Abstract
Background
Peripheral blood DNA methylation may be associated with breast cancer, but studies of candidate genes and global and genome-wide DNA methylation have been inconsistent.
Methods
We ...performed an epigenome-wide study using Infinium HumanMethylation450 BeadChips with prospectively collected blood DNA samples from the Sister Study (1552 cases, 1224 subcohort). Differentially methylated cytosine-phosphate-guanine sites (dmCpGs) were identified using case-cohort proportional hazard models and replicated using deposited data from European Prospective Investigation into Cancer and Nutrition in Italy (EPIC-Italy) (n = 329). The correlation between methylation and time to diagnosis was examined using robust linear regression. Causal or consequential relationships of methylation to breast cancer were examined by Mendelian randomization using OncoArray 500 K single-nucleotide polymorphism data. All statistical tests were two-sided.
Results
We identified 9601 CpG markers associated with invasive breast cancer (false discovery rate = q < 0.01), with 510 meeting a strict Bonferroni correction threshold (10–7). A total of 2095 of these CpGs replicated in the independent EPIC-Italy dataset, including 144 meeting the Bonferroni threshold. Sister Study women who developed ductal carcinoma in situ had methylation similar to noncases. Most (1501, 71.6%) dmCpGs showed lower methylation in invasive cases. In case-only analysis, methylation was statistically significantly associated (false discovery rate = q < 0.05) with time to diagnosis for 892 (42.6%) of the dmCpGs. Analyses based on genetic association suggest that methylation differences are likely a consequence rather than a cause of breast cancer. Pathway analysis shows enrichment of breast cancer-related gene pathways, and dmCpGs are overrepresented in known breast cancer susceptibility genes.
Conclusions
Our findings suggest that the DNA methylation profile of blood starts to change in response to invasive breast cancer years before the tumor is clinically detected.
Anorexia and bulimia nervosa may have long-term effects on overall and reproductive health. We studied predictors of self-reported eating disorders and associations with later health events. We ...estimated odds ratios (ORs) for these associations in 47,759 participants from the Sister Study. Two percent (n = 967) of participants reported a history of an eating disorder. Risk factors included being non-Hispanic white, having well-educated parents, recent birth cohort (OR = 2.16, 95% confidence interval CI: 2.01-2.32 per decade), and having a sister with an eating disorder (OR = 3.68, CI: 1.92-7.02). As adults, women who had experienced eating disorders were more likely to smoke, to be underweight, to have had depression, to have had a later first birth, to have experienced bleeding or nausea during pregnancy, or to have had a miscarriage or induced abortion. In this descriptive analysis, we identified predictors of and possible long-term health consequences of eating disorders. Eating disorders may have become more common over time. Interventions should focus on prevention and mitigation of long-term adverse health effects.
Glyphosate is the most commonly used herbicide worldwide, with both residential and agricultural uses. In 2015, the International Agency for Research on Cancer classified glyphosate as "probably ...carcinogenic to humans," noting strong mechanistic evidence and positive associations for non-Hodgkin lymphoma (NHL) in some epidemiologic studies. A previous evaluation in the Agricultural Health Study (AHS) with follow-up through 2001 found no statistically significant associations with glyphosate use and cancer at any site.
The AHS is a prospective cohort of licensed pesticide applicators from North Carolina and Iowa. Here, we updated the previous evaluation of glyphosate with cancer incidence from registry linkages through 2012 (North Carolina)/2013 (Iowa). Lifetime days and intensity-weighted lifetime days of glyphosate use were based on self-reported information from enrollment (1993-1997) and follow-up questionnaires (1999-2005). We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) using Poisson regression, controlling for potential confounders, including use of other pesticides. All statistical tests were two-sided.
Among 54 251 applicators, 44 932 (82.8%) used glyphosate, including 5779 incident cancer cases (79.3% of all cases). In unlagged analyses, glyphosate was not statistically significantly associated with cancer at any site. However, among applicators in the highest exposure quartile, there was an increased risk of acute myeloid leukemia (AML) compared with never users (RR = 2.44, 95% CI = 0.94 to 6.32, Ptrend = .11), though this association was not statistically significant. Results for AML were similar with a five-year (RRQuartile 4 = 2.32, 95% CI = 0.98 to 5.51, Ptrend = .07) and 20-year exposure lag (RRTertile 3 = 2.04, 95% CI = 1.05 to 3.97, Ptrend = .04).
In this large, prospective cohort study, no association was apparent between glyphosate and any solid tumors or lymphoid malignancies overall, including NHL and its subtypes. There was some evidence of increased risk of AML among the highest exposed group that requires confirmation.
