Journal Article

Identifying epigenetic biomarkers of established prognostic factors and survival in a clinical cohort of individuals with oropharyngeal cancer

Pawlita, Michael, Kazmi, Nabila, Dudding, Tom, Penfold, Chris, Ness, Andy, Ingarfield, Kate, Relton, Caroline, Haley, Chris, Suderman, Matthew, Zeng, Yanni, Smith, George Davey, Langdon, Ryan, Gaunt, Tom, Bretherick, Andrew, Richmond, Rebecca, Waterboer, Tim, Walker, Rosie M., Ho, Karen, Thomas, Steve, Elliott, Hannah R.

2020

Overview

Background Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conducted single-site and differentially methylated region (DMR) epigenome-wide association studies (EWAS) of these factors, in addition to ∼ 3-year survival, using Illumina Methylation EPIC DNA methylation profiles from whole blood in 409 individuals as part of the Head and Neck 5000 (HN5000) study. Overlapping sites between each factor and survival were then assessed using two-step Mendelian randomization to assess whether methylation at these positions causally affected survival. Results Using the MethylationEPIC array in an OPC dataset, we found novel CpG associations with smoking, alcohol consumption and ~ 3-year survival. We found no CpG associations below our multiple testing threshold associated with HPV16 E6 serological response (used as a proxy for HPV infection). CpG site associations below our multiple-testing threshold ( P Bonferroni < 0.05) for both a prognostic factor and survival were observed at four gene regions: SPEG (smoking), GFI1 (smoking), PPT2 (smoking) and KHDC3L (alcohol consumption). Evidence for a causal effect of DNA methylation on survival was only observed in the SPEG gene region (HR per SD increase in methylation score 1.28, 95% CI 1.14 to 1.43, P 2.12 × 10 −05 ). Conclusions Part of the effect of smoking on survival in those with oropharyngeal cancer may be mediated by methylation at the SPEG gene locus. Replication in data from independent datasets and data from HN5000 with longer follow-up times is needed to confirm these findings.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Adult / Alcohol / Alcohol Drinking - adverse effects / Alcohol Drinking - genetics / Annotations / Biomarkers / Biomarkers - analysis / Biomedical and Life Sciences / Biomedicine / Cancer epigenetics and diagnostics / Case-Control Studies / Cohort analysis / Cohort Studies / CpG islands / CpG Islands - genetics / Deoxyribonucleic acid / DNA / DNA Methylation / Epigenesis, Genetic - genetics / Epigenetic inheritance / Epigenetics / Epigenome - genetics / Epigenomics - methods / Female / Gene Function / Genetics / Head & neck cancer / Head and neck / Health aspects / Human Genetics / Human papillomavirus / Humans / Infection / Infections / Male / Medical prognosis / Mendelian Randomization Analysis - methods / Methylation / Middle Aged / Muscle Proteins - genetics / Oncogene Proteins, Viral - blood / Oropharyngeal cancer / Oropharyngeal Neoplasms - etiology / Oropharyngeal Neoplasms - genetics / Oropharyngeal Neoplasms - mortality / Oropharyngeal Neoplasms - virology / Papillomavirus infections / Papillomavirus Infections - complications / Papillomavirus Infections - genetics / Pharyngeal cancer / Prognosis / Protein Serine-Threonine Kinases - genetics / Proteins - genetics / Repressor Proteins - blood / Risk Factors / Smoking / Smoking - adverse effects / Smoking - genetics / SpeG gene / Survival / Survival Rate / Throat cancer / Viral infections