Pan-cancer expression, methylation, and prognostic significance of α7 nicotinic acetylcholine receptor in tumor immunology

The α7 nicotinic acetylcholine receptor (α7nAChR), functioning as a critical ligand-gated ion channel in the nervous system, has recently been implicated to play a role in various non-neuronal tissues. Nonetheless, a comprehensive understanding of its expression patterns, mechanisms of epigenetic control, and functions within the tumor microenvironment (TME) across various malignancies is still lacking. To address this gap, we performed an extensive multi-cancer investigation of CHRNA7 spanning 31 tumor types, leveraging datasets from The Cancer Genome Atlas and Genotype-Tissue Expression databases, including its expression patterns, methylation characteristics, genomic instability, and prognostic significance. Additionally, the potential immunomodulatory effects of α7nAChR were investigated through integration of multiple algorithms. The results revealed that CHRNA7 is significantly overexpressed in 11 cancer types, including cholangiocarcinoma, glioblastoma, and lung squamous cell carcinoma, whereas it is underexpressed in 11 other cancer types, including breast cancer (BRCA) and lung adenocarcinoma (LUAD). A noteworthy finding was the inverse correlation between CHRNA7 expression levels and the staging system recommended by the World Health Organization for specific cancers, such as cervical squamous cell carcinoma and thyroid carcinoma. Another interesting finding is that CHRNA7 plays dual prognostic roles [1] as a protective factor in low-grade glioma and rectal adenocarcinoma and [2] as a risk factor in adrenocortical carcinoma, BRCA, and LUAD. Genomic analyses revealed that copy number variations and single nucleotide variations of CHRNA7 are significantly associated with survival outcomes in cancers such as liver hepatocellular carcinoma (LIHC) and kidney renal clear cell carcinoma. Moreover, these genetic variations exhibit cancer type-specific correlations with tumor mutational burden and microsatellite instability, with positive associations in colon adenocarcinoma and esophageal squamous cell carcinoma. Epigenetic studies indicated that methylation of the CHRNA7 promoter is inversely correlated with its mRNA expression level in certain cancers such as BRCA and LUAD. Additionally, CHRNA7 promoter methylation shows significant interactions with DNA mismatch repair genes and cancer stemness characteristics. Analysis of the TME revealed a positive association between high CHRNA7 expression and immune cell infiltration and immune checkpoint molecule expression in cancers such as BRCA and LIHC, suggesting its potential role in modulating tumor immune evasion and influencing treatment responses. Functional enrichment analysis confirmed that CHRNA7 is involved in key biological pathways, including cholinergic signaling, DNA damage repair, and cell proliferation regulation. In conclusion, this study provides a comprehensive pan-cancer characterization of CHRNA7, offering novel insights into its potential role as a prognostic biomarker and immunotherapeutic target. These findings could facilitate the development of personalized cancer treatment strategies customized according to the expression level and functional status of CHRNA7.