Abstract
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.
Highlights
Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide [1]
To identify candidate master transcription factors (TFs) from microsatellite stability (MSS) CRC samples, the coltron method was first performed using the published H3k27ac ChIP-Seq data based on enhancers from Rank Order of Super Enhancers (ROSE)
The findings of this study indicated that the expression of ASCL2 might influence the immune evasion in MSS patients, which may advance the understanding of poor immune checkpoint blockade (ICB) therapies to MSS CRC patients clinically
Summary
CRC is the third most common cancer and the fourth most common cause of cancer-related death worldwide [1]. Genomic instability is a key feature underlying CRC, which classifies this cancer into two main groups, microsatellite instability (MSI) and microsatellite stability (MSS) [4]. In CRC, about 15% of the patients have the MSI phenotype with the mutations of MLH1, MLH3, MSH2, MSH3, MSH6, and PMS2 in DNA mismatch repair pathway [7]. Patients with MSI CRC have a better prognosis than those patients with MSS [7, 9, 10]. Immune checkpoint blockade (ICB) therapies have shown encouraging results in patients with MSI CRC; the response of MSS patients (accounts for about 85% in CRC) to these immunotherapies remains poor [11]. Urgent needs exist to understand the resistant mechanism of MSS CRC to ICB therapies
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