Epigenetic stratification of head and neck cancer survivors reveals differences in lycopene levels, alcohol consumption, and methylation of immune regulatory genes

Abstract

Background Inflammation has been associated with higher rates of recurrence and mortality in head and neck cancer (HNC). While the biological mechanisms predisposing patients to heightened inflammatory states remain largely unknown, DNA methylation has been proposed to reflect systemic inflammation. In this analysis, we attempt to identify meaningful epigenetic patterns in HNC survivors by stratifying individuals based on DNA methylation profiles in leukocytes. Results We used hierarchical clustering to uncover three distinct methylation patterns among HNC survivors. Each group displayed a unique methylation signature in inflammatory pathways including cytokine and B-cell receptor signaling. Additionally, we examined physiological, clinical, and lifestyle parameters related to inflammation, such as circulating carotenoid and cytokine levels, cancer treatment type, and alcohol consumption. Specifically, we identified one group of survivors who had significant differential methylation of transcriptional and translational regulators as well as genes in the T-cell receptor signaling pathway, including hypermethylation of CD40 ligand (CD40LG) and Tec protein tyrosine kinase (TEC) and hypomethylation of CD8A. This group also displayed high circulating lycopene levels. We identified another group that had distinctive methylation in the toll-like receptor (TLR) signaling pathway, including hypomethylation of TLR5, a component of the inhibitor of nuclear factor-kappa B kinase complex (CHUK), and two mitogen-activated protein kinases (MAP3K8 and MAP2K3). This group also had hypermethylation of mitochondrial ribosomal genes along with higher rates of alcohol consumption. Conclusion The correlation between lycopene, alcohol consumption, DNA methylation, and inflammation warrants further investigation and may have implications in future recommendations and interventions to impact health outcomes in HNC survivors.

Comprehensive Analysis of 5-Methylcytosine Profiles of Messenger RNA in Human High-Grade Serous Ovarian Cancer by MeRIP Sequencing

“…15 In addition, the demethylation of MAP2K3 is related to inflammation and immune regulation in HNSCC patients. 16 However, the gene signatures and prognostic values of m5C-related regulators in HGSOC remain unknown.…”

Dietary Carotenoids in Head and Neck Cancer—Molecular and Clinical Implications

“…Consumption of proper amounts of phytochemicals was also shown to determine the physiological response to inflammation and intracellular oxidation processes [36,[221][222][223][224].…”

“…Moreover, inflammation has been associated with higher probability of recurrence and death due to head and neck cancer. It has been proposed that DNA methylation signatures in leukocytes may reflect systemic inflammation in HNC; in this regard, epigenetic stratification of HNC survivors has been observed to display various levels of lycopene concentration and alcohol dependence, as well as epigenetic changes (DNA methylation) in immune regulatory genes [ 36 , 37 ]. Recent publications comparing circulating carotenoid and cytokine levels with quantified factors such as alcohol abuse and tobacco dependence also suggest an association between DNA methylation and inflammation [ 36 , 37 ].…”

The Role of Bioactive Compounds in Natural Products Extracted from Plants in Cancer Treatment and Their Mechanisms Related to Anticancer Effects

“…As for carotenoids, a number of studies have confirmed its regulation for epigenetic processes. Moody et al had thoroughly described the relationship between lycopene and DNA methylation [ 144 ], in which they also indicated that lycopene may exert and alter DNA methylation through systemic antioxidant effect because study has shown that lycopene levels are negatively correlated with oxidative stress [ 145 ]. Furthermore, an inverse correlation between lycopene intake and methylation of a CpG in the paraoxonase1 (PON1) promoter had been demonstrated [ 146 ].…”