Importance The biological processes that underlie the association of neighborhood environment with chronic diseases, such as cancer, remain poorly understood. Objective To determine whether differences in breast tissue DNA methylation are associated with neighborhood deprivation among Black and White women with breast cancer. Design, Setting, and Participants This cross-sectional study collected breast tissue from women undergoing surgery for breast cancer between January 1, 1993, and December 31, 2003. Participants were recruited through the University of Maryland Medical Center, with additional collection sites at Baltimore-area hospitals. Data analysis was performed from March 1 through December 1, 2022. Exposure Year 2000 census tract–level socioeconomic deprivation measured via neighborhood deprivation index (NDI) as a standardized score, with Black and White race being ascertained through self-report. Main Outcome and Measures The primary outcome was tissue DNA methylation using genome-wide measurements. The secondary outcome was tissue gene expression. Results Participants included 185 women with breast cancer (110 Black [59.5%], 75 White [40.5%]). Mean (SD) age at surgery was 56.0 (14.1) years. Neighborhood deprivation was higher for Black women than for White women (Mean [SD] NDI, 2.96 [3.03] for Black women and −0.54 [1.91] for White women; difference, −3.50; 95% CI, −4.22 to −2.79; P < .001). In unstratified analysis, 8 hypomethylated CpG sites were identified as associated with the NDI, including sites in 2 tumor suppressor genes, LRIG1 and WWOX. Moreover, expression of the 2 genes inversely correlated with neighborhood deprivation. In the race-stratified analysis, the negative correlation between the LRIG1 gene body CpG site cg26131019 and the NDI remained significant in Black women. A neighborhood deprivation–associated decrease in gene expression was also observed for LRIG1 and WWOX in tumors from Black women. Conclusions and Relevance In this study, high neighborhood deprivation was associated with differences in tissue DNA methylation and gene expression among Black women. These findings suggest that continued investment in public health interventions and policy changes at the neighborhood level may help to remedy biological alterations that could make minoritized populations more susceptible to chronic diseases.

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 β 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 (β=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.

Background Inadequate maternal nutrition during early fetal development can create permanent alterations in the offspring, leading to poor health outcomes. While nutrients involved in one-carbon cycle metabolism are important to fetal growth, associations with specific nutrients remain inconsistent. This study estimates associations between maternal vitamins B12, B6 (pyridoxal phosphate [PLP] and 4-pyridoxic acid [PA]), and homocysteine (Hcy) concentrations, offspring weight (birth weight and 3-year weight gain), and DNA methylation at four differentially methylated regions (DMRs) known to be involved in fetal growth and development (H19, MEG3, SGCE/PEG10, and PLAGL1). Methods Study participants (n = 496) with biomarker and birth weight data were enrolled as part of the Newborn Epigenetics STudy. Weight gain data were available for 273 offspring. Among 484 mother-infant pairs, DNA methylation at regulatory sequences of genomically imprinted genes was measured in umbilical cord blood DNA using bisulfite pyrosequencing. We used generalized linear models to estimate associations. Results Multivariate adjusted regression models revealed an inverse association between maternal Hcy concentration and male birth weight (β = −210.40, standard error (SE) = 102.08, p = 0.04). The offspring of the mothers in the highest quartile of B12 experienced lower weight gain between birth and 3 years compared to the offspring of the mothers in the lowest (β = −2203.03, SE = 722.49, p = 0.003). Conversely, maternal PLP was associated with higher weight gain in males; higher maternal PLP concentrations were also associated with offspring DNA methylation levels at the MEG3 DMR (p < 0.01). Conclusions While maternal concentrations of B12, B6, and Hcy do not associate with birth weight overall, they may play an important role in 3-year weight gain. This is the first study to report an association between maternal PLP and methylation at the MEG3 DMR which may be an important epigenetic tag for maternal B vitamin adequacy.

