scholarly journals Genetically Predicted Levels of DNA Methylation Biomarkers and Breast Cancer Risk: Data From 228 951 Women of European Descent

2019 ◽  
Vol 112 (3) ◽  
pp. 295-304 ◽  
Author(s):  
Yaohua Yang ◽  
Lang Wu ◽  
Xiao-Ou Shu ◽  
Qiuyin Cai ◽  
Xiang Shu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Statistical Power ◽  
Prediction Models ◽  
Statistical Tests ◽  
Critical Role ◽  
White Blood Cells ◽  
Cpg Sites

Abstract Background DNA methylation plays a critical role in breast cancer development. Previous studies have identified DNA methylation marks in white blood cells as promising biomarkers for breast cancer. However, these studies were limited by low statistical power and potential biases. Using a new methodology, we investigated DNA methylation marks for their associations with breast cancer risk. Methods Statistical models were built to predict levels of DNA methylation marks using genetic data and DNA methylation data from HumanMethylation450 BeadChip from the Framingham Heart Study (n = 1595). The prediction models were validated using data from the Women’s Health Initiative (n = 883). We applied these models to genomewide association study (GWAS) data of 122 977 breast cancer patients and 105 974 controls to evaluate if the genetically predicted DNA methylation levels at CpG sites (CpGs) are associated with breast cancer risk. All statistical tests were two-sided. Results Of the 62 938 CpG sites CpGs investigated, statistically significant associations with breast cancer risk were observed for 450 CpGs at a Bonferroni-corrected threshold of P less than 7.94 × 10–7, including 45 CpGs residing in 18 genomic regions, that have not previously been associated with breast cancer risk. Of the remaining 405 CpGs located within 500 kilobase flaking regions of 70 GWAS-identified breast cancer risk variants, the associations for 11 CpGs were independent of GWAS-identified variants. Integrative analyses of genetic, DNA methylation, and gene expression data found that 38 CpGs may affect breast cancer risk through regulating expression of 21 genes. Conclusion Our new methodology can identify novel DNA methylation biomarkers for breast cancer risk and can be applied to other diseases.

scholarly journals Methylation-Based Biological Age and Breast Cancer Risk

2019 ◽  
Vol 111 (10) ◽  
pp. 1051-1058 ◽  
Author(s):  
Jacob K Kresovich ◽  
Zongli Xu ◽  
Katie M O’Brien ◽  
Clarice R Weinberg ◽  
Dale P Sandler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Cox Regression ◽  
Disease Risk ◽  
Statistical Tests ◽  
Biological Age ◽  
Cancer Case ◽  
Increased Risk

Abstract Background Age is one of the strongest predictors of cancer, chronic disease, and mortality, but biological responses to aging differ among people. Epigenetic DNA modifications have been used to estimate “biological age,” which may be a useful predictor of disease risk. We tested this hypothesis for breast cancer. Methods Using a case-cohort approach, we measured baseline blood DNA methylation of 2764 women enrolled in the Sister Study, 1566 of whom subsequently developed breast cancer after an average of 6 years. Using three previously established methylation-based “clocks” (Hannum, Horvath, and Levine), we defined biological age acceleration for each woman by comparing her estimated biological age with her chronological age. Hazard ratios and 95% confidence intervals for breast cancer risk were estimated using Cox regression models. All statistical tests were two-sided. Results Each of the three clocks showed that biological age acceleration was statistically significantly associated with increased risk of developing breast cancer (5-year age acceleration, Hannum’s clock: hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.00 to 1.21, P = .04; Horvath’s clock: HR = 1.08, 95% CI = 1.00 to 1.17, P = .04; Levine’s clock: HR = 1.15, 95% CI = 1.07 to 1.23, P < .001). For Levine’s clock, each 5-year acceleration in biological age corresponded with a 15% increase in breast cancer risk. Although biological age may accelerate with menopausal transition, age acceleration in premenopausal women independently predicted breast cancer. Case-only analysis suggested that, among women who develop breast cancer, increased age acceleration is associated with invasive cancer (odds ratio for invasive = 1.09, 95% CI = 0.98 to 1.22, P = .10). Conclusions DNA methylation-based measures of biological age may be important predictors of breast cancer risk.

scholarly journals DNA Methylation in Benign Breast Epithelium in Relation to Age and Breast Cancer Risk

