DNA methylation modifies the association between obesity and survival after breast cancer diagnosis (original) (raw)
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Obesity and menopause modify the epigenomic profile of breast cancer
Endocrine-related cancer, 2017
Obesity is a high risk factor for breast cancer. This relationship could be marked by a specific methylome. The current work was aimed to explore the impact of obesity and menopausal status on variation in breast cancer methylomes. Data from Infinium 450K array-based methylomes of 64 breast tumor were coupled with information on BMI and menopausal status. Additionally, DNA methylation results were validated in 18 non-tumor and 81 tumor breast samples. Breast tumors arising in either pre- or postmenopausal women stratified by BMI or menopausal status alone were not associated with a specific DNA methylation pattern. Intriguingly, the DNA methylation pattern identified in association with the high-risk group (postmenopausal women with high BMI (>25) and premenopausal women with normal or low BMI<25) exclusively characterized by hypermethylation of 1,287 CpG sites as compared with the low risk group. These CpG sites included the promoter region of fourteen protein-coding genes of...
Journal of Cancer, 2015
Little is known about how modifiable lifestyle factors interact with the epigenome to influence disease. Body mass index (BMI, weight kg/height m2) and physical activity are associated with postmenopausal breast cancer, but the mechanisms are not well-understood. We hypothesized that BMI or physical activity may modify the association between markers of global DNA methylation and postmenopausal breast cancer risk. Resources from a population-based case-control study (~1300 postmenopausal women) were used to construct logistic regression models. We explored whether the association between breast cancer and global methylation, assessed using the luminometric methylation assay (LUMA) and long interspersed elements-1 (LINE-1) methylation in white blood cell DNA, was modified by BMI or recreational physical activity (RPA). The LUMA-breast cancer association was modified by BMI (multiplicative p=0.03) and RPA (p=0.004). Non-obese women in the highest quartile of LUMA experienced a greater...
American Journal of Clinical Nutrition, 2011
Background: The mechanism of the observed association between body mass, particularly centralized body fat, and postmenopausal breast cancer risk is not well understood. Objective: We hypothesized that body mass may affect DNA methylation through increased estrogen and chronic inflammation. The association between body mass and promoter methylation in breast tumors was investigated in a population-based, case-control study. Design: The promoter methylation of E-cadherin, p16, and RAR-b 2 genes was assessed in breast tumor blocks from 803 pre-and postmenopausal cases by using real-time methylation-specific polymerase chain reaction. Unconditional logistic regression was used to derive the adjusted OR and 95% CI for case-case comparisons of tumors with and without promoter methylation of the genes. Results: The frequency of promoter methylation was 20% for E-cadherin, 25.9% for p16, and 27.5% for RAR-b 2 . There was no difference in the prevalence of the DNA methylation of individual genes by BMI, waist-to-hip ratio (WHR), or lifetime weight change between the age of 20 y and the present. However, in a case-case comparison of postmenopausal breast cancer, a greater WHR was associated with an increased likelihood of 1 of the 3 genes being methylated (OR: 1.85; 95% CI: 1.10, 3.11; P-trend , 0.02). Conclusions: We showed that WHR was associated with DNA promoter methylation of 1 of 3 genes in postmenopausal breast tumors. It may be that the association of body fat composition and postmenopausal breast cancer is related to altered DNA methylation. However, future studies in other populations and with an examination of the methylation of more genes are needed.
Body Mass Index is Associated with Gene Methylation in Estrogen Receptor-Positive Breast Tumors
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2015
Background:Although obesity is associated with breast cancer incidence and prognosis, the underlying mechanisms are poorly understood. Identification of obesity-associated epigenetic changes in breast tissue may advance mechanistic understanding of breast cancer initiation and progression. The goal of this study, therefore, was to investigate associations between obesity and gene methylation in breast tumors. Methods: Using the Illumina GoldenGate Cancer I Panel, we estimated the association between body mass index (BMI) and gene methylation in 345 breast tumor samples from Phase I of the Carolina Breast Cancer Study, a population based case-control study. Multivariable linear regression was used to identify sites that were differentially methylated by BMI. Stratification by tumor estrogen receptor status was also conducted. Results: In the majority of the 935 probes analyzed (87%), the average beta value increased with obesity (BMI ≥ 30). Obesity was significantly associated with d...
