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

Abstract

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.

R methylCIPHER: A Methylation Clock Investigational Package for Hypothesis-Driven Evaluation & Research

“…[1]. This aligns well with the plethora of publications reporting the associations of acceleration of the Horvath multi-issue, PhenoAge, and GrimAge predictors with biological changes [37][38][39], and disease risk or mortality [40][41][42][43][44][45]. While this produces some standardization in the field, these clocks are not necessarily the optimal choice in all cases.…”

Differences in DNA Methylation-Based Age Prediction Within Twin Pairs Discordant for Cancer

“…In line with this, recent studies on breast (Sehl et al, 2020) and head and neck cancers (Xiao, Beitler et al, 2021) have shown that DNAmAA in blood increases significantly after cancer treatment. It has been further shown that the survivors of esophageal cancer have blood DNAmAA close to zero, whereas those who died within the 3-year follow-up had highly elevated DNAmAA (Beynon et al, 2022). Additionally, adult survivors of childhood cancers have higher DNAmAA than adults with no childhood cancer diagnosis (Qin et al, 2021).…”