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

Rhona A Beynon; Suzanne M Ingle; Ryan J Langdon; Margaret T May; Richard M Martin; Andrew R Ness; Matthew J Suderman; Kate Ingarfield; Riccardo E Marioni; Daniel L McCartney; Tim  Waterboer; Michael  Pawlita; Caroline L Relton; George Davey Smith; Rebecca Richmond

doi:10.1186/s13148-021-01220-4

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

Rhona A Beynon^*, Suzanne M Ingle, Ryan J Langdon, Margaret T May, Richard M Martin, Andrew R Ness, Matthew J Suderman, Kate Ingarfield, Riccardo E Marioni, Daniel L McCartney, Tim Waterboer, Michael Pawlita, Caroline L Relton, George Davey Smith, Rebecca Richmond

^*Corresponding author for this work

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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.

Original language	English
Article number	1
Number of pages	13
Journal	Clinical Epigenetics
Volume	14
Issue number	1
DOIs	https://doi.org/10.1186/s13148-021-01220-4
Publication status	Published - 3 Jan 2022

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2022, The Author(s).

Structured keywords

ICEP

Keywords

Epigenetic clock
epigenetic ageing
oropharyngeal cancer
DNA methylation
mortality
prediction

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s13148-021-01220-4

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8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival
Martin, R. M.
1/10/20 → 30/09/25
Project: Research
IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. & Davey Smith, G.
1/04/18 → 31/03/23
Project: Research

Cite this

Beynon, R. A., Ingle, S. M., Langdon, R. J., May, M. T., Martin, R. M., Ness, A. R., Suderman, M. J., Ingarfield, K., Marioni, R. E., McCartney, D. L., Waterboer, T., Pawlita, M., Relton, C. L., Davey Smith, G., & Richmond, R. (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), Article 1. https://doi.org/10.1186/s13148-021-01220-4

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

abstract = "BackgroundEpigenetic 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.ResultsIEAAHannum 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).ConclusionIn 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.",

keywords = "Epigenetic clock, epigenetic ageing, oropharyngeal cancer, DNA methylation, mortality, prediction",

author = "Beynon, {Rhona A} and Ingle, {Suzanne M} and Langdon, {Ryan J} and May, {Margaret T} and Martin, {Richard M} and Ness, {Andrew R} and Suderman, {Matthew J} and Kate Ingarfield and Marioni, {Riccardo E} and McCartney, {Daniel L} and Tim Waterboer and Michael Pawlita and Relton, {Caroline L} and {Davey Smith}, George and Rebecca Richmond",

note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = jan,

day = "3",

doi = "10.1186/s13148-021-01220-4",

language = "English",

volume = "14",

journal = "Clinical Epigenetics",

issn = "1868-7075",

publisher = "Springer Verlag",

number = "1",

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Beynon, RA , Ingle, SM , Langdon, RJ, May, MT, Martin, RM, Ness, AR, Suderman, MJ, Ingarfield, K, Marioni, RE, McCartney, DL, Waterboer, T, Pawlita, M, Relton, CL, Davey Smith, G & Richmond, R 2022, 'Epigenetic biomarkers of ageing are predictive of mortality risk in a longitudinal clinical cohort of individuals diagnosed with oropharyngeal cancer', Clinical Epigenetics, vol. 14, no. 1, 1. https://doi.org/10.1186/s13148-021-01220-4

TY - JOUR

T1 - Epigenetic biomarkers of ageing are predictive of mortality risk in a longitudinal clinical cohort of individuals diagnosed with oropharyngeal cancer

AU - Beynon, Rhona A

AU - Ingle, Suzanne M

AU - Langdon, Ryan J

AU - May, Margaret T

AU - Martin, Richard M

AU - Ness, Andrew R

AU - Suderman, Matthew J

AU - Ingarfield, Kate

AU - Marioni, Riccardo E

AU - McCartney, Daniel L

AU - Waterboer, Tim

AU - Pawlita, Michael

AU - Relton, Caroline L

AU - Davey Smith, George

AU - Richmond, Rebecca

N1 - Funding Information: 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. Publisher Copyright: © 2022, The Author(s).

PY - 2022/1/3

Y1 - 2022/1/3

N2 - BackgroundEpigenetic 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.ResultsIEAAHannum 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).ConclusionIn 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.

AB - BackgroundEpigenetic 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.ResultsIEAAHannum 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).ConclusionIn 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.

KW - Epigenetic clock

KW - epigenetic ageing

KW - oropharyngeal cancer

KW - DNA methylation

KW - mortality

KW - prediction

U2 - 10.1186/s13148-021-01220-4

DO - 10.1186/s13148-021-01220-4

M3 - Article (Academic Journal)

C2 - 34980250

SN - 1868-7075

VL - 14

JO - Clinical Epigenetics

JF - Clinical Epigenetics

IS - 1

M1 - 1

ER -

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

Abstract

Bibliographical note

Structured keywords

Keywords

UN SDGs

Access to Document

Handle.net

Embargoed Document

Fingerprint

Projects

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Cite this