Gene promoter methylation is associated with increased mortality among women with breast cancer
Breast Cancer Research and Treatment, 2010
To better understand breast cancer etiology and progression, we explored the association between promoter methylation status of three breast cancer related genes (BRCA1, APC and p16) and survival in a large cohort of women with breast cancer. About 800 archived tumor tissues were collected from women diagnosed with a first primary invasive or in situ breast cancer in 1996-1997. The vital status of the participants was followed through the end of year 2005 with a mean follow up time of 8.0 years. Promoter methylation was assessed by methylation-specific PCR (for BRCA1) and MethyLight (for APC and p16). The association of promoter methylation and breast cancer mortality was evaluated by Cox-proportional hazards models. Methylated promoters were found in 59.0%, 48.4% and 3.6% of the tumor samples for BRCA1, APC and p16, respectively. Breast cancer-specific mortality was strongly associated with promoter methylation of p16 [HR and 95% CI: 3.53(1.83-6.78)], whereas the associations with of BRCA1 and APC were less pronounced [HR and 95% CI: 1.81(1.18-2.78) and 1.46(0.98-2.17), respectively]. Similar associations were observed with allcause mortality. As the number of methylated genes increased, the risk of breast cancer-specific mortality also increased in a dose-dependent manner (p, trend=0.01). Importantly, even with our results stratified by hormone receptor status, promoter methylation of the three genes remained predictive of mortality. Our results suggest that promoter methylation could be promising epigenetic markers to be considered for breast cancer survival.
Epigenetic Biomarkers of Breast Cancer Risk: Across the Breast Cancer Prevention Continuum
Advances in experimental medicine and biology, 2016
Epigenetic biomarkers, such as DNA methylation, can increase cancer risk through altering gene expression. The Cancer Genome Atlas (TCGA) Network has demonstrated breast cancer-specific DNA methylation signatures. DNA methylation signatures measured at the time of diagnosis may prove important for treatment options and in predicting disease-free and overall survival (tertiary prevention). DNA methylation measurement in cell free DNA may also be useful in improving early detection by measuring tumor DNA released into the blood (secondary prevention). Most evidence evaluating the use of DNA methylation markers in tertiary and secondary prevention efforts for breast cancer comes from studies that are cross-sectional or retrospective with limited corresponding epidemiologic data, raising concerns about temporality. Few prospective studies exist that are large enough to address whether DNA methylation markers add to the prediction of tertiary and secondary outcomes over and beyond standa...
The Journal of nutrition, 2015
Lower levels of global DNA methylation in tissue and blood have been associated with increased cancer risk. Conversely, cross-sectional analyses of healthier lifestyle patterns have been associated with higher levels of global DNA methylation. In this trial, we explored the associations between changes in lifestyle modifications (diet, weight loss), metabolic markers, and global epigenetic biomarkers in white blood cells. Study participants were Hispanic, African American, and Afro-Caribbean overweight and sedentary female breast cancer survivors (n = 24) who participated in a larger randomized, crossover, pilot study of a 6-mo weight loss intervention and who had available blood specimens. Anthropometric measures, a food-frequency questionnaire, and peripheral blood were collected at baseline, 6 mo, and 12 mo. Plasma samples were analyzed for metabolic markers (insulin, glucose). We measured DNA methylation of long interspersed nucleotide element 1 (LINE-1) and satellite 2 by pyros...
Epigenome-wide DNA methylation and risk of breast cancer: a systematic review
BMC Cancer
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 compari...
DNA Methylation and Breast Cancer Risk: An Epigenome-Wide Study of Normal Breast Tissue and Blood
Cancers
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 ...
Background: Lower levels of global DNA methylation in tissue and blood have been associated with increased cancer risk. Conversely, cross-sectional analyses of healthier lifestyle patterns have been associated with higher levels of global DNA methylation. Objective: In this trial, we explored the associations between changes in lifestyle modifications (diet, weight loss), metabolic markers, and global epigenetic biomarkers in white blood cells. Methods: Study participants were Hispanic, African American, and Afro-Caribbean overweight and sedentary female breast cancer survivors (n = 24) who participated in a larger randomized, crossover, pilot study of a 6-mo weight loss intervention and who had available blood specimens. Anthropometric measures, a food-frequency questionnaire, and peripheral blood were collected at baseline, 6 mo, and 12 mo. Plasma samples were analyzed for metabolic markers (insulin, glucose). We measured DNA methylation of long interspersed nucleotide element 1 (LINE-1) and satellite 2 by pyrosequencing and MethyLight, respectively, and global DNA methylation by the luminometric methylation assay (LUMA). Results: DNA methylation of LINE-1 was statistically significantly elevated at 6 mo [75.5% vs. 78.5% (P < 0.0001)] and 12 mo [75.5% vs. 77.7% (P < 0.0001)], compared to baseline. Over a 12-mo period, changes in percentage body fat and plasma glucose concentrations were positively associated with LINE-1 DNA methylation (b = 0.19, P = 0.001) and LUMA DNA methylation levels (b = 0.24, P = 0.02), respectively. Similarly, 12-mo changes in dietary measures such as vegetable (b = 0.009, P = 0.048), protein (b = 0.04, P = 0.001), and total caloric (b = 0.05, P = 0.01) intake were positively associated with changes in LUMA DNA methylation, as was intake of fruit positively associated with changes in LINE-1 DNA methylation (b = 0.004, P = 0.02). Conclusions: Our hypothesis-generating results suggest that lifestyle modifications may be associated with changes in global DNA methylation detectable at 6 and 12 mo. These biomarkers may be useful intermediate biomarkers to use in future intervention trials. This trial was registered at clinicaltrials.gov as NCT00811824.