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Studying time-dependent exposure mixtures has gained increasing attentions in environmental health research. When a scalar outcome is of interest, distributed lag (DL) models have been employed to characterize the exposures effects distributed over time on the mean of final outcome. However, there is a methodological gap on investigating time-dependent exposure mixtures with different quantiles of outcome. In this paper, we introduce semiparametric partial-linear single-index (PLSI) DL quantile regression, which can describe the DL effects of time-dependent exposure mixtures on different quantiles of outcome and identify susceptible periods of exposures. We consider two time-dependent exposure settings: discrete and functional, when exposures are measured in a small number of time points and at dense time grids, respectively. Spline techniques are used to approximate the nonparametric DL function and single-index link function, and a profile estimation algorithm is proposed. Through extensive simulations, we demonstrate the performance and value of our proposed models and inference procedures. We further apply the proposed methods to study the effects of maternal exposures to ambient air pollutants of fine particulate and nitrogen dioxide on birth weight in New York University Children's Health and Environment Study (NYU CHES).

Neighborhood walkability (NW) has been linked to increased physical activity, which in turn is associated with lower concentrations of sex hormones and higher concentration of SHBG in women. However, no study has directly examined the association of NW with female sex hormone levels.We conducted a cross-sectional study to evaluate the association between NW and circulating levels of sex hormones and SHBG in pre- and post-menopausal women.We included 797 premenopausal and 618 postmenopausal women from the New York University Women's Health Study (NYUWHS) who were healthy controls in previous nested case-control studies in which sex hormones (androstenedione, testosterone, DHEAS, estradiol and estrone) and SHBG had been measured in serum at enrollment. Baseline residential addresses were geo-coded and the Built Environment and Health Neighborhood Walkability Index (BEH-NWI) was calculated. Generalized Estimating Equations were used to assess the association between BEH-NWI and sex hormone and SHBG concentrations adjusting for individual- and neighborhood-level factors.In premenopausal women, a one standard deviation (SD) increment in BEH-NWI was associated with a 3.5% (95% CI 0.9%-6.1%) lower DHEAS concentration. In postmenopausal women, a one SD increment in BEH-NWI was related to an 8.5% (95% CI 5.4%-11.5%) lower level of DHEAS, a 3.7% (95% CI 0.5%-6.8%) lower level of testosterone, a 1.8% (95% CI 0.5%-3.0%) lower level of estrone, and a 4.2% (95% CI 2.7%-5.7%) higher level of SHBG. However, the associations with respect to DHEAS and estrone became apparent only after adjusting for neighborhood-level variables. Sensitivity analyses using fixed effects meta-analysis and inverse probability weighting accounting for potential selection bias yielded similar results.Our findings suggest that NW is associated with lower concentrations of androgens and estrone, and increased SHBG, in postmenopausal women, and lower levels of DHEAS in premenopausal women.

BACKGROUND/OBJECTIVES: Folates found in natural foods are thought to protect against cancer. However, folic acid (FA), a synthetic form of folate used in supplements and fortified foods, may increase breast cancer risk if present in unmetabolized form (UMFA) in the circulation. This study examined the associations of serum UMFA and 5-methyltetrahydrofolate (5-mTHF), the predominant form of circulating folate, with breast cancer risk. SUBJECTS/METHODS: We conducted a nested case-control study in a prospective cohort. 553 cases of invasive breast cancer, diagnosed before mandatory FA fortification of grain in the US in 1998, were individually-matched to 1,059 controls. Serum UMFA and 5-mTHF were measured using liquid chromatography-tandem mass spectrometry in stored serum samples, and 5-mTHF was corrected for storage degradation. RESULTS: Serum UMFA was not associated with breast cancer risk: the percentage of women with detectable levels of UMFA was similar in cases and controls (18% and 20%, respectively; p = 0.46). Two tag-SNPs in the promoter region of the FA-metabolizing gene were also not associated with risk. There was a marginally significant inverse association of 5-mTHF(corrected) with breast cancer risk (odds ratio for the highest vs. lowest quintile = 0.69, 95% CI = 0.49 to 0.97; p(trend) = 0.08). CONCLUSION: Circulating UMFA was not associated with breast cancer risk. These results apply to countries without mandatory FA food fortification. Studies are needed in countries with mandatory fortification, where levels of UMFA are much higher than in our study.

The aims of the NYU Children’s Health and Environment Study (CHES) are to evaluate influences of prenatal non-persistent chemical exposures on fetal and postnatal growth and pool our data with the US National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) Program to answer collaborative research questions on the impact of the preconceptual, prenatal, and postnatal environment on childhood obesity, neurodevelopment, pre/peri/postnatal outcomes, upper and lower airway outcomes, and positive health. Eligible women were ≥ 18 years old, 25 weeks gestation. These have been followed by questionnaire and specimen collection at birth and regular postpartum intervals.

Excessive gestational weight gain (GWG) and pre-pregnancy obesity affect a significant portion of the US pregnant population and are linked with negative maternal and child health outcomes. The objective of this study was to explore associations of pre-pregnancy body mass index (pBMI) and GWG with longitudinally measured maternal urinary metabolites throughout pregnancy.Among 652 participants in the New York University Children's Health and Environment Study, a longitudinal pregnancy cohort, targeted metabolomics were measured in serially collected urine samples throughout pregnancy. Metabolites were measured at median 10 (T1), 21 (T2), and 29 (T3) weeks gestation using the Biocrates AbsoluteIDQ® p180 Urine Extension kit. Acylcarnitine, amino acid, biogenic amine, phosphatidylcholine, lysophosphatidylcholine, sphingolipid, and sugar levels were quantified. Pregnant people 18 years or older, without type 1 or 2 diabetes and with singleton live births and valid pBMI and metabolomics data were included. GWG and pBMI were calculated using weight and height data obtained from electronic health records. Linear mixed effects models with interactions with time were fit to determine the gestational age-specific associations of categorical pBMI and continuous interval-specific GWG with urinary metabolites. All analyses were corrected for false discovery rate.Participants with obesity had lower long-chain acylcarnitine levels throughout pregnancy and lower phosphatidylcholine and glucogenic amino acids and higher phenylethylamine concentrations in T2 and T3 compared with participants with normal/underweight pBMI. GWG was associated with taurine in T2 and T3 and C5 acylcarnitine species, C5:1, C5-DC, and C5-M-DC, in T2.pBMI and GWG were associated with the metabolic environment of pregnant individuals, particularly in relation to mid-pregnancy. These results highlight the importance of both preconception and prenatal maternal health.

BACKGROUND AND AIM: Air pollution is a health risk in pregnant women and young children. Despite the importance of refined exposure assessments particularly at low exposure levels, characterization...

