Whole blood DNA methylation aging markers predict colorectal cancer survival: a prospective cohort study

Abstract

Background Blood DNA methylation-based aging algorithms predict mortality in the general population. We investigated the prognostic value of five established DNA methylation aging algorithms for patients with colorectal cancer (CRC). Methods AgeAccelHorvath, AgeAccelHannum, DNAmMRscore, AgeAccelPheno and AgeAccelGrim were constructed using whole blood epi-genomic data from 2206 CRC patients. After a median follow-up of 6.2 years, 1079 deaths were documented, including 596 from CRC. Associations of the aging algorithms with survival outcomes were evaluated using the Cox regression and survival curves. Harrell’s C-statistics were computed to investigate predictive performance. Results Adjusted hazard ratios (95% confidence intervals) of all-cause mortality for patients in the third compared to the first tertile were 1.66 (1.32, 2.09) for the DNAmMRscore, 1.35 (1.14, 1.59) for AgeAccelPheno and 1.65 (1.37, 2.00) for AgeAccelGrim, even after adjustment for age, sex and stage. AgeAccelHorvath and AgeAccelHannum were not associated with all-cause or CRC-specific mortality. In stage-specific analyses, associations were much stronger for patients with early or intermediate stage cancers (stages I, II and III) than for patients with metastatic (stage IV) cancers. Associations were weaker and less often statistically significant for CRC-specific mortality. Adding DNAmMRscore, AgeAccelPheno or AgeAccelGrim to models including age, sex and tumor stage improved predictive performance moderately. Conclusions DNAmMRscore, AgeAccelPheno and AgeAccelGrim could serve as non-invasive CRC prognostic biomarkers independent of other commonly used markers. Further research should aim for tailoring and refining such algorithms for CRC patients and to explore their value for enhanced prediction of treatment success and treatment decisions.

Epigenetic drift association with cancer risk and survival, and modification by sex

“…This finding was consistently reproduced in other studies [26, 27]. We and others previously found that these epigenetic aging measures were associated with risk of and survival from specific types of cancers, but the contribution of the epigenetic drift as a whole has received less attention [28-32]. A recent study [33] has identified genome-wide methylation sites at which there was chronological age-by-sex interaction and found that most of them were on the X chromosome.…”

Comparative validation of three DNA methylation algorithms of ageing and a frailty index in relation to mortality: results from the ESTHER cohort study

“…DNA from whole blood samples obtained at recruitment was extracted using a salting-out procedure [ 22 ]. Genome-wide DNAm was assessed with the Infinium Methylation EPIC BeadChip kit (EPIC, Illumina, San Diego, CA, USA) [ 15 , 21 ]. The laboratory work was done following the manufacturer's instruction in the Genomics and Proteomics Core Facility at the German Cancer Research Center, Heidelberg, Germany (DKFZ) as previously described [ 23 ].…”

“…Differences between PhenoAge and GrimAge and chronological age are commonly being referred to as measures of epigenetic age acceleration and termed as AgeAccelPheno and AgeAccelGrim, respectively. AgeAccelPheno, AgeAccelGrim, and MRscore were shown to be highly correlated with all-cause mortality and cancer-specific mortality across various study populations [ [14] , [15] , [16] ]. However, the predictive performance of the three DNAm algorithms and mortality has not been evaluated in the same study population, and it is therefore unclear to what extent results on their predictive performance are comparable or reflect differences in the assessed study populations.…”

Promising Epigenetic Biomarkers for the Early Detection of Colorectal Cancer: A Systematic Review

“…Moreover, three algorithms. DNAmMRscore (DNAm mortality risk score), DNAm PhenoAge acceleration (AgeAccelPheno), and DNAm GrimAge acceleration (AgeAccelGrim) can be positively associated with colorectal cancer-specific mortality [ 21 ]; blood DNA methylation profiles can be measured using the Infinium Methylation EPIC BeadChip Kit that covers over 850,000 CpG sites (Illumina, Inc, San Diego, CA, USA). Three methylation-based measures of biological aging PhenoAge, GrimAge, and methylation-predicted telomere length were associated with CRC risk and other cancers such as lung, kidney, and urothelial cancer [ 22 ].…”