肿瘤突变负荷与肿瘤浸润性免疫细胞在结直肠癌预后及进展中的作用

Role of tumor mutational burden and tumor-infiltrating immune cells in the prognosis and progression of colorectal cancer

目的:本文旨在通过分析结直肠癌(colorectal cancer,CRC)中肿瘤突变负荷(tumor mutational burden,TMB)、肿瘤浸润性免疫细胞(tumor-infiltrating immune cells,TICs)及临床病理特征三者之间的相互关系,探讨TMB及TICs在CRC进展中的相互作用及临床意义。方法:下载癌症基因组(The Cancer Genome Atlas,TCGA)数据库中CRC患者的相关数据,包括肿瘤突变、基因表达及相关临床信息等。利用R语言分别计算每个肿瘤样本的TMB值及TICs百分比,并分析TMB值及TICs百分比与临床病理参数和5年总生存率的相关性。根据TMB中位值将肿瘤样本分成高TMB组(n=224)和低TMB组(n=246),比较2组5年总生存率。筛选出差异表达基因和差异表达TICs,通过基因本体论(Gene Ontology,GO)、京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)及基因集富集分析(Gene Set Enrichment Analysis,GSEA)寻找其潜在相关的免疫机制和功能。结果:根据TCGA数据,>65岁CRC患者的TMB值更高,发生血管及淋巴结转移的肿瘤TMB值较低(P<0.001)。与低TMB组相比,高TMB组CRC患者的5年总生存率更低(P<0.05)。116个差异表达基因主要涉及药物代谢及白细胞跨内皮迁移信号通路;4种差异表达的TICs为CD4+T细胞、滤泡辅助性T细胞、M0及M1巨噬细胞。结论:TMB是一个重要的评价CRC预后和免疫治疗的指标,可以通过与TICs相互作用调节免疫微环境,从而影响CRC预后及免疫治疗的效果。

Objective:This study aimed to investigate the association between tumor mutational burden(TMB),tumorinfiltrating immune cells(TICs)and clinicopathological features,and their clinical implications in the progression and prognosis of colorectal cancer(CRC).Methods:Data relating to CRC were downloaded from The Cancer Genome Atlas(TCGA)database,including genetic mutation files,RNA-seq data,and clinical information.TMB value and percentage of TICs of each tumor sample were calculated separately using R language;then correlation analysis was performed between these indices,clinicopathological parameters,and the 5-year overall survival rate.Based on the median TMB values,tumors samples were divided into a high TMB group(n=224)and a low TMB group(n=246).Five-year overall survival rates were compared between the 2 groups.Differentially expressed genes(DEGs)and TICs between high-TMB and low-TMB groups were screened and the potential immune mechanism and functions were identified by Gene Ontology(GO),Kyoto Encyclopedia of Genes and Genomes(KEGG)and Gene Set Enrichment Analysis(GSEA).Results:Based on TCGA data,CRC patients>65 years had higher TMB values;but tumors with lymph node invasion and vascular invasion had a lower TMB values(P<0.001).Compared with the low-TMB group,CRC patients in the high-TMB group had shorter 5-year overall survival rate(P<0.05).A total of 116 DEGs involved in signaling pathway of drug metabolism and leukocyte transendothelial migration,and four special types of TICs,including CD4^(+)T cells,follicular helper T cells,M0 and M1 macrophages,were identified.Conclusion:TMB is an important prognostic and immunotherapeutic index in CRC,which can interact with TICs to modulate the tumor microenvironment of CRC and therefore impact the prognosis of CRC and the efficacy of immunotherapy.