Background There is a paucity of prospective cohort studies evaluating neighborhood walkability in relation to the risk of death. Methods We geocoded baseline residential addresses of 13,832 women in the New York University Women's Health Study (NYUWHS) and estimated the Built Environment and Health Neighborhood Walkability Index (BEH-NWI) for each participant circa 1990. The participants were recruited from 1985 to 1991 in New York City and followed for an average of 27 years. We conducted survival analyses using Cox proportional hazards models to assess the association between neighborhood walkability and risk of death from any cause, obesity-related diseases, cardiometabolic diseases, and obesity-related cancers. Results Residing in a neighborhood with a higher neighborhood walkability score was associated with a lower mortality rate. Comparing women in the top versus the lowest walkability tertile, the hazards ratios (and 95% CIs) were 0.96 (0.93-0.99) for all-cause, 0.91 (0.86-0.97) for obesity-related disease, and 0.72 (0.62-0.85) for obesity-related cancer mortality, respectively, adjusting for potential confounders at both the individual and neighborhood level. We found no association between neighborhood walkability and risk of death from cardiometabolic diseases. Results were similar in analyses censoring participants who moved during follow-up, using multiple imputation for missing covariates, and using propensity scores matching women with high and low neighborhood walkability on potential confounders. Exploratory analyses indicate that outdoor walking and average BMI mediated the association between neighborhood walkability and mortality. Conclusion Our findings are consistent with a protective role of neighborhood walkability in obesity-related mortality in women, particularly obesity-related cancer mortality.

Objective To describe the long-term mortality experience of a cohort of enlisted men who served on nuclear-powered submarines in the United States Navy and breathed recirculated filtered air for extended periods of time. Methods In this historical cohort study we estimated Standardized Mortality Ratios (SMRs) and used within-cohort Poisson regression analyses to address healthy worker biases. Results 3,263 deaths occurred among 85,498 men during 1,926,875 person-years of follow-up from 1969 to 1995. SMRs were reduced for most cause-of-death categories, prostate cancer had a twofold elevation. In within-cohort comparisons, prostate cancer mortality did not increase with duration of submarine service, but ischemic heart disease mortality increased 26% per 5 years of submarine service. Conclusions Long periods of submarine service do not increase mortality in most cause-of-death categories. Increased mortality from ischemic heart disease likely reflects the effects of tobacco smoke.

Fetal exposure to environmental chemicals has been associated with adverse health outcomes in children and later into adulthood. While several studies have examined correlations and variability of non-persistent chemical exposures throughout pregnancy, many do not capture more recent exposures, particularly in New York City. Our goal was to characterize exposure to phthalates, bisphenols, polycyclic aromatic hydrocarbons, and organophosphate pesticides among pregnant women residing in New York City who enrolled in the New York University Children's Health and Environment Study (NYU CHES) between 2016 and 2018. We measured urinary chemical metabolite concentrations in 671 women at early, mid, and late pregnancy (median 10.8, 20.8, and 29.3 weeks, respectively). We calculated Spearman correlation coefficients among chemical concentrations at each measurement time point. We compared changes in population-level urinary metabolites at each stage using paired Wilcoxon signed-rank tests and calculated intraclass correlation coefficients (ICCs) to quantify intra-individual variability of metabolites across pregnancy. Geometric means and ICCs were compared to nine other pregnancy cohorts that recruited women in 2011 or later as well as nationally reported levels from women of child-bearing age. Compared with existing cohorts, women in NYU CHES had higher geometric means of organophosphate pesticides (Σdiethylphosphates = 28.7 nmol/g cr, Σdimethylphosphates = 57.3 nmol/g cr, Σdialkyl phosphates = 95.9 nmol/g cr), bisphenol S (0.56 μg/g cr), and 2-naphthalene (8.98 μg/g cr). Five PAH metabolites and two phthalate metabolites increased between early to mid and early to late pregnancy at the population level. Spearman correlation coefficients for chemical metabolites were generally below 0.50. Intra-individual exposures varied over time, as indicated by low ICCs (0.22-0.88, median = 0.38). However, these ICCs were often higher than those observed in other pregnancy cohorts. These results provide a general overview of the chemical metabolites measured in NYU CHES in comparison to other contemporary pregnancy cohorts and highlight directions for future studies.

Maternal diet, prior to and during pregnancy, plays an important role in the immediate and long-term health of the mother and her offspring. Our objectives were to assess diet quality among a large, diverse, urban cohort of pregnant women, and examine associations with sociodemographic and health behavior characteristics. Data were from 1,325 pregnant women enrolled in New York University Children's Health and Environment Study (NYU CHES). Diet quality was assessed using the Healthy Eating Index (HEI)-2015. Mean total HEI-2015 score was 74.9 (SD = 8.5); 376 (28%), 612 (46%), 263 (20%), and 74 (6%) of women had scores that fell into the grade range of A/B, C, D, and F, respectively. Mean HEI-2015 component scores were high for fruit and whole grains and low for protein-related, sodium, and fat-related components. In multivariable linear regression models, Hispanic women scored 1.65 points higher on the total HEI-2015 (95% CI: 0.21, 3.10) compared to non-Hispanic White women, while younger age (

Context We previously reported that anti-Müllerian hormone (AMH), a marker of ovarian reserve, is positively associated with breast cancer risk, consistent with other studies. Objective This study assessed whether risk factors for breast cancer are correlates of AMH concentration. Methods This cross-sectional study included 3831 healthy premenopausal women (aged 21-57, 87% aged 35-49) from 10 cohort studies among the general population. Results Adjusting for age and cohort, AMH positively associated with age at menarche (P Conclusion This is the largest study of AMH and breast cancer risk factors among women from the general population (not presenting with infertility), and it suggests that most associations are limited to women over 40, who are approaching menopause and whose AMH concentration is declining.

PURPOSE: The soluble receptor for advanced glycation end products (sRAGE) and endogenous secretory RAGE (esRAGE) have been considered as biomarkers of several chronic diseases. However, the temporal reliability of their concentrations in the circulation is yet to be demonstrated. We evaluated whether a single measurement of serum sRAGE and esRAGE could serve as an estimate for usual serum levels in epidemiologic studies. METHODS: Serum sRAGE and esRAGE were measured using ELISAs in three yearly samples from 36 participants in the New York University Women’s Health Study. The intraclass correlation coefficient (ICC) was used to evaluate temporal reliability. RESULTS: The intra- and inter-batch coefficients of variation were 3.0% and 14.8% for sRAGE and 6.5% and 34.7% for esRAGE, and decreased to 0.4% and 2.1% for sRAGE and 1.0% and 6.3% for esRAGE after log(2)-transformation of the data. On the original scale, the ICCs of a single measurement of serum sRAGE and esRAGE were 0.89 (95% CI: 0.82, 0.94) and 0.87 (95% CI: 0.79, 0.93), respectively, and were similar using log(2)-transformed data. CONCLUSION: Our results indicate that a single measurement of serum sRAGE and esRAGE is a sufficiently reliable measure of their usual levels that can be used in epidemiologic studies.

A strong positive association has been observed between circulating anti‐Mullerian hormone (AMH), a biomarker of ovarian reserve, and breast cancer risk in three prospective studies. Confirming thi ...

