Alexandra J. White

Recreational and household physical activity at different time points and DNA global methylation

BACKGROUND DNA methylation patterns are heritable but can change over time and in response to exposures. Lower global DNA methylation, which may result in increased genomic and chromosomal instability, has been associated with increased cancer risk. Physical activity is a modifiable factor that has been inversely related to the risk of cancer. Changes in DNA methylation may be a mechanism by which lifestyle and environment factors influence disease. We investigated the relationship between DNA methylation and physical activity in a sample of women enroled in The Sister Study, a large United States (U.S.) cohort study of women aged 35-74 years with a family history of breast cancer. METHODS Global DNA methylation was measured using bisulphite-converted DNA and pyrosequencing of a LINE-1 repetitive sequence in the peripheral blood of 647 non-Hispanic white women. Physical activity (average hours per week) was retrospectively assessed for three time periods: childhood (ages 5-12), teenage years (ages 13-19) and the previous 12 months. FINDINGS Compared with women with physical activity levels below the median for all three time periods, those at or above the median physical activity for one (β = 0.20, 95% confidence interval (CI): -0.10, 0.49), two (β = 0.22, 95% CI: -0.08, 0.52) or all three (β = 0.33, 95% CI: 0.01, 0.66) time periods had increased global methylation. INTERPRETATION Maintaining higher levels of physical activity over these three time periods was associated with increased global DNA methylation, consistent with reported associations between exercise and decreased cancer risk.

Exposure to multiple sources of polycyclic aromatic hydrocarbons and breast cancer incidence

BACKGROUND Despite studies having consistently linked exposure to single-source polycyclic aromatic hydrocarbons (PAHs) to breast cancer, it is unclear whether single sources or specific groups of PAH sources should be targeted for breast cancer risk reduction. OBJECTIVES This study considers the impact on breast cancer incidence from multiple PAH exposure sources in a single model, which better reflects exposure to these complex mixtures. METHODS In a population-based case-control study conducted on Long Island, New York (N=1508 breast cancer cases/1556 controls), a Bayesian hierarchical regression approach was used to estimate adjusted posterior means and credible intervals (CrI) for the adjusted odds ratios (ORs) for PAH exposure sources, considered singly and as groups: active smoking; residential environmental tobacco smoke (ETS); indoor and outdoor air pollution; and grilled/smoked meat intake. RESULTS Most women were exposed to PAHs from multiple sources, and the most common included active/passive smoking and grilled/smoked food intake. In multiple-PAH source models, breast cancer incidence was associated with residential ETS from a spouse (OR=1.20, 95%CrI=1.03, 1.40) and synthetic firelog burning (OR=1.29, 95%CrI=1.06, 1.57); these estimates are similar, but slightly attenuated, to those from single-source models. Additionally when we considered PAH exposure groups, the most pronounced significant associations included total indoor sources (active smoking, ETS from spouse, grilled/smoked meat intake, stove/fireplace use, OR=1.45, 95%CrI=1.02, 2.04). CONCLUSIONS Groups of PAH sources, particularly indoor sources, were associated with a 30-50% increase in breast cancer incidence. PAH exposure is ubiquitous and a potentially modifiable breast cancer risk factor.

Overall and central adiposity and breast cancer risk in the sister study

Greater body mass index (BMI), a measure of overall adiposity, is associated with a higher risk of postmenopausal breast cancer. The role of central adiposity, often measured by waist circumference, is less well understood, especially among premenopausal women. The objective of the current study was to examine multiple measures of adiposity in relation to breast cancer in a prospective cohort study.

