Dataset Information

DNA methylation derived systemic inflammation indices are associated with head and neck cancer development and survival.

ABSTRACT: OBJECTIVES:Head and neck squamous cell carcinoma (HNSCC) is often associated with chronic systemic inflammation (SI). In the present study, we assessed if DNA methylation-derived SI (mdSI) indices: Neutrophil-to-Lymphocyte ratio (mdNLR) and Lymphocyte-to-Monocyte ratio (mdLMR) are associated with the presence of HNSCC and overall survival (OS). MATERIALS AND METHODS:We used two peripheral blood DNA methylation datasets: an HNSCC case-control dataset (n?=?183) and an HNSCC survival dataset (n?=?407) to estimate mdSI indices. We then performed multivariate regressions to test the association between mdSI indices, HNSCC development and OS. RESULTS:Multivariate logistic regression revealed that elevated mdNLR was associated with increased odds of being an HNSCC case (OR?=?3.25, 95% CI?=?2.14-5.34, P?=?4?×?10-7) while the converse was observed for mdLMR (OR?=?0.88, 95% CI?=?0.81-0.90, P?=?2?×?10-3). In the HNSCC survival dataset, HPV16-E6 seropositive HNSCC cases had an elevated mdLMR (P?=?9?×?10-5) and a lower mdNLR (P?=?0.003) compared to seronegative patients. Multivariate Cox regression in the HNSCC survival dataset revealed that lower mdLMR (HR?=?1.96, 95% CI?=?1.30-2.95, P?=?0.0013) but not lower mdNLR (HR?=?0.68, 95% CI?=?0.46-1.00, P?=?0.0501) was associated with increased risk of death. CONCLUSION:Our results indicate that mdSI estimated by DNA methylation data is associated with the presence of HNSCC and overall survival. The mdSI indices may be used as a valuable research tool to reliably estimate SI in the absence of cell-based estimates. Rigorous validation of our findings in large prospective studies is warranted in the future.

SUBMITTER: Ambatipudi S

PROVIDER: S-EPMC6156796 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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DNA methylation derived systemic inflammation indices are associated with head and neck cancer development and survival.

Ambatipudi Srikant S Langdon Ryan R Richmond Rebecca C RC Suderman Matthew M Koestler Devin C DC Kelsey Karl T KT Kazmi Nabila N Penfold Christopher C Ho Karen M KM McArdle Wendy W Ring Susan M SM Pring Miranda M Waterboer Tim T Pawlita Michael M Gaunt Tom R TR Davey Smith George G Thomas Steve S Ness Andy R AR Relton Caroline L CL

Oral oncology 20180905

<h4>Objectives</h4>Head and neck squamous cell carcinoma (HNSCC) is often associated with chronic systemic inflammation (SI). In the present study, we assessed if DNA methylation-derived SI (mdSI) indices: Neutrophil-to-Lymphocyte ratio (mdNLR) and Lymphocyte-to-Monocyte ratio (mdLMR) are associated with the presence of HNSCC and overall survival (OS).<h4>Materials and methods</h4>We used two peripheral blood DNA methylation datasets: an HNSCC case-control dataset (n = 183) and an HNSCC survival ...[more]

PMID: 30220325

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Project description:BackgroundHead and neck squamous cell carcinoma (HNSCC) is a common cancer characterized by late diagnosis and poor prognosis. The aim of this study was to identify a novel ferroptosis-related DNA methylation signature as an alternative diagnosis index for patients with HNSCC.MethodsMethylome and transcriptome data of 499 HNSCC patients, including 275 oral squamous cell carcinoma (OSCC) samples, were obtained from The Cancer Genome Atlas (TCGA). An additional independent methylation dataset of 50 OSCC patients from the NCBI Gene Expression Omnibus (GEO) database was used for validation. As an index of ferroptosis activity, the ferroptosis score (FS) of each patient was inferred from the transcriptome data using single-sample gene set enrichment analysis. Univariate, multivariate, and LASSO Cox regression analyses were used to select CpG sites for the construction of a ferroptosis-related DNA methylation signature for diagnosis of patients.ResultsWe initially inferred the FS of each TCGA HNSCC patient and divided the samples into high- and low-FS subgroups. Results showed that the high-FS subgroup displayed poor overall survival. Moreover, 378 differentially methylated CpG sites (DMCs) were identified between the two HNSCC subgroups, with 16 selected to construct a 16-DNA methylation signature for risk prediction in HNSCC patients using the LASSO and multivariate Cox regression models. Relative operating characteristic (ROC) curve analysis showed great predictive efficiency for 1-, 3-, and 5-year HNSCC survival using the 16-DNA methylation signature. Its predictive efficiency was also observed in OSCC patients from the TCGA and GEO databases. In addition, we found that the signature was associated with the fractions of immune types in the tumor immune microenvironment (TIME), suggesting potential interactions between ferroptosis and TIME in HNSCC progression.ConclusionsWe established a novel ferroptosis-related 16-DNA methylation signature that could be applied as an alternative tool to predict prognosis outcome in patients with HNSCC, including OSCC.

Project description:Advanced head and neck squamous cell carcinoma (HNSCC) is associated with a poor prognosis, and biomarkers that predict response to treatment are highly desirable. The primary aim was to predict progression-free survival (PFS) with a multivariate risk prediction model. Experimental covariates were derived from blood samples of 56 HNSCC patients which were prospectively obtained within a Phase 2 clinical trial (NCT02633800) at baseline and after the first treatment cycle of combined platinum-based chemotherapy with cetuximab treatment. Clinical and experimental covariates were selected by Bayesian multivariate regression to form risk scores to predict PFS. A 'baseline' and a 'combined' risk prediction model were generated, each of which featuring clinical and experimental covariates. The baseline risk signature has three covariates and was strongly driven by baseline percentage of CD33+CD14+HLADRhigh monocytes. The combined signature has six covariates, also featuring baseline CD33+CD14+HLADRhigh monocytes but is strongly driven by on-treatment relative change of CD8+ central memory T cells percentages. The combined model has a higher predictive power than the baseline model and was successfully validated to predict therapeutic response in an independent cohort of nine patients from an additional Phase 2 trial (NCT03494322) assessing the addition of avelumab to cetuximab treatment in HNSCC. We identified tissue counterparts for the immune cells driving the models, using imaging mass cytometry, that specifically colocalized at the tissue level and correlated with outcome. This immune-based combined multimodality signature, obtained through longitudinal peripheral blood monitoring and validated in an independent cohort, presents a novel means of predicting response early on during the treatment course. Daiichi Sankyo Inc, Cancer Research UK, EU IMI2 IMMUCAN, UK Medical Research Council, European Research Council (335326), Merck Serono. Cancer Research Institute, National Institute for Health Research, Guy's and St Thomas' NHS Foundation Trust and The Institute of Cancer Research. NCT02633800.

Dataset Information

DNA methylation derived systemic inflammation indices are associated with head and neck cancer development and survival.

Publications

DNA methylation derived systemic inflammation indices are associated with head and neck cancer development and survival.

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