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

Laura Moody,Sylvia L Crowder,Sharon A Spencer,Ashley Delk-Licata,Molly Black,Julie L Locher,Yuan-Xiang Pan,Hong Chen,Anna E Arthur,John W Erdman,William R Carroll,Laura Q Rogers,Wendy Demark-Wahnefried,Andrew D Fruge

doi:10.1186/s13148-020-00930-5

Abstract

BackgroundInflammation 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.ResultsWe 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.ConclusionThe 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.

Highlights

Cancer is driven by genomic instability that impacts cell growth, metabolism, and inflammation
We first considered hypermethylated Differentially methylated probes (DMP), which consisted of the 3733 DMPs that were hypermethylated compared withthe blue group and the 5322 DMPs that were hypermethylated compared with the pink group
Centromere protein A (CENP-A) nucleosome assembly, double-strand break repair via non-homologous end-joining (NHEJ), signal recognition particle (SRP)-dependent targeting to membrane, and mitochondrial translational termination were significantly enriched for hypermethylated DMPs (Fig. 1d)

Summary

Introduction

Cancer is driven by genomic instability that impacts cell growth, metabolism, and inflammation. Previous studies have found that carotenoid intake and plasma concentration are associated with DNA methylation in blood leukocytes, especially surrounding inflammatory genes [5, 6] This is of particular interest, considering that uncontrolled chronic inflammation can induce tumorigenesis via the growth factor activity of cytokines as well as persistent production of reactive oxygen species [7, 8]. 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

Methods

Results

Conclusion