Epigenetic Drift Association with Cancer Risk and Survival, and Modification by Sex

Abstract

To investigate age- and sex-specific DNA methylation alterations related to cancer risk and survival, we used matched case–control studies of colorectal (n = 835), gastric (n = 170), kidney (n = 143), lung (n = 332), prostate (n = 869) and urothelial (n = 428) cancers, and mature B-cell lymphoma (n = 438). Linear mixed-effects models were conducted to identify age-, sex- and age-by-sex-associated methylation markers using a discovery (controls)-replication (cases) strategy. Replication was further examined using summary statistics from Generation Scotland (GS). Associations between replicated markers and risk of and survival from cancer were assessed using conditional logistic regression and Cox models (hazard ratios (HR)), respectively. We found 32,659, 23,141 and 48 CpGs with replicated associations for age, sex and age-by-sex, respectively. The replication rates for these CpGs using GS summary data were 94%, 86% and 91%, respectively. Significant associations for cancer risk and survival were identified at some individual age-related CpGs. Opposite to previous findings using epigenetic clocks, there was a strong negative trend in the association between epigenetic drift and risk of colorectal cancer. Methylation at two CpGs overlapping TMEM49 and ARX genes was associated with survival of overall (HR = 0.91, p = 7.7 × 10−4) and colorectal (HR = 1.52, p = 1.8 × 10−4) cancer, respectively, with significant age-by-sex interaction. Our results may provide markers for cancer early detection and prognosis prediction.

Using proteomics and metabolomics to identify therapeutic targets for senescence mediated cancer: genetic complementarity method

“…Our study results on the relationship between HannumAge and cancer were consistent with Li et al, 2022 prospective cohort study, which revealed a strong dose-response relationship between epigenetic clock and cancer risk (29). Similarly, case-control study of lung cancer (n=332) reported a strong positive correlation (Beta=0.13, P<2.2×10 -16 ) between methylation and both age and lung cancer risk (30). In addition, a 2019 study demonstrated a significant correlation between standardized measurements of rapid epigenetic aging and cancer incidence (HR: 1.50, P=3.4×10 −3 ) (10).…”

Temporal associations between leukocytes DNA methylation and blood lipids: a longitudinal study

“…All these findings indicated a potential role for TMEM49 in TC homeostasis. In addition, the methylation level of TMEM49 was also associated with waist circumference [ 32 ], survival of cancer overall [ 33 ], and chemotherapy in breast cancer patients [ 34 ].…”

Hormones and Sex-Specific Medicine in Human Physiopathology

“…More specifically, the protumorigenic and antitumorigenic attributes of ER and ER, respectively, have been acknowledged [134]. In summary, the fact that women tend to use more photoprotective cosmetic products on their skin and the biological structural differences between male and female skin layers should also be considered, but further studies are imperative to clarify the enigmatic involvement of the age axis [135,136].…”