DNA methylome analysis identifies accelerated epigenetic ageing associated with postmenopausal breast cancer susceptibility

Abstract

Aim of the study A vast majority of human malignancies are associated with ageing, and age is a strong predictor of cancer risk. Recently, DNA methylation-based marker of ageing, known as ‘epigenetic clock’, has been linked with cancer risk factors. This study aimed to evaluate whether the epigenetic clock is associated with breast cancer risk susceptibility and to identify potential epigenetics-based biomarkers for risk stratification. Methods Here, we profiled DNA methylation changes in a nested case–control study embedded in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (n = 960) using the Illumina HumanMethylation 450K BeadChip arrays and used the Horvath age estimation method to calculate epigenetic age for these samples. Intrinsic epigenetic age acceleration (IEAA) was estimated as the residuals by regressing epigenetic age on chronological age. Results We observed an association between IEAA and breast cancer risk (OR, 1.04; 95% CI, 1.007–1.076, P = 0.016). One unit increase in IEAA was associated with a 4% increased odds of developing breast cancer (OR, 1.04; 95% CI, 1.007–1.076). Stratified analysis based on menopausal status revealed that IEAA was associated with development of postmenopausal breast cancers (OR, 1.07; 95% CI, 1.020–1.11, P = 0.003). In addition, methylome-wide analyses revealed that a higher mean DNA methylation at cytosine-phosphate-guanine (CpG) islands was associated with increased risk of breast cancer development (OR per 1 SD = 1.20; 95 %CI: 1.03–1.40, P = 0.02) whereas mean methylation levels at non-island CpGs were indistinguishable between cancer cases and controls. Conclusion Epigenetic age acceleration and CpG island methylation have a weak, but statistically significant, association with breast cancer susceptibility.

DNA methylation‐based biological aging and cancer risk and survival: Pooled analysis of seven prospective studies

“…Weak evidence of increased cancer mortality risk was reported (based on 34 deaths: HR 5 1.05, 95% CI: 0.99-1.12), which is consistent with the findings of our study. A recent and larger-scale European study which included 480 breast cancer cases and matched controls 30 reported an increased risk associated with IEAA-Horvath (OR per one year 5 1.04, 95%CI: 1.01-1.08). The association appeared to be confined to postmenopausal women, but heterogeneity by menopausal status was not tested.…”

Randomized controlled trial of increasing physical activity on objectively measured and self‐reported cognitive functioning among breast cancer survivors: The memory & motion study

“…Physical activity may also reduce the impact of accelerated aging observed in cancer survivors . At the cellular level, dynamic, epigenetic DNA methylation profiles are associated with aging, cancer, physical activity, and cognition . It is important to note that age‐related DNA methylation is associated with age‐related gene transcription .…”

Epigenetics and Precision Oncology

“…Specifically, numerous studies have been published documenting age-related DNA hypermethylation and acceleration of this process could be a biomarker of cancer risk (15-18). Data from an in vivo model demonstrated that age-related methylation changes in blood accelerate during the development of myelodysplastic syndromes and acute myeloid leukemia (AML) (15).…”

“…In a case-control study of breast cancer, peripheral blood DNA methylation was evaluated with respect to an age estimator; residuals in the model defined a measure of intrinsic epigenetic age acceleration (IEAA). A one unit increase in IEAA as determined by regression of epigenetic on chronological age, was reported to increase the risk of developing breast cancer by 4% (OR, 1.04; 95% CI, 1.007-1.0076) (17,18). Another recent study reported that the extent of age-related DNA hypermethylation varies by tissue and is correlated with site-specific lifetime cancer risk (15).…”