Colorectal cancer (CRC) has two major subtypes, microsatellite instability (MSI) and microsatellite stability (MSS) based on the genomic instability. In this study, using computational programs, we identified 9 master transcription factors (TFs) based on epigenomic profiling in MSS CRC samples. Notably, unbiased gene set enrichment analysis (GSEA) showed that several master TFs were strongly associated with immune-related functions in TCGA MSS CRC tissues, such as interferon gamma (IFN-γ) and interferon alpha (IFN-α) responses. Focusing to the top candidate, ASCL2, we found that CD8⁺ T cell infiltration was low in ASCL2 overexpressed MSS CRC samples. Compared with other gastrointestinal (GI) cancers (gastric cancer, MSI CRC, and esophageal cancer), ASCL2 is specifically upregulated in MSS CRC. Moreover, we identified 28 candidate genes in IFN-γ and IFN-α response pathways which were negatively correlated with ASCL2. Together, these results link transcriptional dysregulation with the immune evasion in MSS CRC, which may advance the understanding of immune resistance and contribute to developing novel treatments of MSS CRC.

中文翻译：

---

结直肠癌微卫星稳定性中与主调节因子 ASCL2 相关的免疫逃逸的潜在机制

结直肠癌（CRC）有两种主要亚型，微卫星不稳定性（MSI）和基于基因组不稳定性的微卫星稳定性（MSS）。在这项研究中，我们使用计算程序根据 MSS CRC 样本中的表观基因组分析确定了 9 个主转录因子 (TF)。值得注意的是，无偏基因集富集分析 (GSEA) 表明，几个主 TF 与 TCGA MSS CRC 组织中的免疫相关功能密切相关，例如干扰素 γ (IFN- γ ) 和干扰素 α (IFN- α ) 反应。关注顶级候选 ASCL2，我们发现 CD8 ⁺在 ASCL2 过表达的 MSS CRC 样本中，T 细胞浸润较低。与其他胃肠道 (GI) 癌症（胃癌、MSI CRC 和食管癌）相比，ASCL2 在 MSS CRC 中特异性上调。此外，我们在 IFN- γ和 IFN- α反应途径中鉴定了 28 个候选基因，它们与 ASCL2 呈负相关。总之，这些结果将转录失调与 MSS CRC 的免疫逃避联系起来，这可能会促进对免疫抵抗的理解，并有助于开发 MSS CRC 的新疗法。