Background: Metabolic differences between human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) and smoking-associated HNSCC may partially explain differences in prognosis. The former relies on mitochondrial oxidative phosphorylation (OXPHOS) while the latter relies on glycolysis. These differences have not been studied in blood. Methods: We extracted metabolites using untargeted liquid chromatography high-resolution mass spectrometry from pretreatment plasma in a cohort of 55 HPV-associated and 82 smoking-associated HNSCC subjects. Metabolic pathway enrichment analysis of differentially expressed metabolites produced pathway-based signatures. Significant pathways ( P < 0.05) were reduced via principal component analysis and assessed with overall survival via Cox models. We classified each subject as glycolytic or OXPHOS phenotype and assessed it with survival. Results: Of 2,410 analyzed metabolites, 191 were differentially expressed. Relative to smoking-associated HNSCC, bile acid biosynthesis ( P < 0.0001) and octadecatrienoic acid beta-oxidation ( P = 0.01), were upregulated in HPV-associated HNSCC, while galactose metabolism ( P = 0.001) and vitamin B6 metabolism ( P = 0.01) were downregulated; the first two suggest an OXPHOS phenotype while the latter two suggest glycolytic. First principal components of bile acid biosynthesis [HR = 0.52 per SD; 95% confidence interval (CI), 0.38–0.72; P < 0.001] and octadecatrienoic acid beta-oxidation (HR = 0.54 per SD; 95% CI, 0.38–0.78; P < 0.001) were significantly associated with overall survival independent of HPV and smoking. The glycolytic versus OXPHOS phenotype was also independently associated with survival (HR = 3.17; 95% CI, 1.07–9.35; P = 0.04). Conclusions: Plasma metabolites related to glycolysis and mitochondrial OXPHOS may be biomarkers of HNSCC patient prognosis independent of HPV or smoking. Future investigations should determine whether they predict treatment efficacy. Impact: Blood metabolomics may be a useful marker to aid HNSCC patient prognosis.

中文翻译：

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HPV 相关与吸烟相关的头颈癌和患者生存率的血浆代谢表型

背景：人乳头瘤病毒 (HPV) 相关的头颈部鳞状细胞癌 (HNSCC) 和吸烟相关的 HNSCC 之间的代谢差异可能部分解释了预后的差异。前者依赖于线粒体氧化磷酸化（OXPHOS），而后者依赖于糖酵解。这些差异尚未在血液中进行研究。方法：我们使用非靶向液相色谱高分辨率质谱法从 55 名 HPV 相关和 82 名吸烟相关 HNSCC 受试者的队列中提取代谢物。差异表达代谢物的代谢途径富集分析产生了基于途径的特征。通过主成分分析减少了显着途径（ P <0.05），并通过 Cox 模型评估了总生存率。我们将每个受试者分类为糖酵解或 OXPHOS 表型，并用存活率对其进行评估。结果：在 2,410 种分析的代谢物中，191 种存在差异表达。与吸烟相关的 HNSCC 相比，胆汁酸生物合成 ( P < 0.0001) 和十八碳三烯酸 β-氧化 ( P = 0.01) 在 HPV 相关 HNSCC 中上调，而半乳糖代谢 ( P = 0.001) 和维生素 B6 代谢 ( P = 0.01) 被下调；前两个表明 OXPHOS 表型，而后两个表明糖酵解。胆汁酸生物合成的第一主成分 [HR = 0.52/SD；95% 置信区间 (CI)，0.38–0.72；P < 0.001] 和十八碳三烯酸β-氧化（HR = 0.54/SD；95% CI，0.38–0.78；P < 0.001）与总生存期显着相关，与 HPV 和吸烟无关。糖酵解与 OXPHOS 表型也与存活率独立相关（HR = 3.17；95% CI，1.07-9.35；P = 0.04）。结论：与糖酵解和线粒体 OXPHOS 相关的血浆代谢物可能是独立于 HPV 或吸烟的 HNSCC 患者预后的生物标志物。未来的调查应确定它们是否能预测治疗效果。影响：血液代谢组学可能是帮助 HNSCC 患者预后的有用标志物。