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Epigenetic age acceleration of early stage hepatocellular carcinoma tightly associated with hepatitis B virus load, immunoactivation, and improved survival.

ABSTRACT: Properly stratifying high-risk individuals with early stage hepatocellular carcinoma (HCC) is essential to identify patients in which the potentially therapies can be offered. To this context, we systematically investigated the prognostic value of epigenetic clock with early stage HCC as well as the association with other molecular characteristics.We computed DNA methylation (DNAm) age of 256 early stage HCC patients and 50 normal samples from TCGA by Horvath clock model. The characteristics of two DNAm age subgroups were differentiated regarding HBV expression, pathway activity, epigenomic, and genomic alteration. Cox regression and restricted cubic spline (RCS) analysis were utilized to evaluate the prognostic value of epigenetic acceleration.DNAm age was significantly associated with chronological age in normal tissue but largely disrupted in tumors (P< .001), and showed significant negative correlation with HBV expression (P< .05). We identified two DNAm age groups (DNAmAge-ACC and DNAmAge-DEC), and the former presented with an immunoactive phenotype (all FDRs<0.05 in enrichment analysis), CpG island hypermethylation (P< .001), and lower mutation burden (P= .018). Every 10-year increase in DNAm age was associated with a 18% decrease in fatality after adjustment for major clinical variables; DNAmAge-ACC had 50% lower mortality risk than DNAmAge-DEC (HR: 0.50, 95% CI: 0.27-0.94, P= .03). RCS revealed the fatality risk significantly decreased as epigenetic age accelerated (P = .04). Conclusions.In summary, we highlighted the prognostic value of epigenetic age acceleration for early stage HCC; better prognosis, relatively lower HBV load, and higher enrichment of immune signatures were tightly associated with epigenetic age accelerated tumors.

SUBMITTER: Fan X

PROVIDER: S-EPMC7646381 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: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. 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. RESULTS:DNAm 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). CONCLUSIONS:DNAm 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.

Project description:BackgroundHypertension and atherosclerosis may partly originate in early life. Altered epigenetic aging may be a mechanism underlying associations of early-life exposures and the development of cardiovascular risk factors in childhood. A discrepancy between chronological age and age predicted from neonatal DNA methylation data is referred to as age acceleration. It may either be positive, if DNA methylation age is older than clinical age, or negative, if DNA methylation age is younger than chronological age. We examined associations of age acceleration at birth ('gestational age acceleration'), and of age acceleration at school-age, with blood pressure and with intima-media thickness and distensibility of the common carotid artery, as markers of vascular structure and function, respectively, measured at age 10 years.ResultsThis study was embedded in the Generation R Study, a population-based prospective cohort study. We included 1115 children with information on cord blood DNA methylation and blood pressure, carotid intima-media thickness or carotid distensibility. Gestational age acceleration was calculated using the Bohlin epigenetic clock, which was developed specifically for cord blood DNA methylation data. It predicts gestational age based on methylation levels of 96 CpGs from HumanMethylation450 BeadChip. We observed no associations of gestational age acceleration with blood pressure, carotid intima-media thickness or carotid distensibility at age 10 years. In analyses among children with peripheral blood DNA methylation measured at age 6 (n = 470) and 10 (n = 449) years, we also observed no associations of age acceleration at these ages with the same cardiovascular outcomes, using the 'skin and blood clock,' which predicts age based on methylation levels at 391 CpGs from HumanMethylation450 BeadChip.ConclusionsOur findings do not provide support for the hypothesis that altered epigenetic aging during the earliest phase of life is involved in the development of cardiovascular risk factors in childhood.

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Epigenetic age acceleration of early stage hepatocellular carcinoma tightly associated with hepatitis B virus load, immunoactivation, and improved survival.

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