Master Transcription Regulators and Transcription Factors Regulate Immune-Associated Differences Between Patients of African and European Ancestry With Colorectal Cancer

Gastro Hep Adv. 2022;1(3):328-341. doi: 10.1016/j.gastha.2022.01.004.


Background and aims: Individuals of African (AFR) ancestry have a higher incidence of colorectal cancer (CRC) than those of European (EUR) ancestry and exhibit significant health disparities. Previous studies have noted differences in the tumor microenvironment between AFR and EUR patients with CRC. However, the molecular regulatory processes that underpin these immune differences remain largely unknown.

Methods: Multiomics analysis was carried out for 55 AFR and 456 EUR patients with microsatellite-stable CRC using The Cancer Genome Atlas. We evaluated the tumor microenvironment by using gene expression and methylation data, transcription factor, and master transcriptional regulator analysis to identify the cell signaling pathways mediating the observed phenotypic differences.

Results: We demonstrate that downregulated genes in AFR patients with CRC showed enrichment for canonical pathways, including chemokine signaling. Moreover, evaluation of the tumor microenvironment showed that cytotoxic lymphocytes and neutrophil cell populations are significantly decreased in AFR compared with EUR patients, suggesting AFR patients have an attenuated immune response. We further demonstrate that molecules called "master transcriptional regulators" (MTRs) play a critical role in regulating the expression of genes impacting key immune processes through an intricate signal transduction network mediated by disease-associated transcription factors (TFs). Furthermore, a core set of these MTRs and TFs showed a positive correlation with levels of cytotoxic lymphocytes and neutrophils across both AFR and EUR patients with CRC, thus suggesting their role in driving the immune infiltrate differences between the two ancestral groups.

Conclusion: Our study provides an insight into the intricate regulatory landscape of MTRs and TFs that orchestrate the differences in the tumor microenvironment between patients with CRC of AFR and EUR ancestry.

Keywords: AFR, African; African Americans.; CMA, Composite Module Analyst; CRC, colorectal cancer; ChAMP, Chip Analysis Methylation Pipeline; Colorectal Cancer; DEGs, differentially expressed genes; DMPs, differentially methylated CpG positions; EUR, European; FDR, false discovery rate; Genomic Profiling; Health Disparities; MCP, microenvironment cell population; MSI-H, microsatellite high; MSI-L, microsatellite low; MSS, microsatellite stable; MTRs, master transcriptional regulators; TCGA, The Cancer Genome Atlas; TFBS, TF binding site; TFs, transcription factors; TMB, tumor mutation burden; TSS, transcription start site.