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

Background Epigenetic clocks are biomarkers of ageing derived from DNA methylation levels at a subset of CpG sites. The difference between predicted age from these clocks and chronological age (“epigenetic age acceleration”) has been shown to predict age-related disease and mortality. We aimed to assess the prognostic value of epigenetic age acceleration with all-cause mortality in a prospective clinical cohort of individuals with head and neck cancer: Head and Neck 5000. Methods 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 ) and one optimised to predict lifespan ( AgeAccelGrim ). 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 measures compared to a clinical model including age, gender, 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 =1.32 (95% CI=1.08, 1.61; p=0.007) and 1.39 (95% CI =1.06, 1.83; p=0.017), 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 Our study demonstrates the potential of epigenetic age acceleration measures to enhance survival prediction in people with oropharyngeal cancer, beyond established prognostic factors.