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To better understand breast cancer etiology and progression, we explored the association between promoter methylation status of three breast cancer-related genes (BRCA1, APC, and p16) and survival in a large cohort of women with breast cancer. About 800 archived tumor tissues were collected from women diagnosed with a first primary invasive or in situ breast cancer in 1996-1997. The vital status of the participants was followed through the end of year 2005 with a mean follow-up time of 8.0 years. Promoter methylation was assessed by methylation-specific PCR (for BRCA1) and MethyLight (for APC and p16). The association of promoter methylation and breast cancer mortality was evaluated by Cox-proportional hazards models. Methylated promoters were found in 59.0, 48.4, and 3.6% of the tumor samples for BRCA1, APC, and p16, respectively. Breast cancer-specific mortality was strongly associated with promoter methylation of p16 [HR and 95% CI: 3.53 (1.83-6.78)], whereas the associations with of BRCA1 and APC were less pronounced [HR and 95% CI: 1.81 (1.18-2.78) and 1.46 (0.98-2.17), respectively]. Similar associations were observed with all-cause mortality. As the number of methylated genes increased, the risk of breast cancer-specific mortality also increased in a dose-dependent manner (P, trend = 0.01). Importantly, even with our results stratified by hormone receptor status, promoter methylation of the three genes remained predictive of mortality. Our results suggest that promoter methylation could be promising epigenetic markers to be considered for breast cancer survival.

BACKGROUND. Although many patients take antioxidant dietary supplements during breast cancer treatment, the benefits of such supplementation are unproven. The authors of this report analyzed the prevalence of and factors associated with antioxidant supplement use during breast cancer (BC) treatment among women who participated in the Long Island Breast Cancer Study Project. METHODS. From 2002 through 2004, women with BC who had participated a case-control study from 1996 to 1997 were invited to participate in a follow-up interview. Antioxidant supplement use was defined as any self-reported intake of supplemental vitamin C, vitamin E, β-carotene, or selenium in individual supplements or multivitamins. RESULTS. Follow-up interview participants were younger, more predominantly white, and of higher socioeconomic status than women who did not respond. Among 764 participants who completed the follow-up interview, 663 (86.8%) reported receiving adjuvant treatment for their BC. Of those 663 women, 401 (60.5%) reported using antioxidants during adjuvant treatment: One hundred twenty of 310 women (38.7%) used antioxidants during chemotherapy, 196 of 464 women (42.2%) used them during radiation, and 286 of 462 women (61.9%) used them during tamoxifen therapy. Of 401 antioxidant users, 278 women (69.3%) used high doses (doses higher than those contained in a Centrum multivitamin). The factors that were associated with high antioxidant supplement use during treatment were higher fruit and vegetable intake at diagnosis (relative risk [RR], 1.71; 95% confidence interval [CI], 1.13-2.59), tamoxifen use (RR, 3.66; 95% CI, 2.32-5.78), ever using herbal products (RR, 3.49; 95% CI, 2.26-5.38), and ever engaging in mind-body practices (RR, 1.72; 95% CI, 1.13-2.64). CONCLUSIONS. Given the common use of antioxidant supplements during BC treatment, often at high doses and in conjunction with other complementary therapies, future research should address the effects of antioxidant supplementation on BC outcomes. Cancer 2009. © 2009 American Cancer Society.

Several epidemiologic studies have reported a positive association between breast cancer risk and high intake of sweets, which may be due to an insulin-related mechanism. We investigated this association in a population-based case-control study of 1,434 cases and 1,440 controls from Long Island, NY. Shortly after diagnosis, subjects were interviewed in-person to assess potential breast cancer risk factors, and self-completed a modified Block food frequency questionnaire, which included 11 items pertaining to consumption of sweets (sweet beverages, added sugars, and various desserts) in the previous year. Using unconditional logistic regression models, we estimated the association between consumption of sweets and breast cancer. Consumption of a food grouping that included dessert foods, sweet beverages, and added sugars was positively associated with breast cancer risk [adjusted odds ratio (OR) comparing the highest to the lowest quartile: 1.27, 95% confidence interval (CI): 1.00-1.61]. The OR was slightly higher when only dessert foods were considered (OR: 1.55, 95% CI: 1.23-1.96). The association with desserts was stronger among pre-menopausal women (OR: 2.00, 95% CI: 1.32-3.04) than post-menopausal women (OR: 1.40, 95% CI: 1.07-1.83), although the interaction with menopause was not statistically significant. Our study indicates that frequent consumption of sweets, particularly desserts, may be associated with an increased risk of breast cancer. These results are consistent with other studies that implicate insulin-related factors in breast carcinogenesis.

