Abstract PO-038: Metabolic-inflammatory investigation of head and neck cancer patient reported neuropsychological factors via multiomics integration of the plasma metabolome, lipidome, and circulating inflammation cytokines
Authors: Eldridge Ronald C. , Lin Yufen , Saba Nabil F. , Miller Andrew , Wommack Evanthia C. , Felger Jennifer , Bruner Deborah W. , Xiao Canhua 
Published: September 2023

Abstract
Background: Neuropsychological factors (NPF) (i.e., fatigue, pain, cognitive dysfunction, depression, stress, and sleep disturbance) are common in head and neck cancer (HNC) and often cluster together. They can impair a patient’s functional status and quality of life and are an obstacle to effective treatment and a full recovery. Metabolism and inflammation may be underlying mechanisms but may work differently across HPV-related and unrelated HNC. We explored the joint interaction of metabolism, inflammation, and NPF via a stratified multiomics network analysis of the pretreatment plasma metabolome, lipidome, and inflammation cytokines across HPV-related and unrelated HNC. Methods: HNC patients completed validated symptom questionnaires (e.g., Multidimensional Fatigue Inventory, Patient Health Questionnaire-8, Perceived Stress Scale, Pittsburg Sleep Quality Index) and donated blood for untargeted (metabolome) and targeted (lipids and cytokines) assays prior to chemoradiotherapy. Metabolites and lipids were measured by liquid-chromatography high resolution mass spectrometry and the cytokines were measured via multiplex assays. A multiomics network analysis algorithm (xMWAS) plotted network graphs for HPV-related and unrelated HNC separately, by estimating pair-wise partial least squares correlations between the metabolites, lipids, cytokines, and NPF variables. To interpret each network, a multilevel community detection algorithm identified highly correlated clusters of variables, representing possible biological relatedness. Metabolic pathway analysis provided functional interpretation of the metabolite-lipid-cytokine-NPF clusters. Results: There were 82 subjects (59 years mean age, 72% male, 81% white, 48% HPV-related) in which, 186 metabolites, 78 lipids, 7 cytokines (C-reactive protein, Tumor necrosis factor-α, interleukin-1β, IL6, IL10, IL1 receptor antagonist, and TNF receptor-1) and 6 NPF were analyzed. We required a minimum correlation of 0.3 and P-value &lt;0.05 to be included in the network. xMWAS modeled 525 correlations in HPV-related HNC compared to 419 correlations in HPV-unrelated. Three clusters were identified for HPV-related HNC: all 6 NPF were contained in a single cluster with 51 metabolites, 10 lipids, but 0 cytokines. Pathway analysis found enriched levels of aminoacyl-tRNA biosynthesis (P&lt;.001), valine, leucine, and isoleucine biosynthesis (P&lt;.001), and glycine, serine and threonine metabolism (P=0.003). Comparatively, five clusters were identified for HPV-unrelated HNC: the 6 NPF were dispersed between two closely linked clusters along with 23 metabolites, 4 lipids, and 4 cytokines (CRP, IL1β, IL10, IL1ra). Enriched pathways included aminoacyl-tRNA biosynthesis (P&lt;.0001), glycine, serine, and threonine metabolism (P&lt;.0001), cysteine and methionine metabolism (P&lt;.0001). Conclusions: In both HPV-related and unrelated HNC, NPF were closely linked via metabolites enriched in amino acid metabolic pathways, suggesting that NPF may have an amino acid metabolic foundation. Cytokines may play a larger role in HPV unrelated HNC.
Citation Format: Ronald C. Eldridge, Yufen Lin, Nabil F. Saba, Andrew Miller, Evanthia C. Wommack, Jennifer Felger, Deborah W. Bruner, Canhua Xiao. Metabolic-inflammatory investigation of head and neck cancer patient reported neuropsychological factors via multiomics integration of the plasma metabolome, lipidome, and circulating inflammation cytokines [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-038.