Sources of polycyclic aromatic hydrocarbons are associated with gene-specific promoter methylation in women with breast cancer

BACKGROUND Tobacco smoke, diet and indoor/outdoor air pollution, all major sources of polycyclic aromatic hydrocarbons (PAHs), have been associated with breast cancer. Aberrant methylation may be an early event in carcinogenesis, but whether PAHs influence the epigenome is unclear, particularly in breast tissue where methylation may be most relevant. We aimed to evaluate the role of methylation in the association between PAHs and breast cancer. METHODS In a population-based case-control study, we measured promoter methylation of 13 breast cancer-related genes in breast tumor tissue (n=765-851 cases) and global methylation in peripheral blood (1055 cases/1101 controls). PAH sources (current active smoking, residential environmental tobacco smoke (ETS), vehicular traffic, synthetic log burning, and grilled/smoked meat intake) were evaluated separately. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS When comparing methylated versus unmethylated genes, synthetic log use was associated with increased ORs for CDH1 (OR=2.26, 95%CI=1.06-4.79), HIN1 (OR=2.14, 95%CI=1.34-3.42) and RARβ (OR=1.80, 95%CI=1.16-2.78) and decreased ORs for BRCA1 (OR=0.44, 95%CI=0.30-0.66). Residential ETS was associated with decreased ORs for ESR1 (OR=0.74, 95%CI=0.56-0.99) and CCND2 methylation (OR=0.65, 95%CI=0.44-0.96). Current smoking and vehicular traffic were associated with decreased ORs for DAPK (OR=0.53, 95%CI=0.28-0.99) and increased ORs for TWIST1 methylation (OR=2.79, 95%CI=1.24-6.30), respectively. In controls, synthetic log use was inversely associated with LINE-1 (OR=0.59, 95%CI=0.41-0.86). DISCUSSION PAH sources were associated with hypo- and hypermethylation at multiple promoter regions in breast tumors and LINE-1 hypomethylation in blood of controls. Methylation may be a potential biologic mechanism for the associations between PAHs and breast cancer incidence.

Urinary incontinence and health-related quality of life among older Americans with and without cancer: a cross-sectional study

BackgroundFew studies have investigated the impact of urinary incontinence (UI) on health-related quality of life (HRQOL) among cancer survivors. UI is prevalent in the general population and can be both an indicator of cancer and a side effect of cancer treatment. UI and cancer diagnoses have been associated with decreases in HRQOL. This study evaluates the prevalence of UI and the impact on HRQOL among older cancer survivors.MethodsThe prevalence of UI among cancer survivors (breast, prostate, bladder, colorectal, lung, and endometrial/uterine cancers) and those without cancer was estimated using the SEER-MHOS database. Factors associated with UI were investigated using logistic regression and the impact of UI on SF-36 scores was determined using linear regression.ResultsOver 36% of SEER-MHOS beneficiaries without cancer reported UI and higher prevalence was noted among cancer survivors (37%-54% depending on cancer type). History of bladder, breast, endometrial/uterine, or prostate cancer was associated with higher prevalence of UI. UI was independently associated with both lower physical component scores (PCS) (−1.27; 95%CI:-1.34,-1.20) and mental component scores (MCS) (−1.75; 95%CI −1.83, -1.68). A suggested decreasing trend in the prevalence of UI was associated with a longer time since cancer diagnosis.ConclusionsUI was highly prevalent, especially in bladder, endometrial/uterine, and prostate cancer survivors. Improved recognition of UI risk among cancer survivors will help clinicians better anticipate and mediate the effect of UI on individuals’ HRQOL.

Indoor air pollution exposure from use of indoor stoves and fireplaces in association with breast cancer: a case-control study

BackgroundPrevious studies suggest that polycyclic aromatic hydrocarbons (PAHs) may adversely affect breast cancer risk. Indoor air pollution from use of indoor stoves and/or fireplaces is an important source of ambient PAH exposure. However, the association between indoor stove/fireplace use and breast cancer risk is unknown. We hypothesized that indoor stove/fireplace use in a Long Island, New York study population would be positively associated with breast cancer and differ by material burned, and the duration and timing of exposure. We also hypothesized that the association would vary by breast cancer subtype defined by p53 mutation status, and interact with glutathione S-transferases GSTM1, T1, A1 and P1 polymorphisms.MethodsPopulation-based, case-control resources (1,508 cases/1,556 controls) were used to conduct unconditional logistic regression to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI).ResultsBreast cancer risk was increased among women reporting ever burning synthetic logs (which may also contain wood) in their homes (OR = 1.42, 95% CI 1.11, 1.84), but not for ever burning wood alone (OR = 0.93, 95% CI 0.77, 1.12). For synthetic log use, longer duration >7 years, older age at exposure (>20 years; OR = 1.65, 95% CI 1.02, 2.67) and 2 or more variants in GSTM1, T1, A1 or P1 (OR = 1.71, 95% CI 1.09, 2.69) were associated with increased risk.ConclusionsBurning wood or synthetic logs are both indoor PAH exposure sources; however, positive associations were only observed for burning synthetic logs, which was stronger for longer exposures, adult exposures, and those with multiple GST variant genotypes. Therefore, our results should be interpreted with care and require replication.

