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

Dugué, Pierre Antoine; Bassett, Julie K.; Joo, Jihoon E.; Jung, Chol Hee; Wong, Ee Ming; Moreno‐Betancur, Margarita; Schmidt, Daniel F.; Makalic, Enes; Li, Shuai; Severi, Gianluca; Hodge, Allison; Buchanan, Daniel D.; English, Dallas R.; Hopper, John L.; Southey, Melissa C.; Giles, Graham G.; Milne, Roger L.

doi:10.1002/ijc.31189

Cited by 175 publications

(192 citation statements)

References 69 publications

(153 reference statements)

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“…All MCCS participants were of European descent, including 25% born in Italy or Greece. Blood DNA methylation was measured for 6,404 participants in one of six nested case‐control studies for breast cancer, colorectal cancer, mature B‐cell neoplasms, urothelial cell carcinoma, kidney cancer, or lung cancer . In the breast cancer study, only women who were included as controls were selected, to avoid the possibility of collider bias .…”

Section: Methodsmentioning

confidence: 99%

Genome‐wide association study of peripheral blood DNA methylation and conventional mammographic density measures

Dugué

Baglietto

et al. 2019

Intl Journal of Cancer

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Age‐ and body mass index (BMI)‐adjusted mammographic density is one of the strongest breast cancer risk factors. DNA methylation is a molecular mechanism that could underlie inter‐individual variation in mammographic density. We aimed to investigate the association between breast cancer risk‐predicting mammographic density measures and blood DNA methylation. For 436 women from the Australian Mammographic Density Twins and Sisters Study and 591 women from the Melbourne Collaborative Cohort Study, mammographic density (dense area, nondense area and percentage dense area) defined by the conventional brightness threshold was measured using the CUMULUS software, and peripheral blood DNA methylation was measured using the HumanMethylation450 (HM450) BeadChip assay. Associations between DNA methylation at >400,000 sites and mammographic density measures adjusted for age and BMI were assessed within each cohort and pooled using fixed‐effect meta‐analysis. Associations with methylation at genetic loci known to be associated with mammographic density were also examined. We found no genome‐wide significant (p < 10−7) association for any mammographic density measure from the meta‐analysis, or from the cohort‐specific analyses. None of the 299 methylation sites located at genetic loci associated with mammographic density was associated with any mammographic density measure after adjusting for multiple testing (all p > 0.05/299 = 1.7 × 10−4). In summary, our study did not find evidence for associations between blood DNA methylation, as measured by the HM450 assay, and conventional mammographic density measures that predict breast cancer risk.

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Section: Methodsmentioning

confidence: 99%

Genome‐wide association study of peripheral blood DNA methylation and conventional mammographic density measures

Dugué

Baglietto

et al. 2019

Intl Journal of Cancer

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“…Nowadays, DNA methylation was a research hotspot about cancer including renal cancers. The heterogeneity of DNA methylation was observed by Dugué et al, with stronger associations for risk of kidney cancer . Additionally, Kumar et al put forward the hypothesis that IQGAP2 and IQGAP3 were promised to be prognosis therapeutic target of specific cancers including renal cancer for the close connection of their methylation and cancers .…”

Section: Discussionmentioning

confidence: 97%

“…H, The apoptosis cells were increased in 5-Aza-dC treatment group and TSA treatment group and co-treatment group displayed more obvious trend (×40) | 6655 LI and YU showed that 5-Aza-dC and TSA could better block the tumour growth. 26 Additionally, Kumar et al put forward the hypothesis that IQGAP2 and IQGAP3 were promised to be prognosis therapeutic target of specific cancers including renal cancer for the close connection of their methylation and cancers. 27 It also reports that RPS6KA4/MIR1237 and AURKC promoter regions are differentially methylated in Wilms' tumour.…”

