Head and neck squamous cell carcinomas (HNSCC) afflict 600,000 persons and cause 300,000 deaths annually worldwide. Recent changes in HNSCC epidemiology demonstrate the importance of disease heterogeneity in prevention and treatment. This research investigated heterogeneity in HNSCC pathobiology, etiology, and survival in three separate studies. In the first study, N=67 formalin-fixed, paraffin-embedded HNSCC (27 human papillomavirus (HPV)-positive, 40 HPV-negative) were retrieved from storage and expression of three tumor angiogenesis markers--epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and NOTCH receptor 1 (NOTCH1)--were compared according to HPV status using immunohistochemistry. HPV-positive tumors under-expressed EGFR relative to HPV-negative (P<0.01) but VEGF (P=0.82) and NOTCH1 (P=0.68) were unrelated to HPV status. EGFR-VEGF, and NOTCH1-VEGF associations were observed in HPV-negative tumors only; and the NOTCH1-EGFR association was observed in HPV-positive tumors only. HPV-positive HNSCC may be less angiogenic than HPV-negative HNSCC.\ud The second study assessed the association between childhood passive smoke exposure (CPSE) and HNSCC using a case-control design (N=862 cases, N=806 frequency-matched controls). CPSE was associated with HNSCC (odds ratio (OR)=1.28, 95% confidence interval (CI): 1.01-1.63) after controlling for adult smoking. Among never-adult-smokers (N=184 cases, N=415 controls) CPSE was associated with oropharyngeal cancer (which is typically HPV-related) more strongly than other HNSCC (OR=2.04, 95% CI: 1.02-4.08 vs. OR=1.08, 95% CI: 0.71-1.66; P-for-heterogeneity=0.08). Assuming a causal association, 16.9% (95% CI: 0.8%-29.4%) of HNSCC would not occur without CPSE. Limiting CPSE may reduce HNSCC risk.\ud The third study assessed overall and disease-specific survival associated with metabolic enzyme genotype in N=159 HNSCC cases. After adjustment for tumor site and stage, N-acteyltransferase-2 (NAT2) fast acetylators had improved survival (vs. slow acetylators) when treated with surgery alone (hazard ratio (HR)=0.26; 95% CI: 0.10-0.66) but not chemoradiotherapy (HR=1.21; 95% CI: 0.54-2.73) or radiotherapy (HR=0.67; 95% CI: 0.31-1.59) (P-for-interaction=0.04). Reduced activity glutathione S-transferase pi-1 (GSTP1) was associated with improved disease-specific survival in men only (HR=0.12; 95% CI: 0.02-0.91; women: HR=2.29; 95% CI=0.41-12.69; P-for-interaction=0.02). Metabolic enzyme genotype modifies HNSCC survival.\ud This research contributes to public health by demonstrating biological differences in HNSCC exploitable for therapy; encouraging public policy to reduce HNSCC incidence; and supporting individualized therapy
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