[show abstract][hide abstract] ABSTRACT: Inter-individual variation in DNA repair capacity is thought to modulate breast cancer risk. The phenotypic mutagen sensitivity assay (MSA) measures DNA strand breaks in lymphocytes; women with familial and sporadic breast cancers have a higher mean number of breaks per cell (MBPC) than women without breast cancer. Here, we explore the relationships between the MSA and the Rad51 gene, which encodes a DNA repair enzyme that interacts with BRCA1 and BRCA2, in BRCA1 mutation carriers and women with sporadic breast cancer.
Peripheral blood lymphoblasts from women with known BRCA1 mutations underwent the MSA (n = 138 among 20 families). BRCA1 and Rad51 genotyping and sequencing were performed to identify SNPs and haplotypes associated with the MSA. Positive associations from the study in high-risk families were subsequently examined in a population-based case-control study of breast cancer (n = 1170 cases and 2115 controls).
Breast cancer diagnosis was significantly associated with the MSA among women from BRCA1 families (OR = 3.2 95%CI: 1.5-6.7; p = 0.004). The Rad51 5'UTR 135 C>G genotype (OR = 3.64; 95% CI: 1.38, 9.54; p = 0.02), one BRCA1 haplotype (p = 0.03) and in a polygenic model, the E1038G and Q356R BRCA1 SNPs were significantly associated with MBPC (p = 0.009 and 0.002, respectively). The Rad51 5'UTR 135C genotype was not associated with breast cancer risk in the population-based study.
Mutagen sensitivity might be a useful biomarker of penetrance among women with BRCA1 mutations because the MSA phenotype is partially explained by genetic variants in BRCA1 and Rad51.
[show abstract][hide abstract] ABSTRACT: The mechanism for the observed association of alcohol consumption breast cancer risk is not known; understanding that mechanism could improve understanding of breast carcinogenesis and optimize prevention strategies. Alcohol may impact breast malignancies or tumor progression by altering DNA methylation. We examined promoter methylation of three genes, the E-cadherin, p16, and retinoic acid-binding receptor-β2 (RAR-β2) genes in archived breast tumor tissues from participants in a population-based case-control study. Real time methylation-specific PCR was performed on 803 paraffin-embedded samples, and lifetime alcohol consumption was queried. Unordered polytomous and unconditional logistic regression were used to derive adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RAR-β2 methylation was not associated with drinking. Among premenopausal women, alcohol consumption was also not associated with promoter methylation for E-cadherin and p16 genes. In case-case comparisons of postmenopausal breast cancer, compared with lifetime never drinkers, promoter methylation likelihood was increased for higher alcohol intake for E-cadherin (OR=2.39; 95% CI, 1.15-4.96), in particular for those with estrogen receptor-negative tumors (OR=4.13; 95% CI, 1.16-14.72), and decreased for p16 (OR=0.52; 95% CI, 0.29-0.92). There were indications that the association with p16 was stronger for drinking at younger ages. Methylation was also associated with drinking intensity independent of total consumption for both genes. We found alcohol consumption was associated with DNA methylation in postmenopausal breast tumors, suggesting that the association of alcohol and breast cancer may be related, at least in part, to altered methylation, and may differ by drinking pattern.
[show abstract][hide abstract] ABSTRACT: Birth weight is emerging as a potentially important risk factor for several chronic diseases with adult onset, including breast cancer. Because participant recall is frequently used to gather data on early life exposures, it is essential that the accuracy of recall be assessed and validated. Self-reported birth weights and birth certificate weights were compared in women aged 35–51 years from the Western New York Exposures and Breast Cancer (WEB) Study, a population-based case–control study. A total of 180 participants had both birth certificate and interview data on birth weight. Participants reported birth weight to one of six categories (<5, 5–5.5, 5.6–7, 7.1–8.5, 8.6–10 and >10 lbs). The Spearman correlation for self-reported and birth certificate weights was 0.67. Sixty percent of participants reported weights with exact agreement with birth certificate; unweighted and weighted kappas (κ) were 0.39 and 0.68, respectively. Spearman correlations were similar for cases (0.67) and controls (0.68). Controls exhibited a significantly higher unweighted κ (0.51) than cases (0.27; P = 0.03), but weighted κ were not statistically different [controls, 0.73; cases, 0.64 (P = 0.32)]. Demographic and anthropometric characteristics were not different between participants who underreported, overreported, or correctly reported their birth weight for either cases or controls. Overall, the level of agreement for report of birth weight and actual birth weight was fair to moderate.
Journal of Developmental Origins of Health and Disease. 03/2010; 1(02):106 - 113.
