Association of FOXP3 rs3761548 With Cancer: Systematic Review and Two Approaches of X-chromosome Genotypic Meta-analysis

Cancer development involves complex interactions between immune mechanisms and the tumor microenvironment, with regulatory T cells (Tregs) being implicated in suppressing anti-tumor immunity. The X-linked gene Forkhead Box P3 (FOXP3), which regulates Tregs' function, and its promoter variant rs3761548 C>A have been widely studied for their role in tumorigenesis. This meta-analysis aims to re-evaluate the association between rs3761548 and cancer risk using two statistical approaches to account for sex-based genotypic differences and X-chromosome statistical challenges. A systematic search of PubMed, Google Scholar, and Scopus identified seventeen eligible case-control studies, including 6719 cancer patients and 6879 healthy controls. The statistical analyses employed an X-linked Generalized Linear Regression Model (GLRM) and a sex-stratified meta-analysis calculating odds ratios with 95% confidence intervals. The results indicated that the presence of the A allele increases cancer risk in White and Asian populations. Furthermore, the A allele and the AA genotype were associated with breast cancer in Asians, while the AC genotype appeared protective against acute lymphoblastic leukemia in Whites possibly through non-random X-chromosome inactivation. The GLRM proved more robust, identifying additional associations and accounting for risk factors. The present study suggests a new statistical approach for analyzing X-linked genotypic data. Additionally, it underscores that the FOXP3 gene could be either oncogenic or tumor suppressor depending on ethnicity, cancer type and genotype distribution among the studied groups since its expression is subject to epigenetic changes related to the rs3761548 C allele.