背景:结肠腺癌(COAD)是当今威胁人类健康的主要恶性肿瘤之一。免疫检查点抑制剂(ICIs)最近开始成为治疗COAD患者的有效选择。但并非所有患者都能从ICI治疗中获益。先前的研究表明,ICI对微卫星不稳定性高(MSI-H)患者具有显着的临床效果,而相反,微卫星稳定/微卫星不稳定性低(MSS/MSI-L)患者的反应有限。
方法:我们使用ATAC-seq,RNA-seq,和来自癌症基因组图谱结肠腺癌(TCGA-COAD)队列的突变数据,以对具有不同MSI状态的COAD样品进行多组学差异分析,然后通过将这些结果与生存分析相结合来进一步筛选基因。我们分析了筛选的基因对COAD患者肿瘤微环境和免疫原性的影响,并随后使用一系列预测指标确定其对COAD患者ICIs疗效的影响。
结果:在TCGA-COAD队列中筛选了12个基因,合并生存分析后,我们确定ATOH1具有显著作用.ATOH1的特点是高染色质可及性,高表达,MSI-H组中COAD患者的高突变。ATOH1高表达的COAD患者预后较好,独特的免疫微环境,在ICI治疗中的疗效较高。富集分析显示,ATOH1高表达的COAD患者体液免疫及其他相关通路显著上调。
结论:我们推测ATOH1可能通过影响肿瘤的免疫微环境和免疫原性来影响COAD患者ICIs治疗的疗效。
BACKGROUND: Colon adenocarcinoma (COAD) is one of the major varieties of malignant tumors threatening human health today. Immune checkpoint inhibitors (ICIs) have recently begun to emerge as an effective option for the treatment of COAD patients, but not all patients can benefit from ICI treatment. Previous studies have suggested that ICIs boast significant clinical effects on patients with microsatellite instability-high (MSI-H), while conversely patients with microsatellite-stable/microsatellite instability-low (MSS/MSI-L) have shown limited response.
METHODS: We used ATAC-seq, RNA-seq, and mutation data from The Cancer Genome Atlas Colon adenocarcinoma (TCGA-COAD) cohort to perform multi-omics differential analysis on COAD samples with different MSI statuses, then further screened genes by additionally combining these results with survival analysis. We analyzed the effects of the screened genes on the tumor microenvironment and immunogenicity of COAD patients, and subsequently determined their influence on the efficacy of ICIs in COAD patients using a series of predictive indexes.
RESULTS: Twelve genes were screened in the TCGA-COAD cohort, and after the combined survival analysis, we identified
ATOH1 as having significant effects.
ATOH1 is characterized by high chromatin accessibility, high expression, and high mutation in COAD patients in the MSI-H group. COAD patients with high
ATOH1 expression are associated with a better prognosis, unique immune microenvironment, and higher efficacy in ICI treatment. Enrichment analysis showed that COAD patients with high
ATOH1 expression displayed significant upregulation in their humoral immunity and other related pathways.
CONCLUSIONS: We speculate that
ATOH1 may influence the efficacy of ICIs therapy in patients with COAD by affecting the immune microenvironment and immunogenicity of the tumor.