[show abstract][hide abstract] ABSTRACT: Aberrant promoter methylation is recognized as an important feature of breast carcinogenesis. We hypothesized that genetic variation of genes for methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR), two critical enzymes in the one-carbon metabolism, may alter DNA methylation levels and thus influence DNA methylation in breast cancer. We evaluated case-control association of MTHFR C677T, A1298C, and MTR A2756G polymorphisms for cases strata-defined by promoter methylation status for each of three genes, E-cadherin, p16, and RAR-beta2 in breast cancer; in addition, we evaluated case-case comparisons of the likelihood of promoter methylation in relation to genotypes using a population-based case-control study conducted in Western New York State. Methylation was evaluated with real-time methylation-specific PCRs for 803 paraffin-embedded breast tumor tissues from women with primary, incident breast cancer. We applied unordered polytomous regression and unconditional logistic regression to derive adjusted odds ratios and 95% confidence intervals. We did not find any association of MTHFR and MTR polymorphisms with breast cancer risk stratified by methylation status nor between polymorphisms and likelihood of promoter methylation of any of the genes. There was no evidence of difference within strata defined by menopausal status, estrogen receptor status, folate intake, and lifetime alcohol consumption. Overall, we found no evidence that these common polymorphisms of the MTHFR and MTR genes are associated with promoter methylation of E-cadherin, p16, and RAR-beta2 genes in breast cancer.
[show abstract][hide abstract] ABSTRACT: Aberrant DNA hypermethylation of gene promoter regions has been increasingly recognized as a common molecular alteration in
carcinogenesis. We evaluated the association between major clinicopathological features and hypermethylation of genes in tumors
among 803 incidence breast cancer cases from a large population-based case–control study conducted in Western New York State.
DNA samples were isolated from archive paraffin embedded tumor tissue and were analyzed for hypermethylation status of the
E-cadherin, p16, and RAR-β
genes using real time methylation-specific polymerase chain reaction. The frequencies of hypermethylation were 20.0% for
E-cadherin, 25.9% for p16, and 27.5% for RAR-β
genes. For postmenopausal women, hypermethylation of E-cadherin tended to be more likely in progesterone receptor (PR) negative than in PR-positive tumors (odds ratio (OR), 1.41; 95% confidence
interval (CI), 0.91–2.18). Hypermethylation of p16 tended to be more frequent among estrogen receptor (ER) negative cases than ER-positive cases (OR, 1.51; 95% CI, 1.01–2.32).
Hypermethylation of RAR-β
gene was inversely associated with histological and nuclear grade of breast cancer.
Breast Cancer Research and Treatment 01/2009; 114(3):559-568. · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Catalase, a ubiquitous heme enzyme, catalyzes conversion of hydrogen peroxide to water and molecular oxygen, protecting cells from oxidative stress. A C/T polymorphism in the promoter region of the CAT gene (rs1001179) affects transcriptional activity and RBC catalase levels. Oxidative stress may explain the observed increased postmenopausal breast cancer risk associated with hormone replacement therapy (HRT). We examined CAT genotype, HRT, and postmenopausal breast cancer risk in the Western New York Exposures and Breast Cancer case-control study. Cases (n = 616) were women with primary, incident, pathologically confirmed breast cancer. Randomly selected controls (n = 1,082) were frequency matched to cases on age and race. Genotype was assayed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) adjusted for potential confounders. CAT genotype alone was not associated with breast cancer risk. Ever use of HRT was associated with increased risk (OR, 1.39; 95% CI, 1.11-1.75). The increase with ever use was more pronounced among those with variant CT or TT CAT genotype (OR, 1.88; 95% CI, 1.29-2.75) than among those with CC (OR, 1.15; 95% CI, 0.86-1.54). Similarly, risk associated with >or=5 years of HRT use was greater among those with at least one variant T allele (OR, 2.32; 95% CI, 1.50-3.59). Increased risk was limited to estrogen receptor-positive tumors. Our findings suggest that CAT genotype modifies the effect of HRT use on breast cancer risk and that HRT may affect risk by affecting oxidative stress.
[show abstract][hide abstract] ABSTRACT: We previously reported that total suspended particulates exposure (a measure of air pollution) at the time of birth was related to increased postmenopausal breast cancer risk. In this study, we examined breast cancer risk in relation to exposure to air pollution from traffic emissions throughout life.
We conducted a case-control study of breast cancer. Participants were women, aged 35-79, residents of Erie and Niagara Counties. Cases had incident, primary, histologically confirmed breast cancer. Controls were randomly selected from the population, frequency-matched on age and race. Using lifetime residential histories, exposure to traffic emissions was modeled for each woman using her residence as a proxy. Estimates were calculated for residence at menarche, her first birth, and 20 and 10 years before interview. Unconditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI).
Higher exposure to traffic emissions at the time of menarche was associated with increased risk of premenopausal breast cancer (OR 2.05, 95% CI 0.92-4.54, p for trend 0.03); and at the time of a woman's first birth for postmenopausal breast cancer (OR 2.57, 95% CI 1.16-5.69, p for trend 0.19). Statistically significant associations were limited to lifetime non-smokers; there was a significant interaction between exposure at time of menarche and smoking for premenopausal women.
Our findings add to accumulating evidence that early life exposures impact breast cancer risk and provide indication of potential importance of traffic emissions in risk of breast cancer.
