乳腺癌新辅助化疗前后肿瘤相关巨噬细胞相关基因变化的生物信息学分析
作者:
作者单位:

1.南华大学附属第二医院,放疗科,湖南 衡阳 421001;2.南华大学附属第二医院,整形美容科,湖南 衡阳 421001;3.南华大学衡阳医学院肿瘤研究所,湖南 衡阳 421001

作者简介:

陈娟,南华大学附属第二医院主治医师,主要从事乳腺癌基础与临床方面的研究。

通信作者:

蒋斌, Email: JiangBin@fsyy.usc.edu.cn

基金项目:

湖南省科技厅临床医疗技术创新引导项目(2020SK51705);湖南省卫计委科研计划基金资助项目(B20180058)。


Bioinformatics analysis of changes in genes associated with tumor-associated macrophages before and after neoadjuvant chemotherapy for breast cancer
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Affiliation:

1.Department of Radiotherapy, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China;2.Department of Plastic Surgery, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China;3.Cancer Research Institute, Hengyang Medical School of University of South China, Hengyang, Hunan 421001, China

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    摘要:

    背景与目的 乳腺癌是全球女性发病率最高的恶性肿瘤,化疗是乳腺癌最重要的治疗方式之一,最近的研究表明,化疗可能通过增强肿瘤微环境中的抗肿瘤免疫力来发挥抗肿瘤效应。因此,本研究通过生物信息学分析明确乳腺癌患者新辅助化疗(NAC)前后肿瘤相关巨噬细胞(TAMs)及相关基因的变化,评估NAC对乳腺癌患者免疫影响。方法 GEO数据库输入“Breast Cancer”,“TAMs”,“Chemotherapy”进行检索,选择人乳腺癌组织的GSE134600数据集进行分析。通过R包(limma函数)筛选乳腺癌患者NAC前后组织样本中差异表达基因(DEGs)。对所有DEGs进行GO功能富集和KEGG通路分析。通过Cytoscape软件对DEGs进行蛋白互作网络可视化,并筛选关键核心基因,通过cBioPortal对10个关键基因进行突变分析。使用R包(CIBERSORT)对GSE134600数据中的免疫细胞分布及相关性进行评估。结果 鉴定出751个乳腺癌NAC前后DEGs(409个上调基因和342个下调基因)。通过GO富集分析DEGs的生物过程(BP)、细胞组分(CC)和分子功能(MF)。在BP中主要富集在I型干扰素(IFN-I)信号通路/病毒应答与防御和病毒生命周期方面;在CC中主要富集在细胞膜的外在成分和细胞膜的细胞质侧方面;在MF中主要富集在细胞因子受体结合、双链RNA结合和脂肽结合方面。KEGG通路富集分析中,DEGs主要富集在甲型H1N1流感、麻疹、丙型肝炎、冠状病毒病COVID-19、NF-κB信号通路、EBV病毒感染、NOD样受体信号通路和阿米巴病信号通路。通过CytoHubba插件筛选出乳腺癌NAC前后TAMs相互作用程度最高的前10个关键基因:IFIT1、ISG15、MX1、MX2、IRF7、RSAD2、IFIT3、IFI35、IFI6、IFITM1。多组学分析发现IFIT1、MX1和MX2主要发生缺失突变,IFIT1主要发生基因深度删除,而MX1和MX2主要发生基因扩增。NAC后乳腺癌组织中M0巨噬细胞、CD8+T细胞及M2巨噬细胞含量减少,M0巨噬细胞与记忆性B细胞成正相关(r=0.64),与未活化的CD4+记忆性T细胞呈负相关(r=-0.66)。结论 所发现的乳腺癌患者NAC前后TAMs相关的DEGs与干扰素信号通路密切相关,提示干扰素信号通路在NAC可能通过改变TAMs而发挥重要作用。同时NAC前后M0巨噬细胞发生明显改变,提示化疗可能通过改变M0巨噬细胞分布及免疫功能调节对肿瘤的免疫应答。

    Abstract:

    Background and Aims Breast cancer is the most prevalent malignancy in women worldwide, and chemotherapy is one of the most important treatment modalities for breast cancer. Recent studies have shown that chemotherapy may exert anti-tumor effects by enhancing anti-tumor immunity in the tumor microenvironment. Therefore, this study was conducted to identify the changes in tumor-associated macrophages (TAMs) and relevant genes before and after neoadjuvant chemotherapy (NAC) in breast cancer patients by bioinformatics analysis and to evaluate the effect of NAC on immune functions in breast cancer patients.Methods Information searching was performed by entering "Breast Cancer", "TAMs", "Chemotherapy" and selecting the human breast cancer tissue in the GEO database, and the GSE134600 dataset was selected for analysis. Differentially expressed genes (DEGs) in tissue samples from breast cancer patients before and after NAC were screened by R package (limma function). GO function enrichment and KEGG pathway analysis were performed for all DRGs. The protein interaction network of DEGs was visualized by Cytoscape software, and hub genes were screened and 10 hub genes were analyzed for mutations by cBioPortal. Immune cell distribution and correlation in GSE134600 data were evaluated using the R package “CIBERSORT”.Results A total of 751 DEGs (409 up-regulated and 342 down-regulated genes) were identified before and after NAC for breast cancer. The biology of DEGs was analyzed by GO enrichment for biological process(BP), cellular component(CC), and molecular function(MF). In BP function, they were mainly enriched in type I interferon(IFN-I) signaling pathway/viral response and defense and viral life cycle; in CC function, they were mainly enriched in extrinsic components of cell membrane and cytoplasmic side of cell membrane; in MF function, they were mainly enriched in cytokine receptor binding, double-stranded RNA binding and lipopeptide binding. In the analysis of KEGG pathway enrichment, DEGs were mainly enriched in influenza A (H1N1), measles, hepatitis C, coronavirus disease COVID-19, NF-κB signaling pathway, EBV virus infection, NOD-like receptor signaling pathway, and amoeba disease signaling pathway. The top 10 hub genes with the highest degree of interaction with TAMs before and after NAC for breast cancer were screened by CytoHubba plug-in: IFIT1, ISG15, MX1, MX2, IRF7, RSAD2, IFIT3, IFI35, IFI6, and IFITM1. Multi-omics analysis revealed that IFIT1, MX1 and MX2 were mainly deletion mutations, IFIT1 mainly had deep gene deletion, while MX1 and MX2 were mainly associated with gene amplifications. The content of M0 macrophages, CD8+T cells and M2 macrophages in breast cancer tissues decreased after NAC, and M0 macrophages were positively correlated with memory B cells (r=0.64) and negatively correlated with unactivated CD4+ memory T cells (r=-0.66).Conclusion The identified DEGs associated with TAMs in breast cancer patients before and after NAC are closely related to interferon signaling pathway, suggesting that interferon signaling pathway may play an important role by altering TAMs in NAC. Meanwhile, M0 macrophages are significantly altered before and after NAC, indicating that chemotherapy may regulate the immune response to tumor by changing the distribution of M0 macrophages and immune function.

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陈娟,蒋斌,黄果,贺秋冬.乳腺癌新辅助化疗前后肿瘤相关巨噬细胞相关基因变化的生物信息学分析[J].中国普通外科杂志,2022,31(5):631-639.
DOI:10.7659/j. issn.1005-6947.2022.05.008

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  • 收稿日期:2021-07-23
  • 最后修改日期:2022-04-11
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  • 在线发布日期: 2022-06-01