Section: Discussionmentioning

confidence: 99%

PON1 hypermethylation is associated with progression of renal cell carcinoma

2019

J Cellular Molecular Medi

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In this study, our aim was to exploring the influences of DNA methylation of PON1 on cell proliferation, migration and apoptosis of renal cancer cells. The genome‐wide methylation array of renal cell carcinoma samples and adjacent tissues were obtained from the cancer genome atlas (TCGA) database. By analysing the DNA methylation and conducting the CpG islands array, methylation status expressed in renal tumour samples and normal renal tissue samples were detected. Methylation‐specific PCR (MS‐PCR) and qRT‐PCR were employed to detect the methylation level and mRNA expression of PON1. Wound‐healing assay, transwell assay and MTT assay were utilized to detecting the migration, invasion and proliferation abilities, respectively. The cell apoptosis was testified by Tunnel assay. In addition, the effect of PON1 on renal cancer cells was verified by experiments in vivo. The methylation status of different genes in renal cell carcinoma samples was obtained by CpG islands arrays and hypermethylated PON1 was selected for further study. PON1 was down‐regulated in renal cell carcinoma tissues detected by qRT‐PCR and Western blot. Both in vitro and vivo experiments indicated that the sunitinib‐resistant in renal cancer cells could be suppressed by treat with 5‐Aza‐dC or TSA, and the effect came out more obvious after 5‐Aza‐dC and TSA co‐treatment. In detail, the demethylation of PON1 inhibited the migration, invasion and proliferation of renal cancer cells and also arrested more cells in G0/G1 phase. The vivo experiment indicated that demethylated PON1 suppressed the growth of tumour. Hypermethylated PON1 promoted migration, invasion and proliferation of sunitinib‐resistance renal cancer cells and arrested more cells in G0/G1 phase.

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“…Identification of the critical elements responsible for the loss of epigenetic surveillance is important for understanding the impact of CpG mutations, polymorphisms, and changes in their surrounding sequences and for designing appropriate diagnostic tools. A better understanding of the mechanisms underlying these processes will also help us identify the environmental factors that play a regulatory role in formulating our epigenome [11,47,48] and their effects on epigenetic heredity [49]. Moreover, it improves our understanding of the splicing and alternative splicing processes, which are still poorly understood [50–52].…”

Section: Discussionmentioning

confidence: 99%

Age-dependent methylation in epigenetic clock CpGs is associated with G-quadruplex, co-transcriptionally formed RNA structures and tentative splice sites

et al. 2018

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Horvath’s epigenetic clock consists of 353 CpGs whose methylation levels can accurately predict the age of individuals. Using bioinformatics analysis, we investigated the conformation, energy characteristics and presence of tentative splice sites of the sequences surrounding the epigenetic clock CpGs, in relation to the median methylation changes in different ages, the presence of CpG islands and their position in genes. Common characteristics in the 100 nt sequences surrounding the epigenetic clock CpGs are G-quadruplexes and/or tentative splice site motifs. Median methylation increases significantly in sequences which adopt less stable structures during transcription. Methylation is higher when CpGs overlap with G-quadruplexes than when they precede them. Median methylation in epigenetic clock CpGs is higher in sequences expressed as single products rather than in multiple products and those containing single donors and multiple acceptors. Age-related methylation variation is significant in sequences without G-quadruplexes, particularly those producing low stability nascent RNA and those with splice sites. CpGs in sequences close to transcription start sites and those which are possibly never expressed (hypothetical proteins) undergo similar extent of age-related median methylation decrease and increase. Preservation of methylation is observed in CpG islands without G-quadruplexes, contrary to CpGs far from CpG islands (open sea). Sequences containing G-quadruplexes and RNA pseudoknots, determining the recognition by H3K27 histone methyltransferase, are hypomethylated. The presented structural DNA and co-transcriptional RNA analysis of epigenetic clock sequences, foreshadows the association of age-related methylation changes with the principle biological processes of DNA and histone methylation, splicing and chromatin silencing.

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

Cited by 175 publications

References 69 publications

Genome‐wide association study of peripheral blood DNA methylation and conventional mammographic density measures

Genome‐wide association study of peripheral blood DNA methylation and conventional mammographic density measures

PON1 hypermethylation is associated with progression of renal cell carcinoma

Age-dependent methylation in epigenetic clock CpGs is associated with G-quadruplex, co-transcriptionally formed RNA structures and tentative splice sites

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