Background: Racial disparities in non-Hodgkin lymphoma (NHL) are not well-elucidated for specific catchment areas, which can influence outcomes. Leveraging regional data from a population-based cancer registry may provide unique opportunities to quantify NHL disparities. Materials and Methods: Using Surveillance, Epidemiology, and End Results (SEER) data for NHL cases diagnosed in Georgia from 2001 to 2015, we examined NHL incidence rates by lymphoma subtype and racial differences in baseline characteristics and outcomes for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Cox regression models identified predictors of overall survival (OS). Results: SEER documented 38,504 NHL cases in Georgia from 2001 to 2015. The age-adjusted incidence rate for NHL in Georgia increased 1.03% per year, and the annual percentage change was 1.72 in blacks compared with 0.84 in whites. Compared with whites, blacks with DLBCL and FL were more likely to be diagnosed at a younger age (DLBCL, 54.1 vs. 65.5 years; P <.0001; FL, 58.4 vs. 64.0 years; P <.0001) and with B symptoms (DLBCL, 44.4% vs. 33.4%; P <.0001; FL, 28.5% vs. 21.4%; P =.004). Across racial categories, age at diagnosis > 60 years, advanced stage, and B symptoms predicted worse OS in DLBCL and FL. Blacks with DLBCL more commonly were diagnosed with stage III/IV disease (55.5% vs. 48.1%; P <.0001) and had worse 5-year relative survival (58.8% vs. 62.3%; P =.01). Conclusions: Regional cancer registry data can be used to define incidence patterns and disparities in outcomes across NHL subtypes to help define key targets for interventions in a catchment area. In a retrospective analysis of 38,504 lymphoma diagnoses in Georgia between 2001 and 2015, we found that, compared with whites, blacks with diffuse large B-cell lymphoma and follicular lymphoma were more likely to present at a younger age and experience B symptoms. Future research utilizing population-based data to address disparities in presentation and outcomes within a catchment area is needed.

BACKGROUND: We hypothesized that epigenetic changes may help to clarify the underlying biologic mechanism linking aspirin use to breast cancer prognosis. Ours is the first epidemiologic study to examine whether global methylation and/or tumor promoter methylation of breast cancer-related genes interact with aspirin use to impact mortality after breast cancer. METHODS: Pre-diagnosis aspirin use was assessed through in-person interviews within the population-based cohort of 1,508 women diagnosed with first primary breast cancer in 1996-1997. Global methylation in peripheral blood was assessed by long interspersed elements-1 (LINE-1) and the luminometric methylation assay. Promoter methylation of thirteen breast cancer-related genes was measured in tumor by methylation-specific PCR and Methyl Light. Vital status was determined by the National Death Index through December 31, 2014 (N=237/597 breast cancer-specific/all-cause deaths identified). We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs), and the likelihood ratio test to evaluate multiplicative interaction. RESULTS: All-cause mortality was elevated among aspirin users with methylated promotor of BRCA1 (HR=1.67; 95%CI=1.26–2.22), but not among those with unmethylated BRCA1 (HR=0.99; 95%CI=0.67–1.45) (pinteraction≤0.05). Decreased breast cancer-specific mortality was found among aspirin users with unmethylated promotor of BRCA1 and PR, and LINE-1 global hypermethylation (HR=0.60, 0.78, and 0.63, respectively; pinteraction≤0.05), although the 95%CIs included the null. CONCLUSIONS: Our current study suggests that the LINE-1 global methylation, and promoter methylation of BRCA1 and PR in tumor may interact with aspirin use to influence mortality following breast cancer.

