Master Transcription Regulators and Transcription Factors Regulate Immune-Associated Differences Between Patients of African and European Ancestry With Colorectal Cancer.
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
Journal
Gastro hep advances
ISSN: 2772-5723
Titre abrégé: Gastro Hep Adv
Pays: Netherlands
ID NLM: 9918350485906676
Informations de publication
Date de publication:
2022
2022
Historique:
received:
20
07
2021
accepted:
20
01
2022
entrez:
17
6
2022
pubmed:
18
6
2022
medline:
18
6
2022
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
Background and Aims
UNASSIGNED
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
UNASSIGNED
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
UNASSIGNED
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
UNASSIGNED
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.
Identifiants
pubmed: 35711675
doi: 10.1016/j.gastha.2022.01.004
pii: S2772-5723(22)00011-5
pmc: PMC9151447
doi:
Types de publication
Journal Article
Langues
eng
Pagination
328-341Informations de copyright
© 2022 The Authors.
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