Background Full-term pregnancy (FTP) at an early age confers long-term protection against breast cancer. Previously, we reported that a FTP imprints a specific gene expression profile in the breast of postmenopausal women. Herein, we evaluated gene expression changes induced by parity in the breast of premenopausal women. Methods Gene expression profiling of normal breast tissue from 30 nulliparous (NP) and 79 parous (P) premenopausal volunteers was performed using Affymetrix microarrays. In addition to a discovery/validation analysis, we conducted an analysis of gene expression differences in P vs. NP women as a function of time since last FTP. Finally, a laser capture microdissection substudy was performed to compare the gene expression profile in the whole breast biopsy with that in the epithelial and stromal tissues. Results Discovery/validation analysis identified 43 differentially expressed genes in P vs. NP breast. Analysis of expression as a function of time since FTP revealed 286 differentially expressed genes (238 up- and 48 downregulated) comparing all P vs. all NP, and/or P women whose last FTP was less than 5 years before biopsy vs. all NP women. The upregulated genes showed three expression patterns: (1) transient: genes upregulated after FTP but whose expression levels returned to NP levels. These genes were mainly related to immune response, specifically activation of T cells. (2) Long-term changing: genes upregulated following FTP, whose expression levels decreased with increasing time since FTP but did not return to NP levels. These were related to immune response and development. (3) Long-term constant: genes that remained upregulated in parous compared to nulliparous breast, independently of time since FTP. These were mainly involved in development/cell differentiation processes, and also chromatin remodeling. Lastly, we found that the gene expression in whole tissue was a weighted average of the expression in epithelial and stromal tissues. Conclusions Genes transiently activated by FTP may have a role in protecting the mammary gland against neoplastically transformed cells through activation of T cells. Furthermore, chromatin remodeling and cell differentiation, represented by the genes that are maintained upregulated long after the FTP, may be responsible for the lasting preventive effect against breast cancer. Electronic supplementary material The online version of this article (10.1186/s13058-019-1128-x) contains supplementary material, which is available to authorized users.

Background Models that accurately predict risk of breast cancer are needed to help younger women make decisions about when to begin screening. Premenopausal concentrations of circulating anti-Müllerian hormone (AMH), a biomarker of ovarian reserve, and testosterone have been positively associated with breast cancer risk in prospective studies. We assessed whether adding AMH and/or testosterone to the Gail model improves its prediction performance for women aged 35–50. Methods In a nested case-control study including ten prospective cohorts (1762 invasive cases/1890 matched controls) with pre-diagnostic serum/plasma samples, we estimated relative risks (RR) for the biomarkers and Gail risk factors using conditional logistic regression and random-effects meta-analysis. Absolute risk models were developed using these RR estimates, attributable risk fractions calculated using the distributions of the risk factors in the cases from the consortium, and population-based incidence and mortality rates. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminatory accuracy of the models with and without biomarkers. Results The AUC for invasive breast cancer including only the Gail risk factor variables was 55.3 (95% CI 53.4, 57.1). The AUC increased moderately with the addition of AMH (AUC 57.6, 95% CI 55.7, 59.5), testosterone (AUC 56.2, 95% CI 54.4, 58.1), or both (AUC 58.1, 95% CI 56.2, 59.9). The largest AUC improvement (4.0) was among women without a family history of breast cancer. Conclusions AMH and testosterone moderately increase the discriminatory accuracy of the Gail model among women aged 35–50. We observed the largest AUC increase for women without a family history of breast cancer, the group that would benefit most from improved risk prediction because early screening is already recommended for women with a family history. Electronic supplementary material The online version of this article (10.1186/s13058-019-1126-z) contains supplementary material, which is available to authorized users.

The New York University Children’s Environmental Health Study (NYU CHES) is an NIH ECHO-funded birth cohort designed to assess the impact of prenatal exposure to environmental chemicals on pr...

// Alireza Khodadadi-Jamayran 1 , Betul Akgol-Oksuz 2 , Yelena Afanasyeva 3 , Adriana Heguy 4, 5 , Marae Thompson 6 , Karina Ray 5 , Ariadna Giro-Perafita 6 , Irma Sanchez 4 , Xifeng Wu 7 , Debu Tripathy 8 , Anne Zeleniuch-Jacquotte 3 , Aristotelis Tsirigos 1, 4 and Francisco J. Esteva 6 1 Applied Bioinformatics Laboratories, NYU School of Medicine, New York, NY, USA 2 Department Bioinformatics and Computational Biology, University of Massachusetts Medical School, Worcester, MA, USA 3 Division of Epidemiology, NYU School of Medicine, New York, NY, USA 4 Department of Pathology, NYU School of Medicine, New York, NY, USA 5 Genome Technology Center, NYU School of Medicine, New York, NY, USA 6 Division of Hematology/Oncology, Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA 7 Department of Epidemiology, UT MD Anderson Cancer Center, Houston, TX, USA 8 Department of Breast Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Francisco J. Esteva, email: francisco.esteva@nyumc.org Aristotelis Tsirigos, email: Aristotelis.Tsirigos@nyumc.org Keywords: breast cancer; gene expression profiling Received: July 08, 2017 Accepted: January 13, 2018 Published: February 05, 2018 ABSTRACT MicroRNAs have been shown to play important roles in breast cancer progression and can serve as biomarkers. To assess the prognostic role of a panel of miRNAs in breast cancer, we collected plasma prospectively at the time of initial diagnosis from 1,780 patients with stage I-III breast cancer prior to definitive treatment. We identified plasma from 115 patients who subsequently developed distant metastases and 115 patients without metastatic disease. Both groups were matched by: age at blood collection, year of blood collection, breast cancer subtype, and stage. The median follow up was 3.4 years (range, 1-9 years). We extracted RNA from plasma and analyzed the expression of 800 miRNAs using Nanostring technology. We then assessed the expression of miRNAs in primary and metastatic breast cancer samples from The Cancer Genome Atlas (TCGA). We found that, miR-24-3p was upregulated in patients with metastases, both in plasma and in breast cancer tissues. Patients whose primary tumors expressed high levels of miR-24-3p had a significantly lower survival rate compared to patients with low mir-24-3p levels in the TCGA cohort (n=1,024). RNA-Seq data of the samples with the highest miR-24-3p expression versus those with the lowest miR-24-3p in the TCGA cohort identified a specific gene expression signature for those tumors with high miR-24-3p. Possible target genes for miR-24-3p were predicted based on gene expression and binding site, and their effects on cancer pathways were evaluated. Cancer, breast cancer and proteoglycans were the top three pathways affected by miR-24-3p overexpression.

Early pregnancy and multiparity are known to reduce the risk of women to develop breast cancer at menopause. Based on the knowledge that the differentiation of the breast induced by the hormones of pregnancy plays a major role in this protection, this work was performed with the purpose of identifying what differentiation-associated molecular changes persist in the breast until menopause. Core needle biopsies (CNB) obtained from the breast of 42 nulliparous (NP) and 71 parous (P) postmenopausal women were analyzed in morphology, immunocytochemistry and gene expression. Whereas in the NP breast, nuclei of epithelial cells were large and euchromatic, in the P breast they were small and hyperchromatic, showing strong methylation of histone 3 at lysine 9 and 27. Transcriptomic analysis performed using Affymetrix HG_U133 oligonucleotide arrays revealed that in CNB of the P breast, there were 267 upregulated probesets that comprised genes controlling chromatin organization, transcription regulation, splicing machinery, mRNA processing and noncoding elements including XIST. We concluded that the differentiation process induced by pregnancy is centered in chromatin remodeling and in the mRNA processing reactome, both of which emerge as important regulatory pathways. These are indicative of a safeguard step that maintains the fidelity of the transcription process, becoming the ultimate mechanism mediating the protection of the breast conferred by full-term pregnancy.