Background Polycyclic aromatic hydrocarbons (PAHs) have been linked to breast cancer in many, but not all, previous studies. PAHs are lipophilic and stored in fat tissue, which we hypothesized may result in constant low-dose exposure to these carcinogens. No previous studies have evaluated whether obesity modifies associations between multiple measures of PAHs and breast cancer incidence. Methods This population-based study included 1,006 postmenopausal women with first primary in situ or invasive breast cancer and 990 age-frequency matched controls. To evaluate effect modification by obesity (adult body mass index (BMI, kg/m 2 ) and weight change) on multiple PAH measures (the biomarker PAH-DNA adducts, and long-term sources active cigarette smoking, living with a smoking spouse, grilled/smoked meat intake, residential synthetic log burning, and vehicular traffic), interaction contrast ratios (ICRs) for the additive scale, and ratio of odds ratios (RORs) with log-likelihood ratio tests (LRT) for the multiplicative scale, were determined using unconditional logistic regression. Results BMI modified the PAH-DNA adduct and postmenopausal breast cancer association on the additive (ICR: 0.49; 95% CI: 0.01, 0.96) and multiplicative (ROR: 1.56; 95% CI: 0.91, 2.68) scales. The odds ratio for detectable vs. non-detectable adducts was increased among women with BMI ≥25 (OR=1.34; 95% CI: 0.94, 1.92), but not in those with BMI < 25 (OR=0.86; 95% CI: 0.57, 1.28) (LRT p=0.1). For most other PAH measures, the pattern of modification by BMI/weight gain was similar, but estimates were imprecise. Conclusions The association between PAH-DNA adducts and breast cancer incidence may be elevated among overweight/obese women.

Background: Obesity is a major public health concern in the United States and should be addressed as early as possible, in childhood. Disparities exist in obesity prevalence and its associated comorbidities by racial/ethnic group, however less is known about the smaller racial/ethnic subclasses that are often aggregated and assumed to be homogeneously at risk. As the racial and ethnic composition of the US shifts towards greater diversity, it is important that epidemiologic research addresses these new challenges. Main body: In this short communication, we focus on Asian American children given that subgroups are historically understudied and emerging evidence among adults suggest heterogeneous associations for both obesity and cardio-metabolic outcomes. Existing limitations in this research area include: (1) identifying the appropriate measurement of adiposity in Asian American children; (2) determining high-risk cutoffs for intervention; and (3) developing strategies to ensure study robustness. Conclusion: Data disaggregation is a necessary approach to understand potentially heterogeneous associations in childhood obesity and cardio-metabolic risk, but epidemiologic investigators must address these challenges. Ultimately, successful strategies could help better identify high risk subgroups, target interventions, and effectively reduce the burden of obesity among American youth.

Background: The cardiotoxic effects of breast cancer therapies are well documented in clinical trials. However, clinical trials often underrepresent those at highest risk for cardiovascular disease (CVD)related outcomes and have limited generalizability to the larger breast cancer population. In addition, racial differences in treatment-associated CVD mortality have yet to be explored. In this study, we sought to quantify the relationship between breast cancer therapies and CVD mortality, and explore whether this effect differed between non-Hispanic black (NHB) and white (NHW) women. Methods: Using data from the Georgia Cancer Registry, we identified women diagnosed with a first primary invasive breast cancer [2010-2014], residing in the metropolitan Atlanta area (n=3,580 NHB; n=4,923 NHW), and followed them for mortality through December 31, 2018. Exposures of interest included therapies with potential cardiotoxic effects including chemotherapy and hormone therapy, which are routinely collected by the GCR. Individual agents are not captured within the GCR, therefore trastuzumab was identified using natural language processing of textual descriptions. We used propensity score weighted Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between each treatment modality and CVD mortality among the overall cohort and by race. Results: In the overall cohort, similar hazards of CVD mortality were found among women treated with chemotherapy (HR =1.10, 95% CI: 0.62, 1.96) and hormone therapy (HR =0.94, 95% CI: 0.59, 1.50), compared to women who did not receive the respective treatments. In contrast, women treated with trastuzumab had a higher hazard of CVD mortality compared to women not treated with trastuzumab (HR =2.05, 95% CI: 0.76, 5.52). In race-specific models, hormone therapy was associated with a higher hazard of CVD mortality among NHB women (HR =2.18, 95% CI: 0.78, 6.12), but not NHW women (HR =0.66, 95% CI: 0.39, 1.13). Similar, albeit attenuated, associations were found for chemotherapy. We were unable to investigate race-specific effects of trastuzumab due to low prevalence and insufficient number of events. Conclusions: In our study, we observed more pronounced associations of chemotherapy and hormone therapy with CVD mortality among NHB women, for whom we know have greater CVD-related comorbidities at breast cancer diagnosis. Patients may benefit from treatment plans that find a balance between curative breast cancer treatment and prevention of CVD-related events and mortality. CVD-related outcomes may be most relevant for women with hormone receptor positive disease due to shared risk factors (e.g., obesity, tobacco use, physical activity) and longer survival.

