Abstract
BackgroundAgeing-associated molecular changes have been assumed to trigger malignant transformations and the epigenetic clock, and the DNA methylation age has been shown to be highly correlated with chronological age. However, the associations between the epigenetic clock and cervical squamous cell carcinoma (CSCC) prognosis, other molecular characteristics, and clinicopathological features have not been systematically investigated. To this end, we computed the DNA methylation (DNAm) age of 252 CSCC patients and 200 normal samples from TCGA and three external cohorts by using the Horvath clock model. We characterized the differences in human papillomavirus (HPV) 16/18 expression, pathway activity, genomic alteration, and chemosensitivity between two DNAm age subgroups. We then used Cox proportional hazards regression and restricted cubic spline (RCS) analysis to assess the prognostic value of epigenetic acceleration.ResultsDNAm age was significantly associated with chronological age, but it was differentiated between tumour and normal tissue (P < 0.001). Two DNAm age groups, i.e. DNAmAge-ACC and DNAmAge-DEC, were identified; the former had high expression of the E6/E7 oncoproteins of HPV16/18 (P < 0.05), an immunoactive phenotype (all FDRs < 0.05 in enrichment analysis), CpG island hypermethylation (P < 0.001), and lower mutation load (P = 0.011), including for TP53 (P = 0.002). When adjusted for chronological age and tumour stage, every 10-year increase in DNAm age was associated with a 12% decrease in fatality (HR 0.88, 95% CI 0.78–0.99, P = 0.03); DNAmAge-ACC had a 41% lower mortality risk and 47% lower progression rate than DNAmAge-DEC and was more likely to benefit from chemotherapy. RCS revealed a positive non-linear association between DNAm age and both mortality and progression risk (both, P < 0.05).ConclusionsDNAm age is an independent predictor of CSCC prognosis. Better prognosis, overexpression of HPV E6/E7 oncoproteins, and higher enrichment of immune signatures were observed in DNAmAge-ACC tumours.
Highlights
Ageing-associated molecular changes have been assumed to trigger malignant transformations and the epigenetic clock, and the DNA methylation age has been shown to be highly correlated with chronological age
Differential correlation between DNA methylation (DNAm) age and chronological age in normal and tumour tissues The study population included 252 tumour samples retrieved from The Cancer Genome Atlas (TCGA) and a total of 200 normal cervical samples as a control from both the TCGA and Gene Expression Omnibus (GEO) data
They were classified as ‘DNAmAge-ACC’ or age accelerated if the shift was greater than zero, and they were classified as ‘DNAmAge-DEC’ or age decelerated if the shift was less than zero
Summary
Ageing-associated molecular changes have been assumed to trigger malignant transformations and the epigenetic clock, and the DNA methylation age has been shown to be highly correlated with chronological age. Ren J et al reported that decreased DNAm age is associated with poor prognosis after adjusting for major clinical variables, including tumour stage and oestrogen receptor status [16], while Kresovich J et al found that DNA methylation-based measures of biological age acceleration are significantly associated with increased risk of developing breast cancer [17]. These studies suggested an essential role for biological age in tumour development and progression
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
