Abstract PO-033: Metabolic differences between human papillomavirus-related and smoking-related squamous cell carcinoma of the head and neck independently predict overall patient survival
Authors: Eldridge Ronald C. , Uppal Karan , Beitler Jonathan , Higgins Kristin , Wommack Evanthia C. , Shin Dong M. , Saba Nabil F. , Miller Andrew , Bruner Deborah W. , Xiao Canhua 
Published: December 2020

Abstract
Background: Human papillomavirus (HPV) status and tobacco use are the strongest prognostic factors of survival for squamous cell carcinoma of the head and neck (SCCHN). Patients with HPV-related SCCHN live more than twice as long as patients with tobacco-related SCCHN. The underlying metabolic dysregulation characterizing these two clinically distinct groups may pose exciting translational targets that are yet unknown. Using a metabolome-wide approach, we investigated the metabolic differences of HPV vs smoking-related SCCHN in a large patient population. We then linked those metabolic differences to patient survival. Methods: We recruited 137 patients from Emory University hospitals and clinics: 55 HPV-positive never smokers (i.e., HPV-related SCCHN) and 82 HPV-negative current or former smokers (i.e., smoking-related SCCHN). We performed untargeted high-resolution metabolomics using liquid chromatography-mass spectrometry on pre-treatment patient plasma at the Emory Clinical Biomarkers Laboratory. Our statistical approach has three steps. 1) Metabolite feature selection: We aggregated the results from two selection algorithms (5-fold cross-validated partial least squares discriminant analysis and support vector machine) to determine the metabolites that differentiated HPV vs smoking-related SCCHN. 2) Metabolic pathway analysis (Mummichog): We identified statistically significant (P&lt;0.05) metabolic pathways stemming from the step 1 metabolites. 3) Metabolic profile and survival analysis: We created a metabolite-based linear principal component using the significant pathway metabolites in step 2 and estimated its association with overall survival using adjusted Cox models. Results: Of the 9,640 extracted metabolites, the two models found 229 that differentiated HPV vs smoking-related SCCHN. Metabolic pathway analysis found fatty acid and steroid metabolism was significantly upregulated in HPV patients: bile acid biosynthesis (P&lt;0.0001), 21-carbon steroid hormone metabolism (P=&lt;0.0001), fatty acid beta-oxidation (P=0.04). Pathways related to sugar metabolism were significantly upregulated in smoking patients: galactose metabolism (P=0.003), starch and sucrose metabolism (P=0.007), hexose phosphorylation (P=0.03), sialic acid metabolism (P=0.03). A principal component comprised of the 16 pathway metabolites was significantly associated with overall survival (HR=1.27 per standard deviation, P=0.01, 95% CI: 1.06-1.51) independent of HPV, smoking, tumor site, age, sex, race, and body mass index. Conclusions: Metabolites corresponding to fatty acid, steroid, and sugar metabolism differentiated HPV-related SCCHN from smoking-related SCCHN. They may be clinically informative as prognostic markers of survival. Our novel findings in patient plasma parallel those from HPV positive vs negative SCCHN cell lines, suggesting that metabolites in blood may be putative biomarkers of tumor metabolic activity and thus potentially useful for drug discovery.
Citation Format: Ronald C. Eldridge, Karan Uppal, Jonathan Beitler, Kristin Higgins, Evanthia C. Wommack, Dong M. Shin, Nabil F. Saba, Andrew Miller, Deborah W. Bruner, Canhua Xiao. Metabolic differences between human papillomavirus-related and smoking-related squamous cell carcinoma of the head and neck independently predict overall patient survival [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-033.