Epigenetic biomarkers of ageing are predictive of mortality risk in a longitudinal clinical cohort of individuals diagnosed with oropharyngeal cancer

Beynon, R. A. et al. (2022) Epigenetic biomarkers of ageing are predictive of mortality risk in a longitudinal clinical cohort of individuals diagnosed with oropharyngeal cancer. Clinical Epigenetics, 14(1), 1. (doi: 10.1186/s13148-021-01220-4) (PMID:34980250) (PMCID:PMC8725548)

Abstract

Background: Epigenetic clocks are biomarkers of ageing derived from DNA methylation levels at a subset of CpG sites. The difference between age predicted by these clocks and chronological age, termed “epigenetic age acceleration”, has been shown to predict age-related disease and mortality. We aimed to assess the prognostic value of epigenetic age acceleration and a DNA methylation-based mortality risk score with all-cause mortality in a prospective clinical cohort of individuals with head and neck cancer: Head and Neck 5000. We investigated two markers of intrinsic epigenetic age acceleration (IEAAHorvath and IEAAHannum), one marker of extrinsic epigenetic age acceleration (EEAA), one optimised to predict physiological dysregulation (AgeAccelPheno), one optimised to predict lifespan (AgeAccelGrim) and a DNA methylation-based predictor of mortality (ZhangScore). Cox regression models were first used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations of epigenetic age acceleration with all-cause mortality in people with oropharyngeal cancer (n = 408; 105 deaths). The added prognostic value of epigenetic markers compared to a clinical model including age, sex, TNM stage and HPV status was then evaluated. Results: IEAAHannum and AgeAccelGrim were associated with mortality risk after adjustment for clinical and lifestyle factors (HRs per standard deviation [SD] increase in age acceleration = 1.30 [95% CI 1.07, 1.57; p = 0.007] and 1.40 [95% CI 1.06, 1.83; p = 0.016], respectively). There was weak evidence that the addition of AgeAccelGrim to the clinical model improved 3-year mortality prediction (area under the receiver operating characteristic curve: 0.80 vs. 0.77; p value for difference = 0.069). Conclusion: In the setting of a large, clinical cohort of individuals with head and neck cancer, our study demonstrates the potential of epigenetic markers of ageing to enhance survival prediction in people with oropharyngeal cancer, beyond established prognostic factors. Our findings have potential uses in both clinical and non-clinical contexts: to aid treatment planning and improve patient stratification.

• Item Type: Articles
• Additional Information: Funding: This work was supported by a Wellcome Trust PhD studentship (110021/Z/15/Z to RAB). The Head and Neck 5000 study was a component of independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). RCR and RMM are supported by a Cancer Research UK (C18281/A19169) programme grant (the Integrative Cancer Epidemiology Programme) and is part of the Medical Research Council Integrative Epidemiology Unit at the University of Bristol supported by the Medical Research Council (MC_UU_12013/1, MC_UU_12013/2 and MC_UU_12013/3) and the University of Bristol. RMM and AN are also supported by NIHR Bristol Biomedical Research Centre, which is funded by the National Institute for Health Research (NIHR) and is a partnership between University Hospitals Bristol NHS Foundation Trust and the University of Bristol. RL was supported by a Cancer Research UK Research PhD studentship (C18281/A20988 to RJL). The views expressed are those of the author(s) and not necessarily those of any funding body. George Davey Smith works in a Unit supported by the Medical Research Council for the Integrative Epidemiology Unit (MC_UU_00011/1 at the University of Bristol.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ingarfield, Kate
• Authors: Beynon, R. A., Ingle, S. M., Langdon, R., May, M., Ness, A., Martin, R. M., Suderman, M., Ingarfield, K., Marioni, R. E., McCartney, D. L., Waterboer, T., Pawlita, M., Relton, C., Smith, G. D., and Richmond, R. C.
• College/School: College of Medical Veterinary and Life Sciences
• Journal Name: Clinical Epigenetics
• Publisher: BioMed Central
• ISSN: 1868-7075
• ISSN (Online): 1868-7083
• Copyright Holders: Copyright © The Author(s) 2022
• First Published: First published in Clinical Epigenetics 14(1):1
• Publisher Policy: Reproduced under a Creative Commons Licence