Cancer Causes and Control 12/2007; 18(9):947-55. · 3.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: While there are quite consistent data regarding associations of body weight and postmenopausal breast cancer, there are now accumulating data that would indicate that weight gain in adult life is more predictive of risk than absolute body weight. There is, however, little known about the relative impact of timing of weight gain in adult life as well as other characteristics of the weight and breast cancer association that might provide insight into the mechanism of the observation. We conducted a population-based case control study of breast cancer (1996-2001), the Western New York Exposures and Breast Cancer Study. Included were 1,166 women with primary, histologically confirmed, incident breast cancer and 2,105 controls frequency-matched on age, race and county of residence. Unconditional logistic regression was used to estimate odds ratios and 95% confidence intervals. We found increased risk of breast cancer associated with lifetime adult weight gain among post- but not premenopausal women, and there was a 4% increase in risk for each 5 kg increase in adult weight. Further there was a tendency toward a stronger association for those with higher waist circumference and those with positive estrogen or progesterone status, and who had never used HRT. We also found an association with risk for weight gain since first pregnancy and for weight gain between the time of the first pregnancy and menopause, independent of body mass index and lifetime adult weight gain. Our results suggest that there are time periods of weight gain that have greater impact on risk, and that central body fat, receptor status and hormone replacement therapy may all affect the observed association.
International Journal of Cancer 01/2007; 119(12):2931-7. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: We examined the association of dietary lignan intake with estrogen receptor negative (ER-) and ER positive (ER+) breast cancer risk in a breast cancer case-control study. Among premenopausal women only, there was a reduced risk of ER- breast cancer for those in the highest compared to the lowest quartile of lignan intake suggesting that the observed negative association of lignans with breast cancer may be limited to ER- tumors.
Breast Cancer Research and Treatment 11/2006; 99(3):309-11. · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: This study focused on geographic clustering of breast cancer based on residence in early life and identified spatio-temporal clustering of cases and controls.
Data were drawn from the WEB study (Western New York Exposures and Breast Cancer Study), a population-based case-control study of incident, pathologically confirmed breast cancer (1996-2001) in Erie and Niagara counties. Controls were frequency-matched to cases on age, race, and county of residence. All cases and controls used in the study provided lifetime residential histories. The k-function difference between cases and controls was used to identify spatial clustering patterns of residence in early life.
We found that the evidence for clustered residences at birth and at menarche was stronger than that for first birth or other time periods in adult life. Residences for pre-menopausal cases were more clustered than for controls at the time of birth and menarche. We also identified the size and geographic location of birth and menarche clusters in the study area, and found increased breast cancer risk for pre-menopausal women whose residence was within the cluster compared to those living elsewhere at the time of birth.
This study provides evidence that early environmental exposures may be related to breast cancer risk, especially for pre-menopausal women.
Cancer Causes and Control 12/2004; 15(9):921-9. · 3.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Lignans are plant compounds metabolized in the mammalian gut to produce the phytoestrogens enterolactone and enterodiol. Because estrogens have been linked to breast cancer etiology, lignans could affect breast cancer risk through modulation of endogenous estrogen metabolism or competitive inhibition with estrogen receptors. We examined breast cancer risk and dietary lignan intake in a population-based case-control study of 1,122 women with primary, incident, histologically confirmed breast cancer and 2,036 controls frequency matched to cases on age and county of residence as part of the Western New York Exposures and Breast Cancer (WEB) Study. Diet was assessed with a self-administered 104-item food frequency questionnaire and other relevant data were collected by detailed in-person interviews. Lignans were expressed as the sum of the dietary precursors secoisolariciresinol and matairesinol. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression, adjusting for age, total energy and other breast cancer risk factors. Premenopausal women in the highest quartile of dietary lignan intake had reduced breast cancer risk (OR = 0.66; 95% CI = 0.44-0.98). No association was observed between lignan intakes and postmenopausal breast cancer. Our results suggest that dietary lignans may be important in the etiology of breast cancer, particularly among premenopausal women.
International Journal of Cancer 10/2004; 111(3):440-3. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although there is clear evidence that smoking is the primary risk factor for lung cancer, not all variation in disease risk is understood. There is some evidence that alcohol may contribute to risk. We examined lifetime and recent (12-24 mo previous) alcohol consumption in relation to risk of lung cancer in a case-control study in western New York. In addition we examined the alcohol dehydrogenase 3 (ADH3) genotype in relation to lung cancer risk; ADH3 is rate limiting in alcohol metabolism and has a functional polymorphism. We interviewed incident, primary, histologically confirmed lung cancer cases (n = 111) in two counties. Controls were randomly selected from among those residing in the counties, frequency-matched to cases for age and race (n = 1546). Lifetime and recent total alcohol and beverage-specific alcohol consumption as well as relevant confounders were assessed by interview. ADH3 genotype was evaluated by a PCR-restriction fragment length polymorphism assay. Because of the small sample size, power was limited and CI were wide. Residual confounding by smoking remains a concern. Although we found a significant trend for increased risk for beer consumption in the recent period (odds ratio 1.67, 95% CI 0.96-2.92, P for trend = 0.05), chance cannot be ruled out as an explanation. We found no evidence of risk related to lifetime alcohol consumption nor evidence that alcohol dehydrogenase genotype modifies risk related to alcohol and lung cancer.
Journal of Nutrition 12/2003; 133(11):3619-24. · 4.20 Impact Factor