Background: It has been suggested that the relative importance of oestrogen-metabolising pathways may affect the risk of oestrogen-dependent tumours including endometrial cancer. One hypothesis is that the 2-hydroxy pathway is protective, whereas the 16α-hydroxy pathway is harmful. Methods: We conducted a case–control study nested within three prospective cohorts to assess whether the circulating 2-hydroxyestrone : 16α-hydroxyestrone (2-OHE1 : 16α-OHE1) ratio is inversely associated with endometrial cancer risk in postmenopausal women. A total of 179 cases and 336 controls, matching cases on cohort, age and date of blood donation, were included. Levels of 2-OHE1 and 16α-OHE1 were measured using a monoclonal antibody-based enzyme assay. Results: Endometrial cancer risk increased with increasing levels of both metabolites, with odds ratios in the top tertiles of 2.4 (95% CI=1.3, 4.6; Ptrend=0.007) for 2-OHE1 and 1.9 (95% CI=1.1, 3.5; Ptrend=0.03) for 16α-OHE1 in analyses adjusting for endometrial cancer risk factors. These associations were attenuated and no longer statistically significant after further adjustment for oestrone or oestradiol levels. No significant association was observed for the 2-OHE1 : 16α-OHE1 ratio. Conclusion: Our results do not support the hypothesis that greater metabolism of oestrogen via the 2-OH pathway, relative to the 16α-OH pathway, protects against endometrial cancer.

Background: It has been proposed that a shift toward 2-hydroxyestrone from 16α-hydroxyestrone metabolic pathway may be inversely associated with breast cancer risk because 2-hydroxyestrone is thought to be less genotoxic and estrogenic than 16α-hydroxyestrone. Methods: We examined the associations of invasive breast cancer risk with circulating 2-hydroxyestrone, 16α-hydroxyestrone, and the 2-hydroxyestrone:16α-hydroxyestrone ratio in a case-control study on premenopausal women nested within a prospective cohort the New York University Women's Health Study. The serum levels of 2-hydroxyestrone and 16α-hydroxyestrone were measured in 377 incident premenopausal breast cancer cases and 377 premenopausal controls, who were matched on age at enrollment, number and dates of blood donations, and day and phase of menstrual cycle. Results: Overall, no significant associations were observed between breast cancer risk and serum levels of 2-hydroxyestrone, 16α-hydroxyestrone, or their ratio. The 2-hydroxyestrone:16α-hydroxyestrone ratio was positively associated with risk for estrogen receptor–positive breast cancer in the analyses controlling for matching factors. However, the association was attenuated and not significant after adjustment for potential confounders (odds ratio for the highest versus the lowest quartile, 2.15; 95% CI, 0.88-5.27; Ptrend = 0.09). Conclusions: The results of the current study do not support the hypothesis that a metabolic shift from 16α-hydroxyestrone toward 2-hydroxyestrone in premenopausal women is associated with reduced risk for breast cancer. The association between the 2-hydroxy:16α-hydroxyestrone ratio and estrogen receptor–positive breast cancer needs to be explored in future studies. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2273–9)

Pregnancy hormones are believed to be involved in the protection against breast cancer conferred by pregnancy. The authors explored the association of maternal breast cancer with human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP). In 2001, a case-control study was nested within the Northern Sweden Maternity Cohort, an ongoing study in which blood samples have been collected from first-trimester pregnant women since 1975. Cases (n = 210) and controls (n = 357) were matched for age, parity, and date of blood donation. Concentrations of hCG and AFP were measured by immunoassay. No overall significant association of breast cancer with either hCG or AFP was observed. However, women with hCG levels in the top tertile tended to be at lower risk of breast cancer than women with hCG levels in the lowest tertile in the whole study population and in subgroups of age at sampling, parity, and age at cancer diagnosis. A borderline-significant decrease in risk with high hCG levels was observed in women who developed breast cancer after the median lag time to cancer diagnosis (> or =14 years; odds ratio = 0.53, 95% confidence interval: 0.27, 1.03; P = 0.06). These findings, though very preliminary, are consistent with a possible long-term protective association of breast cancer risk with elevated levels of circulating hCG in the early stages of pregnancy.

To evaluate the associations of breast cancer risk with polymorphisms in the XPC and XPD/ERCC2 DNA nucleotide excision repair genes, a case-control study nested within a prospective cohort of 14,274 women was conducted. Genotypes were characterized for 612 incident, invasive breast cancer cases and their 1:1 matched controls. The homozygous variant of a poly(AT) insertion/deletion polymorphism in intron 9 of the XPC gene (XPC-PAT+/+), was associated with breast cancer risk [odds ratio (OR) = 1.45, 95% confidence interval: 1.07-1.97], after adjustment for other breast cancer risk factors. The breast cancer risk associated with XPC-PAT+/+ did not differ by age at diagnosis. There was an indication of an interaction (p = 0.08) between the XPC-PAT+/+ genotype and cigarette smoking. Ever smokers with the XPC-PAT+/+ genotype were at elevated risk of breast cancer (OR = 1.56, CI: 0.95-2.58), but no differences were observed among never smokers. Analyses of the ERCC2 Lys751Gln polymorphism did not show an association with breast cancer risk, either overall or at younger ages. The results suggest that breast cancer risk is related to the XPC haplotype tagged by the XPC-PAT+/+ insertion-deletion polymorphism in intron 9. Further study of the XPC haplotypes and their interactions with smoking in relation to breast cancer risk is needed.

Validity of biobank studies on hormone associated cancers depend on the extent the sample preservation is affecting the hormone measurements. We investigated the effect of long-term storage (up to 22 years) on immunoassay measurements of three groups of hormones and associated proteins: sex-steroids [estradiol, progesterone, testosterone, dihydroepiandrosterone sulphate (DHEAS), sex hormone-binding globulin (SHBG)], pregnancy-specific hormones [human chorionic gonadotropin (hCG), placental growth hormone (pGH), alpha-fetoprotein (AFP)], and insulin-like growth factor (IGF) family hormones exploiting the world largest serum bank, the Finnish Maternity Cohort (FMC). Hormones of interest were analyzed in a random sample of 154 Finnish women in the median age (29.5 years, range 25 to 34 years) of their first pregnancy with serum samples drawn during the first trimester. All hormone measurements were performed using commercial enzyme-linked- or radio-immunoassays. Storage time did not correlate with serum levels of testosterone, DHEAS, hCG, pGH and total IGFBP-1. It had a weak or moderate negative correlation with serum levels of progesterone (Spearman's ranked correlation coefficient (r(s))=- 0.36), IGF-I (r(s)=-0.23) and IGF binding protein (BP)-3 (r(s)=-0.38), and weak positive correlation with estradiol (r(s)=0.23), SHBG (r(s)=0.16), AFP (r(s)=0.20) and non-phosphorylated IGF binding protein (BP)-1 (r(s)=0.27). The variation of all hormone levels studied followed the kinetics reported for early pregnancy. Bench-lag time (the time between sample collection and freezing for storage) did not materially affect the serum hormone levels. In conclusion, the stored FMC serum samples can be used to study hormone-disease associations, but close matching for storage time and gestational day are necessary design components of all related biobank studies.

Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes other than the vitamin D receptor (VDR) gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA) gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1), and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1). SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OH) D concentration in GWAS were also associated with plasma 25(OH) D in our study (p-trend < 0.005). After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OH) D with breast cancer risk, do not support an association between vitamin D and breast cancer risk.

Background: The role of insulin-like growth factor (IGF)-I in breast cancer remains controversial, despite numerous reports on the association of the hormone with breast cancer or high-risk mammographic densities. We hypothesized that exposure to elevated IGF-I during early pregnancy, a period characterized by intense cell proliferation in the breasts and in the presence of high concentrations of sex steroids, will be associated with increased maternal risk to develop a breast malignancy. Methods: The Northern Sweden Maternity Cohort is an ongoing prospective study, collecting blood samples from first-trimester-pregnant women since 1975 as part of screening for infectious diseases. A case-control study (212 cases and 369 controls) was nested among Northern Sweden Maternity Cohort members who delivered singleton babies. RIA was used to measure IGF-I and IGF-II levels. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). Results: Breast cancer risk increased with increasing IGF-I (top tertile OR, 1.7; 95% CI, 1.1-2.7). The association was stronger among the primiparous (OR, 2.2; 95% CI, 1.1-4.4) than in the nonprimiparous women (OR, 1.4; 95% CI, 0.7-2.8). Upper-tertile risks seemed to decrease within the 33-year groups of age at sampling, from 2.5 (0.9-7.6) to 2.1 (0.9-5.0) and 1.2 (0.5-2.5), respectively. There was no association of breast cancer with first-trimester-pregnancy IGF-II. Conclusions: The study offers further evidence that IGF-I is important in breast cancer. Our findings suggest that the adverse effect of IGF-I on the breast may be stronger before the remodeling of the gland induced by a first pregnancy. (Cancer Epidemiol Biomarkers Prev 2006;15(12):2489–93)

Background: It has been hypothesized that predominance of the 2-hydroxylation estrogen metabolism pathway over the 16α-hydroxylation pathway may be inversely associated with breast cancer risk. Methods: We examined the associations of invasive breast cancer risk with circulating 2-hydroxyestrone (2-OHE1), 16α-hydroxyestrone (16α-OHE1), and the 2-OHE1:16α-OHE1 ratio in a case–control study of postmenopausal women nested within two prospective cohorts: the New York University Women's Health Study (NYUWHS) and the Northern Sweden Mammary Screening Cohort (NSMSC), with adjustment for circulating levels of estrone, and additional analyses by tumor estrogen receptor (ER) status. Levels of 2-OHE1 and 16α-OHE1 were measured using ESTRAMET 2/16 assay in stored serum or plasma samples from 499 incident breast cancer cases and 499 controls, who were matched on cohort, age, and date of blood donation. Results: Overall, no significant associations were observed between breast cancer risk and circulating levels of 2-OHE1, 16α-OHE1, or their ratio in either cohort and in combined analyses. For 2-OHE1, there was evidence of heterogeneity by ER status in models adjusting for estrone (P ≤ 0.03). We observed a protective association of 2-OHE1 with ER+ breast cancer [multivariate-adjusted OR for a doubling of 2-OHE1, 0.67 (95% confidence interval [CI], 0.48–0.94; P = 0.02)]. Conclusions: In this study, higher levels of 2-OHE1 were associated with reduced risk of ER+ breast cancer in postmenopausal women after adjustment for circulating estrone. Impact: These results suggest that taking into account the levels of parent estrogens and ER status is important in studies of estrogen metabolites and breast cancer. Cancer Epidemiol Biomarkers Prev; 23(7); 1290–7. ©2014 AACR.

Introduction: Experimental evidence suggests a protective role for circulating 25-hydroxyvitamin D (25(OH) D) in breast cancer development, but the results of epidemiological studies have been inconsistent. Methods: We conducted a case-control study nested within two prospective cohorts, the New York University Women's Health Study and the Northern Sweden Mammary Screening Cohort. Blood samples were collected at enrollment, and women were followed up for breast cancer ascertainment. In total, 1,585 incident breast cancer cases were individually-matched to 2,940 controls. Of these subjects, 678 cases and 1,208 controls contributed two repeat blood samples, at least one year apart. Circulating levels of 25(OH) D were measured, and multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Results: No association was observed between circulating levels of 25(OH) D and overall breast cancer risk (multivariate-adjusted model OR = 0.94, 95% CI = 0.76-1.16 for the highest vs. lowest quintile, ptrend = 0.30). The temporal reliability of 25(OH)D measured in repeat blood samples was high (intraclass correlation coefficients for season-adjusted 25(OH) D > 0.70). An inverse association between 25(OH) D levels and breast cancer risk was observed among women who were = 45 years of age (ORQ5-Q1 = 0.48, 95% CI = 0.30-0.79, ptrend = 0.01) or premenopausal at enrollment (ORQ5-Q1 = 0.67, 95% CI = 0.48-0.92, ptrend = 0.03). Conclusions: Circulating 25(OH) D levels were not associated with breast cancer risk overall, although we could not exclude the possibility of a protective effect in younger women. Recommendations regarding vitamin D supplementation should be based on considerations other than breast cancer prevention.

Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants (SNPs and repeat polymorphisms) in hormone-related genes are associated with sex hormone levels. However, the relationship observed between these genetic variants and breast cancer risk has been inconsistent. We conducted a case-control study nested within two prospective cohorts to assess the relationship between specific genetic variants in hormone-related genes and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were included in the study. We did not observe an association between potential functional genetic polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect on breast cancer risk. This work was supported by National Cancer Institute grants R01 CA081212, R01 CA098661 and P30 CA016087 and Center grant ES000260 from the National Institute of Environmental Health Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Background Taurine (2-aminoethanesulfonic acid), a conditionally essential sulfur-containing amino acid, is mainly obtained from diet in humans. Experimental studies have shown that taurine’s main biological actions include bile salt conjugation, blood pressure regulation, anti-oxidation, and anti-inflammation. Methods We conducted a prospective case-control study nested in the New York University Women’s Health Study, a cohort study involving 14,274 women enrolled since 1985. Taurine was measured in pre-diagnostic serum samples of 241 stroke cases and 479 matched controls. Results There was no statistically significant association between serum taurine and stroke risk in the overall study population. The adjusted ORs for stroke were 1.0 (reference), 0.87 (95% CI, 0.59–1.28), and 1.03 (95% CI, 0.69–1.54) in increasing tertiles of taurine (64.3–126.6, 126.7–152.9, and 153.0–308.5 nmol/mL, respectively). A significant inverse association between serum taurine and stroke risk was observed among never smokers, with an adjusted OR of 0.66 (95% CI, 0.37–1.18) and 0.50 (95% CI, 0.26–0.94) for the second and third tertile, respectively (p for trend = 0.01), but not among past or current smokers (p for interaction < 0.01). Conclusions We observed no overall association between serum taurine and stroke risk, although a protective effect was observed in never smokers, which requires further investigation. Taurine, Stroke, Epidemiology, Prospective, Case-control study, NYUWHS.

