Association between Atopic Dermatitis and Colorectal Cancer: TET2 as a Shared Gene Signature and Prognostic Biomarker

Abstract

Background: Recent studies have linked atopic dermatitis (AD) to colorectal cancer (CRC) risk. Their causality and potential molecular mechanisms remain unclear. Methods: We performed Mendelian randomization (MR) analysis to evaluate the causality between AD and CRC. Summary statistic data-based Mendelian randomization (SMR) analysis was used to identify CRC-related causal genes. Transcriptome analyses and immunohistochemical methods were applied to investigate the shared gene signature and potential mechanisms that contribute to the pathogenesis of both AD and CRC. A predictive analysis was performed to examine the shared gene signature associated with immunotherapy response in CRC. Results: MR analysis indicated a causal association between AD and a decreased risk of CRC. SMR analysis uncovered TET2 as a CRC-related causal gene, showing an inverse relationship with the risk of CRC. Transcriptome analyses identified TET2 as a shared gene signature between AD and CRC. Decreased TET2 expression is associated with impaired demethylation and worse prognosis in CRC patients. We observed ten pathways related to the inflammatory response and immune regulation that may be shared mechanisms underlying both AD and CRC. These findings were validated through single-cell analysis. TET2 shows promise as a powerful predictive biomarker for cancer prognosis and immunotherapy response in CRC. Conclusion: There is a causal association between AD and a decreased risk of CRC. AD may influence the occurrence of CRC by modulating immune and inflammatory responses. TET2 could serve as a potential biomarker for prognosis and may be considered a novel therapeutic target for methylation and immune-related interventions.

Keywords: Mendelian randomization; TET2; WGCNA.; atopic dermatitis; colorectal cancer.

Figure 1

Workflow of this study design. (A) Mendelian randomization revealed the causality between atopic dermatitis and colorectal cancer. (B) Bioinformatic analyses revealed the shared genes between atopic dermatitis and colorectal cancer.

Figure 2

Identification, validation and evaluation of the shared hub gene TET2. (A) Volcano maps of DEGs in the AD dataset GSE182740. The volcano graphs show the DEGs expression distribution. Based on adj. P < 0.05 and |logFC| ≥2 cutoff criteria; red dots indicate up-regulated genes, while green dots represent the down-regulated genes. (B) Heatmaps of DEGs in GSE182740. The heatmaps display the top 23 up-regulated down-regulated genes in the dataset. (C) Intersection of CRC-related protective causal genes and AD down-regulated genes of AD. (D) Validation of shared causal genes in nonpaired samples from the CRC cohort in TCGA. (E) Validation of shared causal genes in paired samples from the CRC cohort in TCGA. (F) Validation of shared causal genes in the AD dataset GSE121212. (G) Overall survival. (H) Disease-specific survival. (I) Progression-free interval. (J) Lymphatic invasion status.

Figure 3

(A) Results of GeneMANIA showing the interactions between TET2 and its related genes. (B) Methylation difference in CRC. (C) Hypermethylated sites of TET2. (D) Overall survival is lower in breast cancer patients with high cg09666717 methylation. (E) Overall survival is lower in breast cancer patients with high cg12306086 methylation. (F) The high cg09666717 methylation and low TET2 expression group showed lower overall survival. (G) The high cg12306086 methylation and low TET2 expression groups showed lower overall survival.

Figure 4

Biological processes and single-cell analysis results associated with TET2. (A) The shared signaling pathways between atopic dermatitis and CRC in the low TET2 expression group. (C) UMAP of fifteen cell types in GSE146771. (D-E) TET2 had high expression levels in macrophages. (F) Upregulated KEGG gene sets.

Figure 5

Visualization of immune cell infiltration. (A) Infiltration of 22 types of immune cells in individual samples in the CRC dataset GSE113513. (B) Infiltration of 22 types of immune cells in individual samples in the atopic dermatitis dataset GSE121212. (C) The difference in immune infiltration proportions between the CRC and control groups. (D) The difference in immune infiltration proportions between the atopic dermatitis and control groups. (E-D) Correlation between TET2 and resting mast cells in AD. (H-J) Correlation between TET2 and resting mast cells in CRC.

Figure 6

Protein expression of TET2 in colorectal cancer and normal colorectal tissues (antibody HPA 039812).

Figure 7

Genomic profiles of CRC patients. The Top 20 driver mutations in (A) the ICI-cohort and (B) the TCGA-CRC cohort. The Top 20 gene mutations in (C) the ICI-cohort and (D) the TCGA-CRC cohort. The association between TET2 mutant status and (E) TMB, (F) neoantigen loads, and (G) MANTIS score in TCGA-CRC cohort. WT=wild type; MT=mutant type.