Association of FOXP3 Gene Polymorphisms with Skin, Vulvar and Ectocervical Squamous Cell Tumors

Background and Objectives: Squamous cell tumors arise from squamous epithelial cells. Polymorphisms in the FOXP3 gene may influence malignancy susceptibility. This study evaluated the potential association of FOXP3 rs3761548 (−3279 A/C) and rs2280883 (IVS9+459 T/C) polymorphisms with preinvasive and invasive squamous cell tumors of sun-exposed skin, sun-protected vulvar skin, and the ectocervix. Materials and Methods: This comparative observational study included 135 women aged >18 years surgically treated for squamous cell tumors of the skin (actinic keratosis, Bowen’s disease, squamous cell carcinoma), vulva (HSIL, differentiated VIN, squamous cell carcinoma), or ectocervix (LSIL, HSIL, squamous cell carcinoma). Sociodemographic, anthropometric, lifestyle, ultraviolet radiation exposure, reproductive, and sexual health data were collected. The FOXP3 rs3761548 and rs2280883 polymorphisms were genotyped; codominant, dominant, recessive, and overdominant genetic models were evaluated. Results: The three groups differed significantly in several sociodemographic, anthropometric, lifestyle, reproductive, and sexual health characteristics. No significant differences were observed for smoking, sun exposure, history of sunburns, contraceptive use, or history of abortions. The minor A allele frequency of rs3761548 was lower in the skin and vulvar tumor groups and slightly higher in the ectocervical tumor group than in reference populations; however, this difference was not significant (p = 0.066). None of the rs3761548 genetic models remained significant after LASSO regression. For rs2280883, the C allele frequency was lower in the skin and ectocervical groups but higher in the vulvar tumor group than the 46.0% reported in the reference population. The dominant model (CC + CT vs. TT) was associated with lower odds of skin tumors, whereas the recessive model (CC vs. TT + CT) was associated with higher odds (both p = 0.037). Conclusions: The distribution of the FOXP3 rs2280883 polymorphism differed according to tumor location. It was significantly associated with cutaneous squamous cell tumors under both dominant and recessive genetic models.