BACKGROUND: The role of estrogen and progesterone in the development of endometrial cancer is well documented. Few studies have examined the association of genetic variants in sex hormone-related genes with endometrial cancer risk. METHODS: We conducted a case-control study nested within three cohorts to examine the association of endometrial cancer risk with polymorphisms in hormone-related genes among 391 cases (92% postmenopausal at diagnosis) and 712 individually-matched controls. We also examined the association of these polymorphisms with circulating levels of sex hormones and SHBG in a cross-sectional analysis including 596 healthy postmenopausal women at blood donation (controls from this nested case-control study and from a nested case-control study of breast cancer in one of the three cohorts). RESULTS: Adjusting for endometrial cancer risk factors, the A allele of rs4775936 in CYP19 was significantly associated (OR(per allele)=1.22, 95% CI=1.01-1.47, p(trend)=0.04), while the T allele of rs10046 was marginally associated with increased risk of endometrial cancer (OR(per allele)=1.20, 95% CI=0.99-1.45, p(trend)=0.06). PGR rs1042838 was also marginally associated with risk (OR(per allele)=1.25, 95% CI=0.96-1.61, p(trend)=0.09). No significant association was found for the other polymorphisms, i.e. CYP1B1 rs1800440 and rs1056836, UGT1A1 rs8175347, SHBG rs6259 and ESR1 rs2234693. Rs8175347 was significantly associated with postmenopausal levels of estradiol, free estradiol and estrone and rs6259 with SHBG and estradiol. CONCLUSION: Our findings support an association between genetic variants in CYP19, and possibly PGR, and risk of endometrial cancer.

Background It is accepted that a woman's lifetime risk of developing breast cancer after menopause is reduced by early full term pregnancy and multiparity. This phenomenon is thought to be associated with the development and differentiation of the breast during pregnancy. Methods In order to understand the underlying molecular mechanisms of pregnancy induced breast cancer protection, we profiled and compared the transcriptomes of normal breast tissue biopsies from 71 parous (P) and 42 nulliparous (NP) healthy postmenopausal women using Affymetrix Human Genome U133 Plus 2.0 arrays. To validate the results, we performed real time PCR and immunohistochemistry. Results We identified 305 differentially expressed probesets (208 distinct genes). Of these, 267 probesets were up- and 38 down-regulated in parous breast samples; bioinformatics analysis using gene ontology enrichment revealed that up-regulated genes in the parous breast represented biological processes involving differentiation and development, anchoring of epithelial cells to the basement membrane, hemidesmosome and cell-substrate junction assembly, mRNA and RNA metabolic processes and RNA splicing machinery. The down-regulated genes represented biological processes that comprised cell proliferation, regulation of IGF-like growth factor receptor signaling, somatic stem cell maintenance, muscle cell differentiation and apoptosis. Conclusions This study suggests that the differentiation of the breast imprints a genomic signature that is centered in the mRNA processing reactome. These findings indicate that pregnancy may induce a safeguard mechanism at post-transcriptional level that maintains the fidelity of the transcriptional process.

The objective of this study was to comprehensively compare the genomic profiles in the breast of parous and nulliparous postmenopausal women to identify genes that permanently change their expression following pregnancy. The study was designed as a two-phase approach. In the discovery phase, we compared breast genomic profiles of 37 parous with 18 nulliparous postmenopausal women. In the validation phase, confirmation of the genomic patterns observed in the discovery phase was sought in an independent set of 30 parous and 22 nulliparous postmenopausal women. RNA was hybridized to Affymetrix HG_U133 Plus 2.0 oligonucleotide arrays containing probes to 54,675 transcripts, scanned and the images analyzed using Affymetrix GCOS software. Surrogate variable analysis, logistic regression, and significance analysis of microarrays were used to identify statistically significant differences in expression of genes. The false discovery rate (FDR) approach was used to control for multiple comparisons. We found that 208 genes (305 probe sets) were differentially expressed between parous and nulliparous women in both discovery and validation phases of the study at an FDR of 10% and with at least a 1.25-fold change. These genes are involved in regulation of transcription, centrosome organization, RNA splicing, cell-cycle control, adhesion, and differentiation. The results provide initial evidence that full-term pregnancy induces long-term genomic changes in the breast. The genomic signature of pregnancy could be used as an intermediate marker to assess potential chemopreventive interventions with hormones mimicking the effects of pregnancy for prevention of breast cancer. Cancer Prev Res; 4(9); 1457–64. ©2011 AACR.

Background: Promoter methylation of tumor suppressor genes is a frequent and early event in breast carcinogenesis. Paired tumor tissue and serum samples from women with breast cancer show that promoter methylation is detectable in both sample types, with good concordance. This suggests the potential for these serum markers to be used for breast cancer detection. Methods: The current study was a case–control study nested within the prospective New York University Women's Health Study cohort aimed to assess the ability of promoter methylation in serum to detect pre-clinical disease. Cases were women with blood samples collected within the 6 months preceding breast cancer diagnosis ( n =50). Each case was matched to 2 healthy cancer-free controls and 1 cancer-free control with a history of benign breast disease (BBD). Results: Promoter methylation analysis of four cancer-related genes: — RASSF1A , GSTP1 , APC and RARβ2 , — was conducted using quantitative methylation-specific PCR. Results showed that the frequency of methylation was lower than expected among cases and higher than expected among controls. Methylation was detected in the promoter region of: RASSF1A in 22.0%, 22.9% and 17.2% of cases, BBD controls and healthy controls respectively; GSTP1 in 4%, 10.4% and 7.1% respectively; APC in 2.0%, 4.4% and 4.2% respectively and RARβ2 in 6.7%, 2.3% and 1.1% respectively. Conclusion: Methylation status of the four genes included in this study was unable to distinguish between cases and either control group. This study highlights some methodological issues to be addressed in planning prospective studies to evaluate methylation markers as diagnostic biomarkers.

Little is known about correlates of first-trimester pregnancy hormones as in most studies maternal hormones have been measured later in gestation. We examined the associations of maternal characteristics and child sex with first-trimester maternal concentrations of four hormones implicated in breast cancer: human chorionic gonadotropin (hCG), alpha-fetoprotein (AFP), insulin-like growth factor (IGF)-I, and IGF-II.About 338 serum samples donated to the Northern Sweden Maternity Cohort (NSMC), 1975-2001, during the first trimester of uncomplicated pregnancies, were analyzed for the hormones of interest as a part of a case-control study. The associations of maternal characteristics and child sex with hormone concentrations were investigated by correlation, general linear regression, and multivariate regression models.In the first trimester, greater maternal age was inversely correlated with IGF-I and IGF-II. In comparison with women carrying their first child, already parous women had higher IGF-I but lower hCG. Greater maternal weight and smoking were inversely correlated with hCG. No differences in hormone levels by child sex were observed.Our analyses indicated that potentially modifiable maternal characteristics (maternal weight and smoking) influence first-trimester pregnancy maternal hormone concentrations.