Organochlorine insecticides DDT and chlordane in relation to survival following breast cancer

Organochlorine insecticides have been studied extensively in relation to breast cancer incidence, and results from two meta‐analyses have been null for late‐life residues, possibly due to measurement error. Whether these compounds influence survival remains to be fully explored. We examined associations between organochlorine insecticides [p,p′‐DDT (dichlorodiphenyltrichloroethane), its primary metabolite, p,p′‐DDE, and chlordane] assessed shortly after diagnosis and survival among women with breast cancer. A population‐based sample of women diagnosed with a first primary invasive or in situ breast cancer in 1996–1997 and with available organochlorine blood measures (n = 633) were followed for vital status through 2011. After follow‐up of 5 and 15 years, we identified 55 and 189 deaths, of which 36 and 74, respectively, were breast cancer‐related. Using Cox regression models, we estimated the multivariable‐adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for lipid‐adjusted organochlorine concentrations with all‐cause and breast cancer‐specific mortality. At 5 years after diagnosis, the highest tertile of DDT concentration was associated with all‐cause (HR = 2.19; 95% CI: 1.02, 4.67) and breast cancer‐specific (HR = 2.72; 95% CI: 1.04, 7.13) mortality. At 15 years, middle tertile concentrations of DDT (HR = 1.42; 95% CI 0.99, 2.06) and chlordane (HR = 1.42; 95% CI: 0.94, 2.12) were modestly associated with all‐cause and breast cancer‐specific mortality. Third tertile DDE concentrations were inversely associated with 15‐year all‐cause mortality (HR = 0.66; 95% CI: 0.44, 0.99). This is the first population‐based study in the United States to show that DDT may adversely impact survival following breast cancer diagnosis. Further studies are warranted given the high breast cancer burden and the ubiquity of these chemicals.

Childhood and Adolescent Pesticide Exposure and Breast Cancer Risk.

Background: To date, epidemiologic studies have not strongly supported an association between pesticide exposure and breast cancer. However, few previous studies had the ability to assess specific time periods of exposure. Studies that relied on adult serum levels of metabolites of organochlorine pesticides may not accurately reflect exposure during developmental periods. Furthermore, exposure assessment often occurred after diagnosis and key tumor characteristics, such as hormone receptor status, have rarely been available to evaluate tumor subtype-specific associations. We examined the association between pesticide exposure during childhood and adolescence and breast cancer risk in the prospective Sister Study cohort (N = 50,884 women) to assess this relation by tumor subtype. Methods: During an average 5-year follow-up, 2,134 incident invasive and in situ breast cancer diagnoses were identified. Residential and farm exposure to pesticides were self-reported at study enrollment during standardized interviews. Multivariable hazard ratios and 95% confidence intervals for breast cancer risk were calculated with Cox proportional hazards regression. Results: HRs were near null for the association between childhood/adolescent pesticide exposure and breast cancer risk overall or among ER+/PR+ invasive tumors. However, among women who were ages 0–18 before the ban of dichlordiphenyltrichloroethane in the US, exposure to fogger trucks or planes was associated with a hazard ratio = 1.3 for premenopausal breast cancer (95% confidence interval: 0.92, 1.7). Conclusion: These findings do not support an overall association between childhood and adolescent pesticide exposure and breast cancer risk. However, modest increases in breast cancer risk were associated with acute events in a subgroup of young women.

