Tumor-Specific Pro-Thrombotic Gene Expression in Head and Neck Squamous Cell Carcinoma: A Multi-Cohort Transcriptomic Analysis

Objectives: Head and neck tumors have been associated with varying risks for venous thromboembolism (VTE). Through a cross-tumor comparison, we assessed site-specific coagulation-related gene expression changes in head and neck squamous cell carcinoma (HNSCC) compared to squamous cell tumors in the esophagus (ESCCa) and lung (LUSC). Further, we assessed the relationship between clinicopathologic features of HNSCC and coagulome gene expression. Methods: RNA-sequencing data from primary tumor tissues of HNSCCa, ESCCa, and LUSC were obtained from The Cancer Genome Atlas (TCGA). Three previously identified pro-thrombotic genes (F3, SERPINE1, and SERPINB2) were analyzed and, for pan-cancer comparisons, gene expression was Z-standardized and summarized as a composite coagulome score. For HNSCCa-specific analyses, gene expression was compared using log2 RSEM counts, contrasting between HPV status, primary tumor site, tumor stage, grade, and demographic characteristics. Results: HNSCCa demonstrated the highest composite coagulome activation (mean Z-score = 0.29, 95% CI: 0.23–0.35) compared with LUSC and ESCCa (mean Z-scores = −0.27 and −0.16, respectively; p < 0.001). Among 487 HNSCCa tumors, HPV-negative tumors exhibited significantly higher composite coagulome expression than HPV-positive tumors (mean ± SD, 11.25 ± 1.39 vs. 10.14 ± 1.30; p < 0.001). Oral cavity tumors demonstrated the highest coagulome expression, while oropharyngeal tumors were most suppressed. Higher histologic grade was inversely associated with coagulome expression (p < 0.001). Patient age, sex, and race were not significantly associated with coagulome expression. Conclusions: HNSCCa exhibits a tumor-specific pro-thrombotic expression profile with substantial heterogeneity driven by HPV status and primary tumor site. Despite elevated tumor-specific pro-coagulant signaling, these findings reflect tumor-specific pro-thrombotic potential rather than clinical VTE risk in HNSCCa, which likely remains context-dependent and may require additional inflammatory or treatment-related triggers to clinically manifest.