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

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

doi:10.1101/679316

Cited by 3 publications

(1 citation statement)

References 74 publications

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“…For instance, Langdon et al identified a panel of DNA methylation biomarkers for early diagnosis of renal cell carcinoma. Besides, DNA methylation of SPEG located at Chr2:220325443-220326041 could potentially regulate oropharyngeal cancer survival [17]. Shen et al reported that hypermethylation of SSTR2 promoter could be used to predict prognosis of laryngeal squamous cell carcinoma in males [18].…”

Section: Introductionmentioning

confidence: 99%

Identification and Validation of a Prognostic Signature Based on Methylation Profiles and Methylation-Driven Gene DAB2 as a Prognostic Biomarker in Differentiated Thyroid Carcinoma

Zhang

Guo

et al. 2022

Disease Markers

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Recurrence is the major death cause of differentiated thyroid carcinoma (DTC), and a better understanding of recurrence risk at early stage may lead to make the optimal medical decision to improve patients' prognosis. The 2015 American Thyroid Association (ATA) risk stratification system primary based on clinic-pathologic features is the most commonly used to describe the initial risk of persistent/recurrent disease. Besides, multiple prognostics models based on multigenes expression profiles have been developed to predict the recurrence risk of DTC patients. Recent evidences indicated that aberrant DNA methylation is involved in the initiation and progression of DTC and can be useful biomarkers for clinical diagnosis and prognosis prediction of DTC. Therefore, there is a need for integrating gene methylation feature to assess the recurrence risk of DTC. Gene methylation profile from The Cancer Genome Atlas (TCGA) was used to construct a recurrence risk model of DTC by successively performed univariate Cox regression, LASSO regression, and multivariate Cox regression. Two Gene Expression Omnibus (GEO) methylation cohorts of DTC were utilized to validate the predictive value of the methylation profiles model as external cohort by receiver operating characteristic (ROC) curve and survival analysis. Besides, CCK-8, colony-formation assay, transwell, and scratch-wound assay were used to investigate the biological significance of critical gene in the model. In our study, we constructed and validated a prognostic signature based on methylation profiles of SPTA1, APCS, and DAB2 and constructed a nomogram based on the methylation-related model, age, and AJCC_T stage that could provide evidence for the long-term treatment and management of DTC patients. Besides, in vitro experiments showed that DAB2 inhibited proliferation, colony-formation, and migration of BCPAP cells and the gene set enrichment analysis and immune infiltration analysis showed that DAB2 may promote antitumor immunity in DTC. In conclusion, promoter hypermethylation and loss expression of DAB2 in DTC may be a biomarker of unfavorable prognosis and poor response to immune therapy.

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Section: Introductionmentioning

confidence: 99%

Identification and Validation of a Prognostic Signature Based on Methylation Profiles and Methylation-Driven Gene DAB2 as a Prognostic Biomarker in Differentiated Thyroid Carcinoma

Zhang

Guo

et al. 2022

Disease Markers

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

Ingle

Langdon

May

et al. 2020

Preprint

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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.

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

et al. 2022

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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.

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

Cited by 3 publications

References 74 publications

Identification and Validation of a Prognostic Signature Based on Methylation Profiles and Methylation-Driven Gene DAB2 as a Prognostic Biomarker in Differentiated Thyroid Carcinoma

Identification and Validation of a Prognostic Signature Based on Methylation Profiles and Methylation-Driven Gene DAB2 as a Prognostic Biomarker in Differentiated Thyroid Carcinoma

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

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

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