Circulating white blood cells and risk of tonsillar and base of tongue squamous cell carcinoma: A retrospective and mendelian randomization study.

This study aimed to investigate the relationship between circula-ting white blood cells (cWBC) and the risk of tonsillar and base of tongue squa-mous cell carcinoma (TSCC/BOT SCC) using retrospective clinical data and Mendelian randomization (MR) analysis. A retrospective cohort of 239 TSCC/BOT SCC patients was analyzed for cWBC subtypes and their association with clinicopathological variables, stratified by human papillomavirus (HPV) status. Blood tests, tumor staging, and immunological markers were included. For cau-sal inference, MR analysis was performed using genome-wide association stu-dy (GWAS) data on cWBC from the Blood Cell Consortium (UK Biobank) and TSCC/BOT SCC outcome data from the FinnGen consortium. Single-nucleotide polymorphisms (SNPs) were chosen based on genome-wide significance (p<5 × 10⁻⁸), low linkage disequilibrium (r² < 0.001), and F-statistic >10. The inverse-variance weighted (IVW) method was used as the primary MR approach, supple-mented by MR-Egger, weighted median, and weighted mode analyses. The retros-pective analysis showed significant differences in cWBC subtypes by gender, age, lifestyle factors, and HPV status. Notably, neutrophils (cNEU) and monocytes (cMON) were strongly associated with tumor stage and immune markers. MR analysis confirmed a causal link between total cWBC count and TSCC/BOT SCC risk (OR=1.516, p=0.005), with no evidence of heterogeneity or pleiotropy. No causal relationship was identified for cWBC subtypes or other head and neck squamous cell carcinoma (HNSCC) sites. This study provides the first compre-hensive evidence supporting a causal role of elevated cWBC in the development of TSCC/BOT SCC. These findings indicate that cWBC may serve as a potential biomarker and therapeutic target in HPV-related or unrelated TSCC/BOT SCC.