Highly penetrant, but rare, mutations in genes involved in double-strand break repair (i.e., BRCA1 and BRCA2 ) are associated with a risk for breast cancer of 40% to 65% by age 70 years ([1][1], [2][2]). Polymorphisms in other double-strand break repair genes are thought to contribute to the risk

Epidemiologic evidence suggests that a full-term pregnancy may affect maternal risk of breast cancer later in life. The objective of this cross-sectional study was to compare circulating levels of maternal hormones affecting breast differentiation (human chorionic gonadotropin and prolactin) and proliferation [α-fetoprotein, insulin-like growth factor I (IGF-I), and estradiol] between women at a low to moderate risk (Asians and Hispanics), as compared with women at a high risk for breast cancer (Caucasians and African-Americans). Between May 2002 and December 2004, a total of 586 pregnant women were approached during a routine prenatal visit. Among them, 450 women (206 Caucasian, 126 Asian, 88 Hispanic, and 30 African-American) met the inclusion criteria and signed the informed consent. Only singleton pregnancies were considered. Blood samples were drawn during the second trimester of pregnancy. Laboratory analyses were done using the IMMULITE 2000 immunoassay system. Gestational age standardized mean levels of estradiol, IGF-I, and prolactin were significantly higher in Hispanic women compared with Caucasian women. Mean concentration of IGF-I was significantly higher in African-American women compared with Caucasian and Asian women. No significant differences in pregnancy hormone levels were observed between Caucasian and Asian (predominantly second-generation Chinese) women in this study. Irrespective of ethnicity, women who had their first pregnancy had substantially higher mean levels of α-fetoprotein, human chorionic gonadotropin, estradiol, and prolactin compared with women who previously had at least one full-term pregnancy. These data suggest that circulating pregnancy hormone levels may explain some of the ethnic differences in breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(11):2123–30)

It has been suggested that phytoestrogens protect against hormone-dependent cancers. Lignans are the main class of phytoestrogens in Western diets. We conducted a prospective study of endometrial cancer and circulating levels of the main human lignan, enterolactone. The design was a case-control study nested within 3 prospective cohort studies, in New York, Sweden and Italy. Serum or plasma samples had been collected at enrollment and stored at -80 degrees C. A total of 153 cases, diagnosed a median of 5.3 years after blood donation, and 271 matched controls were included. No difference in circulating enterolactone was observed between cases (median, 19.2 nmol/L) and controls (18.5 nmol/L). Adjusting for body mass index, the odds ratio for the top tertile of enterolactone, as compared to the lowest was 1.2 (95% CI, 0.7-2.0; p for trend = 0.53). Lack of association was observed in both pre- and postmenopausal women. No correlation was observed between enterolactone and circulating estrogens or SHBG in healthy postmenopausal women. These results do not support a protective role of circulating lignans, in the range of levels observed, against endometrial cancer.

Purpose The aim of the study is to determine the reliability during a 2-year period of several newly developed iron-related assays to assess their potential for use in prospective epidemiologic studies. Methods We assessed the temporal reliability of several iron-related assays by using three serum samples collected at yearly intervals from 50 postmenopausal participants in a large prospective study. Results We observed high reliability coefficients for ferritin (0.78; 95% confidence interval [CI], 0.67–0.86), soluble transferrin receptor (sTfR; 0.79; 95% CI, 0.69–0.87), sTfR/ferritin ratio (0.74; 95% CI, 0.62–0.83), and hepcidin (0.89; 95% CI, 0.84–0.94). In a subset of 30 women, lower reliability was observed for serum iron (0.50; 95% CI, 0.29–0.70), unsaturated iron-binding capacity (0.55; 95% CI, 0.34–0.73), total iron-binding capacity (0.60; 95% CI, 0.40–0.76), and serum transferrin saturation rate (0.44; 95% CI, 0.22–0.65). The reliability of anti-5-hydroxymethyl-2′-deoxyuridine autoantibody titers, a biomarker of oxidized DNA damage, one of the mechanisms by which iron is thought to impact disease risk, was very high (0.97, 95% CI, 0.5–0.99). Conclusions Our results show that some newly developed iron-related assays could be useful tools to assess iron–disease associations in prospective cohorts that collect a single blood sample.

The "gonadotropin hypothesis" postulates that gonadotropin overstimulation of ovarian epithelium results in its increased proliferation and subsequent malignant transformation. To address this hypothesis, we assessed the association between prediagnostic serum levels of follicle-stimulating hormone (FSH) and the risk of epithelial ovarian cancer in postmenopausal women who were part of a case-control study nested within three prospective cohorts in New York City, Umeå, Sweden, and Milan, Italy. Case subjects were 88 women with primary invasive epithelial ovarian cancer diagnosed between 3 months and 13.1 years after the blood donation. Controls were 168 women who were free of cancer and matched the case on cohort, age, and enrollment date. Serum FSH was determined using a quantitative immunoradiometric assay. FSH concentrations were similar in women who subsequently received a diagnosis of epithelial ovarian cancer (median, 44.0 mIU/ml; range, 13.8-101.2) and in controls (median, 43.4 mIU/ml; range, 13.5-109.5; P = 0.17). Compared with women in the lowest third, women in the highest third of serum FSH were not at increased risk of epithelial ovarian cancer after an adjustment for potential confounders (odds ratio, 0.85; 95% confidence interval, 0.36-1.99). These observations provide no evidence for an association between circulating FSH and risk of epithelial ovarian cancer in postmenopausal women and do not appear to support the gonadotropin hypothesis of epithelial ovarian carcinogenesis.

We previously reported that having completed a full term pregnancy (FTP) confers specific gene expression patterns in the breast of healthy postmenopausal women [Belitskaya-Levy, I. et al. 2011, Peri, S. et al. 2012 and Russo, J. 2012]. In the present work, we report on gene expression differences in the breast of parous versus nulliparous healthy premenopausal women. Using Affymetrix Human Genome U133 Plus 2.0 microarrays, we analyzed the gene expression profile of breast tissue from 30 nulliparous (NP) and 79 parous (P) premenopausal volunteers between the ages of 30 and 47 years who were free of breast pathology. Because of the known short-term increase in breast cancer risk preceding the long-term protective effect of FTP, we also examined gene expression differences in P vs. NP women as a function of time since last FTP. Through multiple regression analysis, controlling for confounders, we found 416 probesets differentially expressed (fold-change ≥ 1.2 and false discovery rate < 10%) comparing all P vs. all NP, and/or, P women whose last FTP was less than 5 years before biopsy vs. all NP women. Among these, 352 probesets, representing 238 genes, were up-regulated, while 64 probesets, representing 48 genes, were down-regulated in parous compared to nulliparous breast. Of interest is that among the up-regulated genes, we observed three expression patterns: 1) transient: genes up-regulated after FTP but whose expression levels rapidly returned to nulliparous levels. These genes were mainly related to immune response (CCL5, CD48, IL7R); 2) long-term changing: genes up-regulated following FTP, whose expression levels decreased with increasing time since last FTP but did not return to nulliparous levels. These genes included genes related to immune response (CD38, CXCL10) and development (DKK3, LAMA2); 3) long-term constant: genes that remained up-regulated in parous compared to nulliparous breast, independent of time since last FTP. These genes were mainly involved in developmental processes (BHLHE22, FZD8, KRT5), cell differentiation (RASGRP1, DSC3) and chromatin remodeling (NAP1L2). This study shows that a FTP induces long-term expression changes in genes related to the processes of development, cell differentiation and chromatin remodeling as we also found in the parous postmenopausal breast. Additionally, the transiently activated genes related to immune response during the first five years after FTP may play a role in the short-term increase of breast cancer risk following FTP. A better understanding of the molecular effects of parity on the breast may help the development of novel strategies for preventing breast cancer. (This work was supported by Avon Foundation for Women Breast Cancer Research Program grant 02-2010-117 and by NIH core grant CA06927 to Fox Chase Cancer Center). Citation Format: Julia Santucci-Pereira, Anne Zeleniuch-Jacquotte, Yelena Afanasyeva, Hua Zhong, Eric A. Ross, Michael Slifker, Suraj Peri, Ricardo López de Cicco, Yubo Zhai, Irma H. Russo, Theresa Nguyen, Fathima Sheriff, Alan A. Arslan, Pal Bordas, Per Lenner, Janet Åhman, Anna-Stina L. Eriksson, Robert Johansson, Göran Hallmans, Paolo Toniolo, Jose Russo. Gene expression profile induced by pregnancy in the breast of premenopausal women. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2360. doi:10.1158/1538-7445.AM2014-2360

