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Association of Epigenetic Clock with Consensus Molecular Subtypes and Overall Survival of Colorectal Cancer.

ABSTRACT: BACKGROUND:Epigenetic clock, or DNA methylation age, has been shown to highly correlate with chronologic age. Epigenetic age acceleration, the difference between DNA methylation age and individual's chronologic age, was observed in colorectal cancer. However, the association of epigenetic age acceleration with colorectal cancer tumor molecular characteristics, clinical characteristics, and patient outcomes has not been systematically investigated. METHODS:DNA methylation ages of 345 patients with colorectal cancer from The Cancer Genome Atlas (TCGA) were computed using the Horvath age prediction model. Multivariate linear regression was used to assess the association of epigenetic age acceleration with molecular and clinical features of colorectal cancer, including consensus molecular subtypes (CMS1-CMS4) and tumor stage Cox proportional hazards regression was used to assess the association of epigenetic age acceleration with survival. RESULTS:Epigenetic age acceleration is significantly associated with CMS. Compared with CMS2, epigenetic age acceleration for CMS1, CMS3, and CMS4 was 23.90 years [P = 5.55E-11; 95% confidence interval (CI): 17.10-30.69], 9.16 years (P = 5.84E-03; 95% CI: 2.68-15.65), and 6.05 years (P = 2.69E-02; 95% CI: 0.70-11.41), respectively. Furthermore, epigenetic age acceleration is statistically significantly and positively associated with total mortality (HR = 1.97; 95% CI: 1.14-3.39; P = 0.014). CONCLUSIONS:Epigenetic age acceleration is associated with colorectal cancer tumor molecular characteristics, and a significant predictor of overall survival of colorectal cancer, along with age and tumor stage. IMPACT:Combining information of colonic tissue epigenetic age acceleration and tumor molecular characteristics may improve prognosis prediction in colorectal cancer.

SUBMITTER: Zheng C

PROVIDER: S-EPMC6774810 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Association of Epigenetic Clock with Consensus Molecular Subtypes and Overall Survival of Colorectal Cancer.

Zheng Chunlei C Li Li L Xu Rong R

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20190802 10

<h4>Background</h4>Epigenetic clock, or DNA methylation age, has been shown to highly correlate with chronologic age. Epigenetic age acceleration, the difference between DNA methylation age and individual's chronologic age, was observed in colorectal cancer. However, the association of epigenetic age acceleration with colorectal cancer tumor molecular characteristics, clinical characteristics, and patient outcomes has not been systematically investigated.<h4>Methods</h4>DNA methylation ages of 3 ...[more]

PMID: 31375479

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Project description:Background and aimsColorectal cancer (CRC) is a heterogeneous disease that can develop via several pathways. Different CRC subtypes, identified based on tumor markers, have been proposed to reflect these pathways. We evaluated the significance of these previously proposed classifications to survival.MethodsParticipants in the population-based Seattle Colon Cancer Family Registry were diagnosed with invasive CRC from 1998 through 2007 in western Washington State (N = 2706), and followed for survival through 2012. Tumor samples were collected from 2050 participants and classified into 5 subtypes based on combinations of tumor markers: type 1 (microsatellite instability [MSI]-high, CpG island methylator phenotype [CIMP] -positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMP-positive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS). Multiple imputation was used to impute tumor markers for those missing data on 1-3 markers. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of subtypes with disease-specific and overall mortality, adjusting for age, sex, body mass, diagnosis year, and smoking history.ResultsCompared with participants with type 4 tumors (the most predominant), participants with type 2 tumors had the highest disease-specific mortality (HR = 2.20, 95% CI: 1.47-3.31); subjects with type 3 tumors also had higher disease-specific mortality (HR = 1.32, 95% CI: 1.07-1.63). Subjects with type 5 tumors had the lowest disease-specific mortality (HR = 0.30, 95% CI: 0.14-0.66). Associations with overall mortality were similar to those with disease-specific mortality.ConclusionsBased on a large, population-based study, CRC subtypes, defined by proposed etiologic pathways, are associated with marked differences in survival. These findings indicate the clinical importance of studies into the molecular heterogeneity of CRC.

Project description:Background: Many biological clocks related to aging have been linked to the development of cancer. A recent study has identified that the inflammatory aging clock was an excellent indicator to track multiple diseases. However, the role of the inflammatory aging clock in glioblastoma (GBM) remains to be explored. This study aimed to investigate the expression patterns and the prognostic values of inflammatory aging (iAge) in GBM, and its relations with stem cells. Methods: Inflammation-related genes (IRG) and their relations with chronological age in normal samples from the Cancer Genome Atlas (TCGA) were identified by the Spearman correlation analysis. Then, we calculated the iAge and computed their correlations with chronological age in 168 patients with GBM. Next, iAge was applied to classify the patients into high- and low-iAge subtypes. Next, the survival analysis was performed. In addition, the correlations between iAge and stem cell indexes were evaluated. Finally, the results were validated in an external cohort. Results: Thirty-eight IRG were significantly associated with chronological age (|coefficient| > 0.5), and were used to calculate the iAge. Correlation analysis showed that iAge was positively correlated with chronological age. Enrichment analysis demonstrated that iAge was highly associated with immune cells and inflammatory activities. Survival analysis showed the patients in the low-iAge subtype had significantly better overall survival (OS) than those in the high-iAge subtype (p < 0.001). In addition, iAge outperformed the chronological age in revealing the correlations with stem cell stemness. External validation demonstrated that iAge was an excellent method to classify cancer subtypes and predict survival in patients with GBM. Conclusions: Inflammatory aging clock may be involved in the GBM via potential influences on immune-related activities. iAge could be used as biomarkers for predicting the OS and monitoring the stem cell.

Dataset Information

Association of Epigenetic Clock with Consensus Molecular Subtypes and Overall Survival of Colorectal Cancer.

Publications

Association of Epigenetic Clock with Consensus Molecular Subtypes and Overall Survival of Colorectal Cancer.

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