Genetic variation in multiple biologic pathways, flavonoid intake, and breast cancer.

Purpose: We previously reported an inverse association between flavonoid intake and breast cancer incidence, which has been confirmed by others, but no studies have considered simultaneously potential interactions of flavonoids with multiple genetic polymorphisms involved in biologically relevant pathways (oxidative stress, carcinogen metabolism, DNA repair, and one-carbon metabolism).

Methods: To estimate interaction effects between flavonoids and 13 polymorphisms in these four pathways on breast cancer risk, we used population-based data (n = 875 cases and 903 controls) and several statistical approaches, including conventional logistic regression and semi-Bayesian hierarchical modeling (incorporating prior information on the possible biologic functions of genes), which also provides biologic pathway-specific effect estimates.

Results: Compared to the standard multivariate model, the results from the hierarchical model indicate that gene-by-flavonoid interaction estimates are attenuated, but more precise.

Parity and breastfeeding among African-American women: differential effects on breast cancer risk by estrogen receptor status in the Women's Circle of Health Study.

Purpose: It has long been held that parity reduces risk of breast cancer. However, accumulating evidence indicates that the effects of parity, as well as breastfeeding, may vary according to estrogen receptor (ER) status. We evaluated these associations in a case-control study among African-American women in New York City and New Jersey.

Body fatness and breast cancer risk in women of African ancestry.

Background: Obesity has been shown to be inversely associated with breast cancer risk in premenopausal women, while increasing risk in postmenopausal women. However, the current evidence is largely based on studies in Caucasian populations. Associations in women of African ancestry (AA), who have a higher prevalence of obesity, have been evaluated in few studies and results suggest different effects.

Body size in early life and breast cancer risk in African American and European American women.

Purpose: There is growing evidence that body size in early life influences lifetime breast cancer risk, but little is known for African American (AA) women.

Methods: We evaluated body size during childhood and young adulthood and breast cancer risk among 1,751 cases [979 AA and 772 European American (EA)] and 1,673 controls (958 AA and 715 EA) in the Women's Circle of Health Study. Odds ratio (OR) and 95 % confidence intervals (CI) were computed using logistic regression models while adjusting for potential covariates.

Racial disparities in red meat and poultry intake and breast cancer risk.

Purpose: Research on the role of red meat and poultry consumption in breast carcinogenesis is inconclusive, but the evidence in African-American (AA) women is lacking. The association between consuming meat and breast cancer risk was examined in the Women's Circle of Health Study involving 803 AA cases, 889 AA controls, 755 Caucasian cases, and 701 Caucasian controls.

Methods: Dietary information was collected using a Food Frequency Questionnaire.

Association of prediagnostic physical activity with survival following breast cancer diagnosis: influence of TP53 mutation status.

Purpose: Physical activity both before and after breast cancer diagnosis has been associated with improved survival. However, it is not clear whether this association differs by molecular features of the tumor or by recency of the physical activity to the time of diagnosis.

Methods: We examined the association of prediagnostic physical activity with survival in a cohort of 1,170 women with primary, incident, and histologically confirmed breast cancer, examining tumor molecular subtypes.

Genetic variants in microRNAs and breast cancer risk in African American and European American women.

MicroRNAs (miRNAs) are an integral part of the post-transcriptional machinery of gene expression and have been implicated in the carcinogenic cascade. Single nucleotide polymorphisms (SNPs) in miRNAs and risk of breast cancer have been evaluated in populations of European or Asian ancestry, but not among women of African ancestry. Here we examined 145 SNPs in six miRNA processing genes and in 78 miRNAs which target genes known to be important in breast cancer among 906 African American (AA) and 653 European American (EA) cases and controls enrolled in the Women's Circle of Health Study.

CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations.

The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.

Does alcohol increase breast cancer risk in African-American women? Findings from a case-control study.

Background: Alcohol is an important risk factor for breast cancer in Caucasian women, but the evidence in African-American (AA) women is limited and results are inconclusive.

Methods: Associations between recent and lifetime drinking and breast cancer risk were evaluated in a large sample of AA women from a case-control study in New York and New Jersey. Multivariable logistic regression models provided odds ratios (ORs) and 95% confidence intervals (CIs).

Germline genetic variants in ABCB1, ABCC1 and ALDH1A1, and risk of hematological and gastrointestinal toxicities in a SWOG Phase III trial S0221 for breast cancer.

Hematological and gastrointestinal toxicities are common among patients treated with cyclophosphamide and doxorubicin for breast cancer. To examine whether single-nucleotide polymorphisms (SNPs) in key pharmacokinetic genes were associated with risk of hematological or gastrointestinal toxicity, we analyzed 78 SNPs in ABCB1, ABCC1 and ALDH1A1 in 882 breast cancer patients enrolled in the SWOG trial S0221 and treated with cyclophosphamide and doxorubicin. A two-SNP haplotype in ALDH1A1 was associated with an increased risk of grade 3 and 4 hematological toxicity (odds ratio=1.

Associations of dietary folate, Vitamins B6 and B12 and methionine intake with risk of breast cancer among African American and European American women.

African American (AA) women are more likely than European American (EA) women to be diagnosed with breast cancer at younger ages and to develop poor prognosis tumors. However, these racial differences are largely unexplained. Folate and other methyl-group nutrients may be related to breast carcinogenesis, but few studies have examined these associations in AA populations.

Cytokine and cytokine receptor genes of the adaptive immune response are differentially associated with breast cancer risk in American women of African and European ancestry.

