Epigenetic mortality predictors and incidence of breast cancer

Abstract

Measures derived using blood DNA methylation are increasingly under investigation as indicators of disease and mortality risk. Three existing epigenetic age measures or "epigenetic clocks" appear associated with breast cancer. Two newly-developed epigenetic mortality predictors may be related to all-cancer incidence, but associations with specific cancers have not been examined in large studies. Using HumanMethylation450 BeadChips to measure blood DNA methylation in 2,773 cancer-free women enrolled in the Sister Study, we calculated two epigenetic mortality predictors: 'GrimAgeAccel' and the 'mortality score' (MS). Using Cox proportional hazard models, neither GrimAgeAccel nor the MS were associated with overall breast cancer incidence (GrimAgeAccel hazard ratio [HR]: 1.06, 95% confidence interval [CI]: 0.98-1.14, P=0.17; MS HR: 0.99, 95% CI: 0.92-1.07, P=0.85); however, a weak, positive association was observed for GrimAgeAccel and invasive breast cancer (HR: 1.08, 95% CI: 0.99-1.17, P=0.08). Stratification of invasive cancers by menopause status at diagnoses revealed the association was predominantly observed for postmenopausal breast cancer (HR: 1.10, 95% CI: 1.01, 1.20, P=0.04). Although the MS was unrelated to breast cancer risk, we find evidence that GrimAgeAccel may be weakly associated with invasive breast cancer, particularly for women diagnosed after menopause.

Biological Aging Measures Based on Blood DNA Methylation and Risk of Cancer: A Prospective Study

“…However, for both PhenoAge and GrimAge , there was overall little attenuation of risk estimates after adjustment for a comprehensive set of sociodemographic and lifestyle cancer risk factors, which may indicate that these measures capture information beyond self-reported questionnaires and on many adverse environmental and lifestyle factors that affect the methylome over the life course. To our knowledge, no data exist on the association of PhenoAge and GrimAge with risk of cancers other than pancreatic cancer ( 29 ) and breast cancer; in the latter case, the Sister Study revealed a reasonably strong association with PhenoAge ( 30 ) (invasive disease; hazard ratio per 5-year increase: 1.13, which is of similar magnitude to our findings for colorectal, kidney, lung, mature B-cell, and urothelial cancers) ( Supplementary Table 4 , available online) but not with GrimAge ( 31 ). Further adjustment for estimated white blood cell proportions slightly attenuated associations with cancer risk overall, although a larger association was observed for GrimAge and lung cancer, similar to observations made for PhenoAge and risk of breast ( 30 ) and pancreatic cancer ( 29 ).…”

DNA methylation-based biomarkers of age acceleration and all-cause death, myocardial infarction, stroke, and cancer in two cohorts: The NAS, and KORA F4

“…However, because of the moderate correlation between DNAm ages, and chronological age, it is not surprising to find predictive power of DNAm clocks for the prevalence, and incidence of age-related health outcomes. Recent studies have revealed that age acceleration (AA), which is the raw residual in the linear regression model with DNAm age regressed on chronological age, is a candidate biomarker for all-cause death, and age-related diseases [13] , [16] , [17] , [18] , [19] , [20] , [21] , [22] . The well documented AA measures are epigenetic age acceleration of intrinsic, and extrinsic (i.e., IEAA, and EEAA) [17] .…”

“…Most recently, Horvath et al showed that PhenoAgeAccel, and GrimAgeAccel had strong predictive power for all-cause death, coronary heart disease, and cancer [13] . However, most related studies, to date, focused on IEAA, and EEAA [17] , [18] , [19] , [20] , and few investigated the associations between PhenoAgeAccel / GrimAgeAccel and multiple health endpoints [ 13 , 21 ].…”

The use of DNA methylation clock in aging research

“…4 For example, three studies involving breast cancer examined the association between DNAm age acceleration and breast cancer incidence. 67,68,77 Two of the studies reported a statistically significant association between DNAm age acceleration and the incidence of postmenopausal invasive cancers of the breast, with no ductal carcinoma in situ association. 67,68 One breast cancer study showed that DNA methylation age estimated by DNAm GrimAge had only a weak positive association with invasive cancers.…”

“…67,68 One breast cancer study showed that DNA methylation age estimated by DNAm GrimAge had only a weak positive association with invasive cancers. 77 Two studies involving lung cancer also showed inconsistent results. 71,78 In contrast, two studies of colorectal cancer reported that DNAm age acceleration is significantly associated with colorectal cancer.…”