Earlier age at menarche is an established risk factor for breast cancer. While age at menarche has been fairly stable over the past half-century, age at breast development (thelarche) has continued ...to decrease. Recently, earlier age at thelarche and a longer time between thelarche and menarche (pubertal tempo) were shown to be associated with increased breast cancer risk. Our objective was to examine how breast cancer risk was associated with pubertal timing and tempo in a prospective US cohort.
Women ages 35-74 years without a history of breast cancer, but who had a sister previously diagnosed with breast cancer, were enrolled in the Sister Study from 2003 to 2009 (N = 50,884). At enrollment, participants reported their ages at thelarche and menarche. Pubertal tempo was age at menarche minus age at thelarche. We estimated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for each pubertal milestone and risk of breast cancer (invasive or ductal carcinoma in situ) using Cox proportional hazards regression. We examined whether associations between age at thelarche and breast cancer risk were modified by birth cohort, race/ethnicity, weight at age 10, and extent of breast cancer family history, as characterized by a Bayesian score based on first-degree family structure.
During follow-up (mean = 9.3 years), 3295 eligible women were diagnosed with breast cancer. Early ages at thelarche (HR = 1.23, 95% CI 1.03-1.46 for < 10 vs. 12-13 years) and menarche (HR = 1.10, 95% CI 1.01-1.20 for < 12 vs. 12-13 years) were positively associated with breast cancer risk. Pubertal tempo was not associated with breast cancer risk (HR = 0.99, 95% CI 0.97-1.02 per 1-year longer tempo). When considering early thelarche (< 10 years) and early menarche (< 12 years) jointly, women with both had a 30% greater risk of breast cancer compared with women with neither risk factor (95% CI 1.07-1.57). The association between age at thelarche and breast cancer risk did not significantly vary by birth cohort, race/ethnicity, childhood weight, or Bayesian family history score.
Earlier ages at thelarche and menarche may enhance susceptibility to breast carcinogenesis. Age at thelarche is an important risk factor to consider given secular trends towards earlier development.
Toxic metals show evidence of carcinogenic and estrogenic properties. However, little is known about the relationship between airborne metals and breast cancer. We evaluated the risk of breast cancer ...in relation to exposure to toxic metallic substances in air, individually and combined, in a US-wide cohort.
Sister Study participants (n = 50,884), breast cancer-free women who had a sister with breast cancer were recruited, from 2003 to 2009. The 2005 Environmental Protection Agency National Air Toxic Assessment's census-tract estimates of metal concentrations in air (antimony, arsenic, cadmium, chromium, cobalt, lead, manganese, mercury, nickel, and selenium) were matched to participants' enrollment residence. We used Cox regression to estimate the association between quintiles of individual metals and breast cancer incidence and weighted quantile sum regression to model the association between the metal mixture and breast cancer.
A total of 2,587 breast cancer cases were diagnosed during follow-up (mean = 7.4 years). In individual chemical analyses comparing the highest to lowest quintiles, postmenopausal breast cancer risk was elevated for mercury (hazard ratio HR = 1.3, 95% confidence interval CI, 1.1, 1.5), cadmium (HR = 1.1, 95% CI, 0.96, 1.3), and lead (HR = 1.1, 95% CI, 0.98, 1.3). The weighted quantile sum index was associated with postmenopausal breast cancer (odds ratio OR = 1.1, 95% CI, 1.0, 1.1). Consistent with the individual chemical analysis, the most highly weighted chemicals for predicting postmenopausal breast cancer risk were lead, cadmium, and mercury. Results were attenuated for overall breast cancer.
Higher levels of some airborne metals, specifically mercury, cadmium, and lead, were associated with a higher risk of postmenopausal breast cancer.
The prevalence of binge drinking in the United States is rising. While alcohol is a risk factor for breast cancer, less is known about the impact of episodic heavy drinking. In 2003-2009, women aged ...35-74 years who were free of breast cancer were enrolled in the Sister Study (n = 50,884). Residents of the United States or Puerto Rico who had a sister with breast cancer were eligible. Multivariable Cox regression was used to estimate adjusted hazard ratios and 95% confidence intervals for breast cancer. During follow-up (mean = 6.4 years), 1,843 invasive breast cancers were diagnosed. Increased breast cancer risk was observed for higher lifetime alcohol intake (for ≥230 drinks/year vs. <60 drinks/year, hazard ratio (HR) = 1.35, 95% confidence interval (CI): 1.15, 1.58). Relative to low-level drinkers (<60 drinks/year), hazard ratios were increased for ever binge drinking (HR = 1.29, 95% CI: 1.15, 1.45) or blacking out (HR = 1.39, 95% CI: 1.17, 1.64). Compared with low-level drinkers who never binged, moderate drinkers (60-229 drinks/year) who binged had a higher risk (HR = 1.25, 95% CI: 1.08, 1.44). There was evidence of effect modification between moderate lifetime drinking and binging (relative excess risk due to interaction = 0.33, 95% CI: 0.10, 0.57). Our findings support the established association between lifetime alcohol intake and breast cancer and provide evidence for an increased risk associated with heavy episodic drinking, especially among moderate lifetime drinkers.