2008 ◽  
Vol 17 (5) ◽  
pp. 1051-1059 ◽  
Author(s):  
David M. Euhus ◽  
Dawei Bu ◽  
Sara Milchgrub ◽  
Xian-Jin Xie ◽  
Aihua Bian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Breast Epithelium

scholarly journals Relation of Quantitative Histologic and Radiologic Breast Tissue Composition Metrics with Invasive Breast Cancer Risk

2021 ◽  
Author(s):  
Mustapha Abubakar ◽  
Shaoqi Fan ◽  
Erin Aiello Bowles ◽  
Lea Widemann ◽  
Máire A Duggan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Invasive Breast Cancer ◽  
Statistical Tests ◽  
Predictive Biomarkers ◽  
Breast Cancer Diagnosis ◽  
Breast Cancer Risk Factor ◽  
Computer Assisted ◽  
Tissue Composition

Abstract Background Benign breast disease (BBD) is a strong breast cancer risk factor but identifying patients that might develop invasive breast cancer remains a challenge. Methods By applying machine-learning to digitized H&E-stained biopsies and computer-assisted thresholding to mammograms obtained circa BBD diagnosis, we generated quantitative tissue composition metrics and determined their association with future invasive breast cancer diagnosis. Archival breast biopsies and mammograms were obtained for women (18-86 years of age) in a case-control study, nested within a cohort of 15,395 BBD patients from Kaiser Permanente Northwest (1970-2012), followed through mid-2015. Cases (n = 514) who developed incident invasive breast cancer and controls (n = 514) were matched on BBD diagnosis age and plan membership duration. All statistical tests were 2-sided. Results Increasing epithelial area on the BBD biopsy was associated with increasing breast cancer risk (Odds ratio [OR]Q4 vs Q1=1.85, 95% confidence interval [CI] = 1.13-3.04; Ptrend=0.02). Conversely, increasing stroma was associated with decreased risk in non-proliferative, but not proliferative, BBD (Pheterogeneity=0.002). Increasing epithelium-to-stroma proportion [ORQ4 vs Q1=2.06, 95% CI = 1.28-3.33; Ptrend=0.002) and percent mammographic density (MBD) (ORQ4 vs Q1=2.20, 95% CI = 1.20-4.03; Ptrend=0.01) were independently and strongly predictive of increased breast cancer risk. In combination, women with high epithelium-to-stroma proportion/high MBD had substantially higher risk than those with low epithelium-to-stroma proportion/low MBD [OR = 2.27, 95% CI = 1.27-4.06; Ptrend=0.005), particularly among women with non-proliferative (Ptrend=0.01) versus proliferative (Ptrend=0.33) BBD. Conclusion Among BBD patients, increasing epithelium-to-stroma proportion on BBD biopsies and percent MBD at BBD diagnosis were independently and jointly associated with increasing breast cancer risk. These findings were particularly striking for women with non-proliferative disease (comprising approximately 70% of all BBD patients), for whom relevant predictive biomarkers are lacking.

DNA methylation and breast cancer risk: value of twin and family studies

2021 ◽  
pp. 67-83
Author(s):  
Shuai Li ◽  
Zhoufeng Ye ◽  
kConFab Investigators ◽  
John L. Hopper ◽  
Melissa C. Southey
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Family Studies

scholarly journals DNA Methylation and Breast Cancer Risk: An Epigenome-Wide Study of Normal Breast Tissue and Blood

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3088 ◽  
Author(s):  
Kaoutar Ennour-Idrissi ◽  
Dzevka Dragic ◽  
Elissar Issa ◽  
Annick Michaud ◽  
Sue-Ling Chang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Breast Tissue ◽  
Normal Breast Tissue ◽  
Normal Breast ◽  
Breast Epithelium ◽  
Normal Breast Epithelium ◽  
Differentially Methylated Genes

