TY - JOUR
T1 - Epigenetic drift association with cancer risk and survival, and modification by sex
AU - Yu, Chenglong
AU - Wong, Ee Ming
AU - Joo, Jihoon Eric
AU - Hodge, Allison M.
AU - Makalic, Enes
AU - Schmidt, Daniel
AU - Buchanan, Daniel D.
AU - Severi, Gianluca
AU - Hopper, John L.
AU - English, Dallas R.
AU - Giles, Graham G.
AU - Southey, Melissa C.
AU - Dugué, Pierre Antoine
N1 - Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/4/2
Y1 - 2021/4/2
N2 - 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.
AB - 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.
KW - Age-by-sex
KW - Ageing
KW - Cancer risk
KW - Cancer survival
KW - DNA methylation
KW - Epigenetic drift
KW - Pre-diagnostic blood
KW - Sex difference
KW - X chromosome
UR - http://www.scopus.com/inward/record.url?scp=85104019002&partnerID=8YFLogxK
U2 - 10.3390/cancers13081881
DO - 10.3390/cancers13081881
M3 - Article
AN - SCOPUS:85104019002
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 8
M1 - 1881
ER -