Srikant Ambatipudi1, Ryan Langdon2, Rebecca C Richmond2, Matthew Suderman2, Devin C Koestler3, Karl T Kelsey4, Nabila Kazmi2, Christopher Penfold5, Karen M Ho6, Wendy McArdle6, Susan M Ring2, Miranda Pring5, Tim Waterboer7, Michael Pawlita7, Tom R Gaunt2, George Davey Smith2, Steve Thomas5, Andy R Ness5, Caroline L Relton2. 1. MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. Electronic address: s.ambatipudi@bristol.ac.uk. 2. MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. 3. Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA. 4. Department of Epidemiology, Brown University, School of Public Health, Providence, RI 02912, USA; Department of Laboratory Medicine & Pathology, Brown University, Providence, RI 02912, USA. 5. National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK. 6. Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. 7. Division of Molecular Diagnostics of Oncogenic Infections, Infection, Inflammation and Cancer Program, German Cancer Research Center, Heidelberg, Germany.
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.
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.
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