Background: Racial disparities in breast cancer (BC) outcomes persist where non-Hispanic black (NHB) women are more likely to die from BC than non-Hispanic white (NHW) women, and the extent of this disparity varies geographically. We evaluated tumor, treatment, and patient characteristics that contribute to racial differences in BC mortality in Atlanta, Georgia, where the disparity was previously characterized as especially large. Methods: We identified 4943 NHW and 3580 NHB women in the Georgia Cancer Registry with stage I-IV BC diagnoses in Atlanta (2010-2014). We used Cox proportional hazard regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) comparing NHB vs NHW BC mortality by tumor, treatment, and patient characteristics on the additive and multiplicative scales. We additionally estimated the mediating effects of these characteristics on the association between race and BC mortality. Results: At diagnosis, NHB women were younger-with higher stage, node-positive, and triple-negative tumors relative to NHW women. In age-adjusted models, NHB women with luminal A disease had a 2.43 times higher rate of BC mortality compared to their NHW counterparts (95% CI = 1.99 to 2.97). High socioeconomic status (SES) NHB women had more than twice the mortality rates than their white counterparts (HR = 2.67, 95% CI = 1.65 to 4.33). Racial disparities among women without insurance, in the lowest SES index, or diagnosed with triple-negative BC were less pronounced. Conclusions: In Atlanta, the largest racial disparities are observed in luminal tumors and most pronounced among women of high SES. More research is needed to understand drivers of disparities within these treatable features.

BACKGROUND: Cadmium (Cd), lead (Pb) and arsenic (As) are common environmental contaminants that have been associated with lower birthweight. Although some essential metals may mitigate exposure, data are inconsistent. This study sought to evaluate the relationship between toxic metals, nutrient combinations and birthweight among 275 mother-child pairs. METHODS: Non-essential metals, Cd, Pb, As, and essential metals, iron (Fe), zinc (Zn), selenium (Se), copper (Cu), calcium (Ca), magnesium (Mg), and manganese (Mn) were measured in maternal whole blood obtained during the first trimester using inductively coupled plasma mass spectrometry. Folate concentrations were measured by microbial assay. Birthweight was obtained from medical records. We used quantile regression to evaluate the association between toxic metals and nutrients due to their underlying wedge-shaped relationship. Ordinary linear regression was used to evaluate associations between birth weight and toxic metals. RESULTS: After multivariate adjustment, the negative association between Pb or Cd and a combination of Fe, Se, Ca and folate was robust, persistent and dose-dependent (p < 0.05). However, a combination of Zn, Cu, Mn and Mg was positively associated with Pb and Cd levels. While prenatal blood Cd and Pb were also associated with lower birthweight. Fe, Se, Ca and folate did not modify these associations. CONCLUSION: Small sample size and cross-sectional design notwithstanding, the robust and persistent negative associations between some, but not all, nutrient combinations with these ubiquitous environmental contaminants suggest that only some recommended nutrient combinations may mitigate toxic metal exposure in chronically exposed populations. Larger longitudinal studies are required to confirm these findings.