ARNTL2是三阴性乳腺癌的一种预后生物标志物，且与免疫细胞浸润相关。
ARNTL2 is a Prognostic Biomarker and Correlates with Immune Cell Infiltration in Triple-Negative Breast Cancer.
作者信息
Wang Xiaoyu, Li Yan, Fu Jianchang, Zhou Kewen, Wang Tinghuai
机构信息
Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People's Republic of China.
出版信息
Pharmgenomics Pers Med. 2021 Nov 10;14:1425-1440. doi: 10.2147/PGPM.S331431. eCollection 2021.
BACKGROUND
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and is associated with poor prognosis. The aberrant expression of circadian genes contributes to the origin and progression of breast cancer. The present study was designed to explore the potential function and prognosis value of circadian genes in TNBC.
METHODS
The transcriptome data of circadian genes were downloaded from The Cancer Genomic Atlas (TCGA), GSE25066 and GSE31448 datasets. The differential expressed circadian genes between non-TNBC and TNBC patients were analysed by Wilcoxon test. Univariate and multivariate Cox regression analyses were employed to identify the prognostic circadian genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) were performed to study the biological functions of ARNTL2. The composition of 22 immune cells in the tumour samples was estimated with CIBERSORT algorithm. The correlations between ARNTL2 expression and tumour-infiltrating immune cells were evaluated by Spearman correlation coefficient.
RESULTS
A total of 8 circadian genes were found to be differentially expressed between non-TNBC and TNBC, but only ARNTL2 has prognostic value. Multivariate Cox analysis identified that ARNTL2 was an independent prognosis factor for overall survival and relapse-free survival in TNBC patients. Functionally, ARNTL2 was mainly involved in immune response processes such as positive regulation of cytokine production, regulation of innate immune response, and cellular responses to molecules of bacterial origin. High expression of ARNTL2 was positively correlated with activated CD4 memory T cells, activated mast cells, and neutrophil infiltration and the expression of markers of neutrophils (ITGAM), dendritic cells (HLA-DRA, HLA-DPA1, ITGAM), Th1 (IL1B, STAT1), Th2 (IL13), Th17 (STAT3) and mast cells (TPSB2, TPSAB1).
CONCLUSION
ARNTL2 may be linked with the functional modulation of the tumour immune microenvironment and serve as a potential biomarker for predicting the prognosis of TNBC patients.
背景
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，预后较差。昼夜节律基因的异常表达有助于乳腺癌的发生和发展。本研究旨在探讨昼夜节律基因在TNBC中的潜在功能和预后价值。
方法
从癌症基因组图谱（TCGA）、GSE25066和GSE31448数据集中下载昼夜节律基因的转录组数据。采用Wilcoxon检验分析非TNBC和TNBC患者之间差异表达的昼夜节律基因。采用单因素和多因素Cox回归分析来确定具有预后价值的昼夜节律基因。进行基因本体论（GO）、京都基因与基因组百科全书（KEGG）和基因集富集分析（GSEA）以研究ARNTL2的生物学功能。用CIBERSORT算法估计肿瘤样本中22种免疫细胞的组成。通过Spearman相关系数评估ARNTL2表达与肿瘤浸润免疫细胞之间的相关性。
结果
共发现8个昼夜节律基因在非TNBC和TNBC之间存在差异表达，但只有ARNTL2具有预后价值。多因素Cox分析确定ARNTL2是TNBC患者总生存和无复发生存的独立预后因素。在功能上，ARNTL2主要参与免疫反应过程，如细胞因子产生的正调控、先天免疫反应的调节以及细胞对细菌来源分子的反应。ARNTL2的高表达与活化的CD4记忆T细胞、活化的肥大细胞、中性粒细胞浸润以及中性粒细胞（ITGAM）、树突状细胞（HLA-DRA、HLA-DPA1、ITGAM）、Th1（IL1B、STAT1）、Th2（IL13）、Th17（STAT3）和肥大细胞（TPSB2、TPSAB1）标志物的表达呈正相关。
结论
ARNTL2可能与肿瘤免疫微环境的功能调节有关，并可作为预测TNBC患者预后的潜在生物标志物。
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