s / Annals of Epidemiology 24 (2014) 682e702 687 Conclusions: Men who serve on nuclear-powered submarines are selected to be healthier than the general public and have lower mortality rates for nearly all causes of death. The excess suicide among menwith short duration of service on nuclear-powered submarines is notable. The increasing trend of mortality from ischemic heart disease with duration of submarine duty may reflect, in part, an effect of environmental tobacco smoke, although confounding by individual tobacco smoking cannot be excluded. P19. Low Dose Ionizing Radiation and Cancer Mortality Among Enlisted Men Stationed on Nuclear-Powered Submarines in the United States Navy George Friedman-Jimenez MD, DrPH, Ikuko Kato MD, PhD, Yelena Afanasyeva MS, Roy E. Shore PhD, DrPH. NYU School of Medicine Purpose: Men stationed on nuclear-powered submarines are occupationally exposed to external ionizing radiation at very low levels. Radiation dose for each individual is closely monitored. Little is known about the cancer mortality experience of this group. Methods: This historical cohort study followed 85,033 enlisted men who served on nuclear-powered submarines in the U.S. Navy between 1969 and 1982 to determine patterns of cancer mortality. Occupational radiation doses were measured by badge dosimeters for each individual for all periods of Navy service potentially involving radiation exposure. Deaths were ascertained through searches of multiple national mortality databases. Within-cohort dose-response relationships were estimated using linear and loglinear Poisson regression models to adjust for multiple confounders. Results: A total of 584 cancer deaths occurred in 1,805,581 person years (up to 27 years) of follow-up. The mean occupational radiation dose received while in the Navy was 5.7 millisieverts (mSv). Excess Relative Risks per 10 mSv and 95% Confidence Intervals are 0.052(-0.03,0.18) for all solid cancers, 0.003(-0.29,0.30) for leukemias excluding chronic lymphocytic leukemia, 0.052(-0.07,0.17) for cancers previously associated with smoking, and 0.012 (-0.10,0.12) for cancers not previously associated with smoking. The 95 percent Confidence Intervals include the null value for all cause-of-death categories analyzed. Conclusions: The Excess Relative Risk and Relative Risk point estimates for most cancers are similar to those reported in previous published studies, however, the 95% Confidence Intervals are wide. Confounding of these estimates by tobacco smoking cannot be excluded for cancers that are associated with smoking. P20. Association Between Work-Related Discrimination and Low Back Pain Among Korean Employees: Role of Labor Union Status as an Effect Modifier Hyoju Sung, Seung-Sup Kim ScD. Korea University Purpose: To investigate the association between work-related discrimination (WRD) and low back pain (LBP) and to explore the role of labor union as an effect modifier. Methods: We analyzed 29,608 employees from the 3rd wave of Korean Working Condition Survey (2011). WRDs from five different reasons were assessed using questions: “Have you ever experienced work-related discrimination during the past 12 months based on your: (1) age, (2) education, (3) birth region, (4) sex, and (5) employment status?” Labor union status was assessed in three categories: (1) employees in a workplace without labor union, (2) employees did not have a union membership in a workplace with labor union, and (3) employees had union membership. Results: In a workplace without labor union, LBP was significantly associated with WRD based on age (OR: 2.08, 95% CI: 1.69, 2.55), education (OR: 1.31, 95% CI: 1.04, 1.64), birth region (OR: 1.44, 95% CI: 1.02, 2.05), sex (OR: 2.89, 95% CI: 2.18, 3.84), and employment status (OR: 2.03, 95% CI: 1.64, 2.51) among female employees after controlling covariates including self-reported ergonomic strains. Similar significant associations were observed among male employees except WRD based on birth region (OR: 1.37, 95% CI: 0.95, 1.97). However, no significant association was observed for both male and female employee in a workplace with labor union regardless of whether or not employee had union membership except sex discrimination among female employees with union membership (OR: 3.77, 95% CI: 1.45, 9.83). Conclusions: WRD was associated with LBP only in workplaces without labor union. P21. Police Stress and Posttraumatic Stress Disorder: The Role of Coping Claudia C. Ma MS, MPH, Michael E. Andrew PhD, Anna Mnatsakanova MS, Tara A. Hartley PhD, Desta Fekedulegn PhD, Erin McCanlies PhD, Ja K. Gu MSPH, John M. Violanti PhD, Cecil M. Burchfiel PhD. NIOSH Purpose: We investigated the cross-sectional associations between police stress and posttraumatic stress disorder (PTSD) symptoms, and the role of coping. Methods: A total score from PTSD Checklist-Civilian Version (PCL-C), a 17item self-report questionnaire, was used for PTSD assessment in 342 officers. Job stress was assessed using the 60-item Spielberger Police Stress Survey. Mean stress indices were computed by averaging the products of the stress rating (0-100) and frequency (events occurring in the previous year to the date of examination) for total and stress subscales including administrative pressure, physical/psychological threats, and lack of support. Active and passive coping scores were derived from the Brief COPE. Simple and multiple linear regression models were used in the analyses. Results: PTSD symptoms were positively associated with total stress (B1⁄40.016, p 75th percentiles). Relative risk (RR) and 95% confidence limits (CI) were calculated using generalized linear models adjusting for site, age, race, and diabetes. Interactions between pollutants and maternal asthma were explored. Results: Preeclampsia was not associated with air pollutants in nulliparas except for a protective effect of ozone observed for themid-range of exposure (25th -75th percentile) compared to the lowest quartile (reference), RR1⁄40.9907, 95% CI: 0.9858, 0.9956. Asthma was associated with a small increased risk (w1%) in all models. Significant interactions with maternal asthmawere observed for PM10 andNOx. Pollutant effect sizes for asthmatics were often greater but not significantly different from non-asthmatics. Conclusion: Air pollutants did not appear to increase preeclampsia beyond the risk associated with nulliparity. Asthma independently increased risk but without substantive interaction with exposure. P23. Disaster-Related Exposures and Health Effects Among U.S. Coast Guard Responders to Hurricanes Katrina and Rita: A Cross-Sectional Study Jennifer Rusiecki PhD, Dana L. Thomas MD, MPH, Ligong Chen MD, MS, Renee Funk DVM, MPH&TM, Jodi McKibben PhD, Melburn R. Dayton MPH. Uniformed Services University