tricarboxylic acid cycle in breast cancer. Ten compounds related to PDHA1 expression were identified from GeneCards. A nomogram model was constructed by integrating the PDHA1 expression, age, radiation therapy, N stage and M stage, and the calibration chart shows that there was excellent consistency between the nomogram prediction and the actual observation.Conclusion The prognosis of breast cancer patients with high PDHA1 expression is worse than that of patients with low PDHA1 expression. The expression level of PDHA1 is a related factor affecting the prognosis of breast cancer patients. The nomogram model constructed based on PDHA1 expression has certain value in estimating the prognosis of breast cancer patients.

    表 1 来自TCGA数据库的乳腺癌样本中PDHA1表达与临床病理学特征之间的关联[n(%)]Table 1 Association between PDHA1 expression and clinicopathologic characteristics in breast cancer samples from the TCGA database [n (%)]
    图1 PDHA1的表达分析 A:PDHA1在不同肿瘤中的表达;B:乳腺癌组织及正常组织中PDHA1的表达情况;C:UALCAN数据库中PDHA1蛋白在乳腺癌和正常组织中的表达情况;D:HPA数据库中PDHA1蛋白在乳腺癌和正常组织中的表达情况Fig.1 Analysis of PDHA1 expression A: Expressions of PDHA1 in different tumors; B: Expressions of PDHA1 in breast cancer and normal tissue; C: Expressions of PDHA1 protein in breast cancer and normal tissues in UALCAN database; D: Expressions of PDHA1 protein in breast cancer and normal tissues in HPA database
    图2 DHA1相互作用蛋白网络分析Fig.2 Analysis of PDHA1 interaction protein network
    图3 PDHA1基因-基因互作网络Fig.3 PDHA1 gene-gene interaction network
    图4 PDHA1表达与乳腺癌的预后的关系Fig.4 Relationship between PDHA1 expression and prognosis of breast cancer
    图5 PDHA1表达与乳腺癌各亚组预后的关系Fig.5 Relationship between PDHA1 expression and prognosis of breast cancer subgroups
    图6 集富集分析 A:PDHA1共表达基因基因集富集分析;B:PDHA1共表达基因基因集富集分析山峦图Fig.6 Enrichment analysis A: Gene set enrichment analysis of PDHA1 co-expressed gene; B: Mountains map for enrichment analysis of PDHA1 co-expressed gene set
    表 2 PDHA1单因素和多因素Cox回归分析Table 2 Univariate Cox regression analysis and multivariate Cox regression analysis of PDHA1
    表 3 PDHA1单因素和多因素Cox回归分析(续)Table 3 Univariate Cox regression analysis and multivariate Cox regression analysis of PDHA1 (continued)
    参考文献
    相似文献
    引证文献
引用本文

杨秋怡,易嘉宁,郭妙兰,范培芝,喻洁,曾杰.铜死亡相关基因PDHA1与乳腺癌的预后关系及列线图的构建[J].中国普通外科杂志,2022,31(11):1471-1482.
DOI:10.7659/j. issn.1005-6947.2022.11.009

复制
分享
文章指标
  • 点击次数:
  • 下载次数:
历史
  • 收稿日期:2022-08-23
  • 最后修改日期:2022-10-07
  • 录用日期:
  • 在线发布日期: 2022-12-07