The association between CD40 gene polymorphisms and the risk of cancer based on a meta-analysis

CD40, a constituent of the tumor necrosis factor (TNF) receptor superfamily, exhibits variable expression across different cancer types. It plays a role in mediating tumor cell proliferation, apoptosis, and survival, as well as antitumor immune responses and the tumor microenvironment. Although some studies have suggested a potential association between CD40 gene polymorphisms and cancer risk, definitive conclusions remain elusive.

We conducted a comprehensive literature search across PubMed, Web of Science, Google Scholar, Embase, and relevant Chinese databases for studies published up to 3 February 2025. Our systematic analysis focused on elucidating the association between CD40 polymorphisms and cancer susceptibility, employing various comparative models and subgroup analyses. We analyzed the differential expression of CD40 between various tumor tissues and their corresponding normal tissues, as well as the impact of CD40 expression levels on the overall survival outcomes of cancer patients using the Gene Expression Profiling Interactive Analysis (GEPIA) database. Based on the NCBI database, we further investigated the distribution characteristics of the mutant allele for four single nucleotide polymorphisms (SNPs) in the CD40 gene across six major global populations. Additionally, we constructed a protein-protein interaction network for CD40 using the STRING database.

By analyzing 10 high-quality studies (comprising 20 case-control studies), we illustrate that the specific CD40 gene polymorphism (rs1883832) has a significant impact on breast cancer susceptibility. However, no significant correlation was found between the other three CD40 polymorphisms (rs4810485, rs1800686, and rs3765459) and tumor susceptibility.

Our study found a strong association between CD40 polymorphisms (rs1883832) and breast cancer risk. However, a limitation of this study is that it did not explore the potential application of CD40 in the early diagnosis of breast cancer, nor did it clarify its impact on patient prognosis or its feasibility as a biomarker. These critical issues will be key directions for future research.