Disparities in breast cancer biology are evident between American women of African ancestry (AA) and European ancestry (EA) and may be due, in part, to differences in immune function. To assess the potential role of constitutional host immunity on breast carcinogenesis, we tested associations between breast cancer risk and 47 single nucleotide polymorphisms (SNPs) in 26 cytokine-related genes of the adaptive immune system using 650 EA (n = 335 cases) and 864 AA (n = 458 cases) women from the Women's Circle of Health Study (WCHS). With additional participant accrual to the WCHS, promising SNPs from the initial analysis were evaluated in a larger sample size (1,307 EAs and 1,365 AAs).

Innate immunity pathways and breast cancer Risk in African American and European-American women in the Women's Circle of Health Study (WCHS).

African American (AA) women are more likely than European American (EA) women to be diagnosed with early, aggressive breast cancer. Possible differences in innate immune pathways (e.g.

Genome-wide association of body fat distribution in African ancestry populations suggests new loci.

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively.

Assessment of the Prognostic Value of Two Common Variants of BRCA1 and BRCA2 Genes in Ovarian Cancer Patients Treated with Cisplatin and Paclitaxel: A Gynecologic Oncology Group Study.

Purpose: BRCA1/BRCA2 germline mutations appear to enhance the platinum-sensitivity, but little is known about the prognostic relevance of polymorphisms in BRCA1/BRCA2 in epithelial ovarian cancer (EOC). This study evaluated whether common variants of BRCA1/BRCA2 are associated with progression-free survival (PFS) and overall survival (OS) in patients with advanced stage sporadic EOC.

Experimental Design: The allelic frequency of BRCA1 (2612C > T, P871L-rs799917) and BRCA2 (114A > C, N372H-rs144848) were determined in normal blood DNA from women in Gynecologic Oncology Group protocol #172 phase III trial with optimally resected stage III EOC treated with intraperitoneal or intravenous cisplatin and paclitaxel (C + P).

Case-only analyses of the associations between polymorphisms in the metastasis-modifying genes BRMS1 and SIPA1 and breast tumor characteristics, lymph node metastasis, and survival.

Lymph node metastases and tumor characteristics predict breast cancer prognosis but correlate imperfectly with likelihood of metastatic relapse. Discovery of genetic polymorphisms affecting metastasis may improve identification of patients requiring aggressive adjuvant therapy to prevent recurrence. We investigated associations between several variants in the BRMS1 and SIPA1 metastasis-modifying genes and lymph node metastases, tumor subtype and grade, recurrence, disease-free survival, and overall survival.

Pregnancy-related characteristics and breast cancer risk.

Breast tissues undergo extensive physiologic changes during pregnancy, which may affect breast carcinogenesis. Gestational hypertension, preeclampsia/eclampsia, gestational diabetes, pregnancy weight gain, and nausea and vomiting (N&V) during pregnancy may be indicative of altered hormonal and metabolic profiles and could impact breast cancer risk. Here, we examined associations between these characteristics of a woman's pregnancy and her subsequent breast cancer risk.

Rethinking sources of representative controls for the conduct of case-control studies in minority populations.

Background: Recruitment of controls remains a challenge in case-control studies and particularly in studies involving minority populations.

Methods: We compared characteristics of controls recruited through random digit dialing (RDD) to those of community controls enrolled through churches, health events and other outreach sources among women of African ancestry (AA) participating in the Women's Circle of Health Study, a case-control study of breast cancer. Odds ratios and 95% confidence intervals were also computed using unconditional logistic regression to evaluate the impact of including the community controls for selected variables relevant to breast cancer and for which there were significant differences in distribution between the two control groups.

Pretreatment levels of circulating Th1 and Th2 cytokines, and their ratios, are associated with ER-negative and triple negative breast cancers.

Immune signatures in breast tumors differ by estrogen receptor (ER) status. The purpose of this study was to assess associations between ER phenotypes and circulating levels of cytokines that co-ordinate cell-mediated [T-helper type 1 (Th1)] and humoral [T-helper type 2 (Th2)] immunity. We conducted a case-case comparison of 523 women with newly diagnosed breast cancer to evaluate associations between 27 circulating cytokines, measured using Luminex XMap technology, and breast cancer phenotypes [ER(-) vs.

Genome-wide association study of age at menarche in African-American women.

African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1).

A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry.

Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers.

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element.

Exposures in early life: associations with DNA promoter methylation in breast tumors.

There is evidence that epigenetic changes occur early in breast carcinogenesis. We hypothesized that early-life exposures associated with breast cancer would be associated with epigenetic alterations in breast tumors. In particular, we examined DNA methylation patterns in breast tumors in association with several early-life exposures in a population-based case-control study.

Serum phospholipid fatty acids, genetic variation in myeloperoxidase, and prostate cancer risk in heavy smokers: a gene-nutrient interaction in the carotene and retinol efficacy trial.

The authors investigated associations of serum phospholipid n-3 and n-6 polyunsaturated fatty acids (PUFAs) and trans-fatty acids with prostate cancer risk, and whether myeloperoxidase G-463A (rs2333227) modified the associations in the Carotene and Retinol Efficacy Trial (CARET) (Seattle, Washington; Irvine, California; New Haven, Connecticut; San Francisco, California; Baltimore, Maryland; and Portland, Oregon, 1985-2003). Prerandomization sera were assayed for fatty acids among 641 men with incident prostate cancer (368 nonaggressive and 273 aggressive (stage III/IV or Gleason score ≥7)) and 1,398 controls. Overall, dihomo-γ-linolenic (quartiles 4 vs.