Epigenetic age, as defined by DNA methylation, may be influenced by air pollution exposure.
To evaluate the relationship between NO2, particulate matter (PM), PM components and accelerated epigenetic ...age.
In a sample of non-Hispanic white women living in the contiguous U.S. (n = 2747), we estimated residential exposure to PM2.5, PM10 and NO2 using a model incorporating land-use regression and kriging. Predictive k-means was used to assign participants to clusters representing different PM2.5 component profiles. We measured DNA methylation (DNAm) in blood using the Illumina's Infinium HumanMethylation450 BeadChip and calculated DNAm age using the Hannum, Horvath and Levine epigenetic clocks. Age acceleration was defined based on residuals after regressing DNAm age on chronological age. We estimated associations between interquartile range (IQR) increases in pollutants and age acceleration using linear regression. For PM2.5, we stratified by cluster membership. We examined epigenome-wide associations using robust linear regression models corrected with false discovery rate q-values.
NO2 was inversely associated with age acceleration using the Hannum clock (β = −0.24, 95% CI: −0.47, −0.02). No associations were observed for PM10. For PM2.5, the association with age acceleration varied by PM2.5 component cluster. For example, with the Levine clock, an IQR increase in PM2.5 was associated with an over 6-year age acceleration in a cluster that has relatively high fractions of crustal elements relative to overall PM2.5 (β = 6.57, 95% CI: 2.68, 10.47), and an almost 2-year acceleration in a cluster characterized by relatively low sulfur fractions (β = 1.88, 95% CI: 0.51, 3.25). In a cluster distinguished by lower relative nitrate concentrations, PM2.5 was inversely associated with age acceleration (β = −1.33, 95% CI: −2.43, −0.23). Across the epigenome, NO2 was associated with methylation at 2 CpG sites.
Air pollution was associated with epigenetic age, a marker of mortality and disease risk, among certain PM2.5 component profiles.
•Associations between PM2.5 and age acceleration varied by PM2.5 component profiles.•NO2 was inversely associated with Hannum clock-defined age acceleration.•NO2 was associated with methylation at 2 individual CpG sites.
Highlights • Telomere shortening predicts numerous diseases and may be a biomarker of aging. • Past research suggests stress may be related to telomere shortening. • We find a very small pooled ...correlation between increased stress and short telomeres. • Future work should address possible publication bias and improve stress measurement.
Particulate matter (PM) is a complex mixture. Geographic variations in PM may explain the lack of consistent associations with breast cancer.
We aimed to evaluate the relationship between air ...pollution, PM components, and breast cancer risk in a United States-wide prospective cohort.
We estimated annual average ambient residential levels of particulate matter
and
in aerodynamic diameter (
and
, respectively) and nitrogen dioxide (
) using land-use regression for 47,433 Sister Study participants (breast cancer-free women with a sister with breast cancer) living in the contiguous United States. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk associated with an interquartile range (IQR) increase in pollutants. Predictive
-means were used to assign participants to clusters derived from
component profiles to evaluate the impact of heterogeneity in the
mixture. For
, we investigated effect measure modification by component cluster membership and by geographic region without regard to air pollution mixture.
During follow-up (
), 2,225 invasive and 623 ductal carcinoma
(DCIS) cases were identified.
and
were associated with breast cancer overall
(95% CI:0.99, 1.11) and 1.06 (95% CI:1.02, 1.11), respectively and with DCIS but not with invasive cancer. Invasive breast cancer was associated with
only in the Western United States
(95% CI:1.02, 1.27) and
only in the Southern United States
(95% CI:1.01, 1.33).
was associated with a higher risk of invasive breast cancer among two of seven identified composition-based clusters. A higher risk was observed
(95% CI: 0.97, 1.60) in a California-based cluster characterized by low S and high Na and nitrate (
) fractions and for another Western United States cluster
(95% CI: 0.90, 2.85), characterized by high fractions of Si, Ca, K, and Al.
Air pollution measures were related to both invasive breast cancer and DCIS within certain geographic regions and PM component clusters. https://doi.org/10.1289/EHP5131.
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