Differential DNA methylation is a potential marker of breast cancer risk. Few studies have investigated DNA methylation changes in normal breast tissue and were largely confounded by cancer field effects. To detect methylation changes in normal breast epithelium that are causally associated with breast cancer occurrence, we used a nested case–control study design based on a prospective cohort of patients diagnosed with a primary invasive hormone receptor-positive breast cancer. Twenty patients diagnosed with a contralateral breast cancer (CBC) were matched (1:1) with 20 patients who did not develop a CBC on relevant risk factors. Differentially methylated Cytosine-phosphate-Guanines (CpGs) and regions in normal breast epithelium were identified using an epigenome-wide DNA methylation assay and robust linear regressions. Analyses were replicated in two independent sets of normal breast tissue and blood. We identified 7315 CpGs (FDR < 0.05), 52 passing strict Bonferroni correction (p < 1.22 × 10−7) and 43 mapping to known genes involved in metabolic diseases with significant enrichment (p < 0.01) of pathways involving fatty acids metabolic processes. Four differentially methylated genes were detected in both site-specific and regions analyses (LHX2, TFAP2B, JAKMIP1, SEPT9), and three genes overlapped all three datasets (POM121L2, KCNQ1, CLEC4C). Once validated, the seven differentially methylated genes distinguishing women who developed and who did not develop a sporadic breast cancer could be used to enhance breast cancer risk-stratification, and allow implementation of targeted screening and preventive strategies that would ultimately improve breast cancer prognosis.

scholarly journals DNA methylation level in blood and relations to breast cancer, risk factors and environmental exposure in Greenlandic Inuit women

2020 ◽  
Vol 127 (4) ◽  
pp. 338-350
Author(s):  
Maria Wielsøe ◽  
Letizia Tarantini ◽  
Valentina Bollati ◽  
Manhai Long ◽  
Eva Cecilie Bonefeld‐Jørgensen
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Dna Methylation ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Environmental Exposure ◽  
Methylation Level ◽  
Cancer Risk Factors ◽  
Breast Cancer Risk Factors

Abstract 5615: Global DNA methylation by LUMA predicts breast cancer risk in a population-based study

2011 ◽  
Author(s):  
Xinran Xu ◽  
Marilie D. Gammon ◽  
James G. Wetmur ◽  
Susan L. Teiltelbaum ◽  
Patrick T. Bradshaw ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Population Based ◽  
Global Dna Methylation ◽  
Population Based Study

scholarly journals Epigenome-wide DNA methylation and risk of breast cancer: a systematic review

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Kaoutar Ennour-Idrissi ◽  
Dzevka Dragic ◽  
Francine Durocher ◽  
Caroline Diorio
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Risk Of Bias ◽  
Global Dna Methylation ◽  
Dna Hypomethylation ◽  
Epigenetic Age ◽  
Potential Biomarker

Abstract Background DNA methylation is a potential biomarker for early detection of breast cancer. However, robust evidence of a prospective relationship between DNA methylation patterns and breast cancer risk is still lacking. The objective of this study is to provide a systematic analysis of the findings of epigenome-wide DNA methylation studies on breast cancer risk, in light of their methodological strengths and weaknesses. Methods We searched major databases (MEDLINE, EMBASE, Web of Science, CENTRAL) from inception up to 30th June 2019, for observational or intervention studies investigating the association between epigenome-wide DNA methylation (using the HM450k or EPIC BeadChip), measured in any type of human sample, and breast cancer risk. A pre-established protocol was drawn up following the Cochrane Reviews rigorous methodology. Study selection, data abstraction, and risk of bias assessment were performed by at least two investigators. A qualitative synthesis and systematic comparison of the strengths and weaknesses of studies was performed. Results Overall, 20 studies using the HM450k BeadChip were included, 17 of which had measured blood-derived DNA methylation. There was a consistent trend toward an association of global blood-derived DNA hypomethylation and higher epigenetic age with higher risk of breast cancer. The strength of associations was modest for global hypomethylation and relatively weak for most of epigenetic age algorithms. Differences in length of follow-up periods may have influenced the ability to detect associations, as studies reporting follow-up periods shorter than 10 years were more likely to observe an association with global DNA methylation. Probe-wise differential methylation analyses identified between one and 806 differentially methylated CpGs positions in 10 studies. None of the identified differentially methylated sites overlapped between studies. Three studies used breast tissue DNA and suffered major methodological issues that precludes any conclusion. Overall risk of bias was critical mainly because of incomplete control of confounding. Important issues relative to data preprocessing could have limited the consistency of results. Conclusions Global DNA methylation may be a short-term predictor of breast cancer risk. Further studies with rigorous methodology are needed to determine spatial distribution of DNA hypomethylation and identify differentially methylated sites associated with risk of breast cancer. Prospero registration number CRD42020147244

Sign in / Sign up

Export Citation Format

Share Document