The association between metabolic health, obesity phenotype and the risk of breast cancer

Beyond the current emphasis on body mass index (BMI), it is unknown whether breast cancer risk differs between metabolically healthy and unhealthy normal weight or overweight/obese women. The Sister Study is a nationwide prospective cohort study. Data came from 50,884 cohort participants aged 35 to 74 years enrolled from 2003 through 2009. Cox proportional hazards models were used to estimate multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CIs) for breast cancer risk. Metabolic abnormalities considered included: high waist circumference (≥88 cm); elevated blood pressure (≥130/85 mm Hg or antihypertensive medication); previously diagnosed diabetes or antidiabetic drug treatment; and cholesterol‐lowering medication use. During follow‐up (mean, 6.4 years), 1,388 invasive breast cancers were diagnosed at least 1 year after enrollment. Compared to women with BMI <25 kg/m2 with no metabolic abnormalities (metabolically healthy normal weight phenotype), women with a BMI <25 kg/m2 and ≥1 metabolic abnormality (metabolically unhealthy, normal weight phenotype) had increased risk of postmenopausal breast cancer (HR = 1.26, 95% CI: 1.01–1.56), as did women with a BMI ≥25 kg/m2 and no metabolic abnormalities (metabolically healthy overweight/obese phenotype) (HR = 1.24, 95% CI: 0.99–1.55). Furthermore, risk of postmenopausal breast cancer was consistently elevated in women with normal BMI and central obesity (normal weight central obesity phenotype) regardless of the criterion used to define central obesity, with HR for waist circumference ≥88 cm, waist circumference ≥80 cm, and waist‐hip ratio ≥0.85 of 1.58, 95% CI: 1.02–2.46; 1.38, 95% CI: 1.09–1.75; and 1.38, 95% CI: 1.02–1.85, respectively. There was an inverse association between premenopausal breast cancer and metabolically healthy overweight/obese phenotype (HR = 0.71, 95% CI: 0.52–0.97). Our findings suggest that postmenopausal women who are metabolically unhealthy or have central adiposity may be at increased risk for breast cancer despite normal BMI.

Gene-Specific Promoter Methylation Status in Hormone-Receptor-Positive Breast Cancer Associates with Postmenopausal Body Size and Recreational Physical Activity

INTRODUCTION Breast cancer, the leading cancer diagnosis among American women, is positively associated with postmenopausal obesity and little or no recreational physical activity (RPA). However, the underlying mechanisms of these associations remain unresolved. Aberrant changes in DNA methylation may represent an early event in carcinogenesis, but few studies have investigated associations between obesity/RPA and gene methylation, particularly in postmenopausal breast tumors where these lifestyle factors are most relevant. METHODS We used case-case unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the associations between body mass index (BMI=weight [kg]/height [m2]) in the year prior to diagnosis, or RPA (average hours/week), and methylation status (methylated vs. unmethylated) of 13 breast cancer-related genes in 532 postmenopausal breast tumor samples from the Long Island Breast Cancer Study Project. We also explored whether the association between BMI/RPA and estrogen/progesterone-receptor status (ER+PR+ vs. all others) was differential with respect to gene methylation status. Methylation-specific PCR and the MethyLight assay were used to assess gene methylation. RESULTS BMI 25-29.9kg/m2, and perhaps BMI≥30kg/m2, was associated with methylated HIN1 in breast tumor tissue. Cases with BMI≥30kg/m2 were more likely to have ER+PR+ breast tumors in the presence of unmethylated ESR1 (OR=2.63, 95% CI 1.32-5.25) and women with high RPA were more likely to have ER+PR+ breast tumors with methylated GSTP1 (OR=2.33, 95% CI 0.79-6.84). DISCUSSION While biologically plausible, our findings that BMI is associated with methylated HIN1 and BMI/RPA are associated with ER+PR+ breast tumors in the presence of unmethylated ESR1 and methylated GSTP1, respectively, warrant further investigation. Future studies would benefit from enrolling greater numbers of postmenopausal women and examining a larger panel of breast cancer-related genes.