Redlining-associated methylation in breast tumors: the impact of contemporary structural racism on the tumor epigenome.

Purpose: Place-based measures of structural racism have been associated with breast cancer mortality, which may be driven, in part, by epigenetic perturbations. We examined the association between contemporary redlining, a measure of structural racism at the neighborhood level, and DNA methylation in breast tumor tissue. Methods: We identified 80 Black and White women diagnosed and treated for a first-primary breast cancer at Emory University Hospitals (2008-2017). Contemporary redlining was derived for census tracts using the Home Mortgage Disclosure Act database. Linear regression models were used to calculate the association between contemporary redlining and methylation in breast tumor tissue. We also examined epigenetic age acceleration for two different metrics, regressing ß values for each cytosine-phosphate-guanine dinucleotide (CpG) site on redlining while adjusting for covariates. We employed multivariable Cox-proportional hazards models and 95% confidence intervals (CI) to estimate the association between aberrant methylation and mortality. Results: Contemporary redlining was associated with 5 CpG sites after adjustment for multiple comparisons (FDR<0.10). All genes were implicated in breast carcinogenesis, including genes related to inflammation, immune function and stress response (ANGPT1, PRG4 and PRG4). Further exploration of the top 25 CpG sites, identified interaction of 2 sites (MRPS28 and cg11092048) by ER status and 1 site (GDP1) was associated with all-cause mortality. Contemporary redlining was associated with epigenetic age acceleration by the Hannum metric (ß=5.35; CI 95%=0.30,10.4) and showed positive but non-significant correlation with the other clock. Conclusion: We identified novel associations between neighborhood contemporary redlining and the breast tumor DNA methylome, suggesting that racist policies leading to inequitable social and environmental exposures, may impact the breast tumor epigenome. Additional research on the potential implications for prognosis is needed.

The associations of objective and perceived neighborhood disadvantage with stress among pregnant black women.

BACKGROUND: Neighborhood disadvantage may impact risk of preterm birth through stress. Few studies have examined how neighborhood disadvantage relates to stress during pregnancy, especially for Black women. METHODS: Secondary data analysis of 572 women in a prospective cohort in Detroit, MI and Columbus, OH. Participants completed questionnaires including the ROSS Neighborhood Disorder Scale, the crime subscale of the Perceived Neighborhood Scale (PNS), and the Perceived Stress Scale. An objective neighborhood disadvantage index (NDI) was created using principal components analysis after geocoding residential addresses and linking to Census data. RESULTS: All models used logistic regression. Adjusted for maternal age and annual household income, perceived stress was positively associated with perceived neighborhood disorder (p < .01). In a separate model, perceived neighborhood crime was positively associated with perceived neighborhood disorder (p = .005). In a joint model adjusted for age and income, the association of disorder with stress was similar in magnitude (p < .01) but the association between crime and stress weakened. The NDI was not associated with perceived stress before or after adjustment for confounders. CONCLUSIONS: Perceived neighborhood disadvantage may capture a different dimension than objective neighborhood disadvantage. Future studies should test stress as a pathway by which neighborhood environment increases risk of preterm birth.

Neighborhood characteristics and breast tumor methylation: using epigenomics to explore cancer outcome disparities.

BACKGROUND: Social exposures may drive epigenetic alterations that affect racial disparities in breast cancer outcomes. This study examined the association between neighborhood-level factors and DNA methylation in non-Hispanic Black and White women diagnosed with breast cancer. METHODS: Genome-wide DNA methylation was measured using the EPIC array in the tumor tissue of 96 women. Linear regression models were used to examine the association between nine neighborhood-level factors and methylation, regressing ß values for each cytosine-phosphate guanine dinucleotide (CpG) site on neighborhood-level factors while adjusting for covariates. Neighborhood data were obtained from the Opportunity Atlas. We used a false discovery rate (FDR) threshold < 0.05, and for CpGs below this threshold, we examined interactions with race. We employed multivariable Cox proportional-hazards models to estimate whether aberrant methylation was associated with all-cause mortality. RESULTS: 26 of the CpG sites were associated with job density or college education (FDR < 0.05). Further exploration of these 26 CpG sites revealed no interactions by race, but a single probe in TMEM204 was associated with all-cause mortality. CONCLUSION: We identified novel associations between neighborhood-level factors and the breast tumor DNA methylome. Our data are the first to show that dysregulation in neighborhood associated CpG sites may be associated with all-cause mortality. Neighborhood-level factors may contribute to differential tumor methylation in genes related to tumor progression and metastasis. This contributes to the increasing body of evidence that area-level factors (such as neighborhood characteristics) may play an important role in cancer disparities through modulation of the breast tumor epigenome.

Examining the association between adiposity and DNA methylation: A systematic review and meta-analysis.

Obesity is associated with widespread differential DNA methylation (DNAm) patterns, though there have been limited overlap in the obesity-associated cytosine-guanine nucleotide pair (CpG) sites that have been identified in the literature. We systematically searched four databases for studies published until January 2020. Eligible studies included cross-sectional, longitudinal, or intervention studies examining adiposity and genome-wide DNAm in non-pregnant adults aged 18-75 in all tissue types. Study design and results were extracted in the descriptive review. Blood-based DNAm results in body mass index (BMI) and waist circumference (WC) were meta-analyzed using weighted sum of Z-score meta-analysis. Of the 10,548 studies identified, 46 studies were included in the systematic review with 18 and nine studies included in the meta-analysis of BMI and WC, respectively. In the blood, 77 and four CpG sites were significant in three or more studies of BMI and WC, respectively. Using a genome-wide threshold for significance, 52 blood-based CpG sites were significantly associated with BMI. These sites have previously been associated with many obesity-related diseases including type 2 diabetes, cardiovascular disease, Crohn's disease, and depression. Our study shows that DNAm at 52 CpG sites represent potential mediators of obesity-associated chronic diseases and may be novel intervention or therapeutic targets to protect against obesity-associated chronic diseases.