Dichlorodiphenyldichloroethane (DDE) and polychlorinated biphenyls (PCB) are widespread environmental contaminants that have been postulated to increase the risk of diseases such as non–Hodgkin's lymphoma, breast cancer, as well as lead to early menopause. Studies assessing the effect of organochlorine exposure often can only measure organochlorine levels once, such as at study enrollment, which may not be an etiologically relevant time period. We assessed the temporal changes in DDE and PCBs and the predictors of those changes using interview data and DDE and PCB measures collected from 123 women who were enrolled in a baseline study from 1978 to 1982 and followed up in 2003 to 2004. Baseline and follow-up organochlorine levels were compared using Spearman correlations (rs), and predictors of the rate of change in log concentration were evaluated using linear regression models. Although serum concentrations dramatically declined (median follow-up to baseline concentration ratio was 16% for DDE and 45% for PCB), baseline and follow-up measures were strongly correlated for DDE (rs = 0.72) and moderately correlated for PCBs (rs = 0.43). Prediction of follow-up PCB levels was substantially improved (rs = 0.75) with data on initial concentration, length of lactation, baseline body mass index, and percent change in body fat, whereas DDE prediction improved slightly (rs = 0.83) with data on lactation and baseline body mass index. These findings suggest that a single organochlorine measure provides considerable information on relative ranking at distant times and that the predictive power can be improved, particularly for PCBs, with information on a few predictors. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2729–36)

We identified 13 historical measurements of polycyclic aromatic hydrocarbons (PAHs) in U.S. vehicular traffic tunnels that were either directly presented as tailpipe emission factors in μg per vehicle-kilometer or convertible to such a form. Tunnel measurements capture fleet cruise emissions. Emission factors for benzo[a]pyrene (BaP) for a tunnel fleet operating under cruise conditions were highest prior to the 1980s and fell from more than 30-μg per vehicle-km to approximately 2-μg/km in the 1990s, an approximately 15-fold decline. Total annual U.S. (cruise) emissions of BaP dropped by a lesser factor, because total annual km driven increased by a factor of 2.7 during the period. Other PAH compounds measured in tunnels over the 40-year period (e.g., benzo[ghi]perylene, coronene) showed comparable reduction factors in emissions. PAH declines were comparable to those measured in tunnels for carbon monoxide, volatile organic compounds, and particulate organic carbon. The historical PAH “source terms” determined from the data are relevant to quantifying the benefits of emissions control technology and can be used in epidemiological studies evaluating the health effects of exposure, such as those undertaken with breast cancer in New York State., Analysis of 13 tunnel studies quantifies the decline since 1961 in benzo[a]pyrene emitted into the air per km of travel by U.S. road vehicles.

Promoter-CpG island hypermethylation is a common molecular defect in cancer cells. It has been proposed as an alternative mechanism to inactivate BRCA1in the breast where somatic mutations of BRCA1 are rare. To better understand breast cancer etiology and progression, we explored the association between BRCA1 promoter methylation status and prognostic factors as well as survival among women with breast cancer. We also examined whether dietary methyl content and functional polymorphisms of genes involved in one-carbon metabolism influenced the methylation pattern. Promoter methylation of BRCA1 was assessed in 851 archived tumor tissues collected from a population-based study of women diagnosed with invasive or in situ breast cancer in 1996–1997, and who were followed for vital status through the end of 2002. About 59% of the tumors were methylated at the promoter of BRCA1. The BRCA1 promoter methylation was more frequent in invasive cancers (p=0.02) and among premenopausal cases (p=0.05). BRCA1 promoter methylation was associated with increased risk of breast cancer-specific mortality (age-adjusted HR 1.71; 95% CI: 1.05–2.78) and all-cause mortality (age-adjusted HR 1.49; 95% CI: 1.02–2.18). Among dietary methyl intakes in the year prior to the baseline interview examined, cases with lowest quintile of choline intake (

Xeroderma pigmentosum complementation group C (XPC) is an important DNA nuclear excision repair (NER) gene that recognizes the damage caused by variety of bulky DNA adducts. We evaluated the association of two common non-synonymous polymorphisms in XPC (Ala499Val and Lys939Gln) with breast cancer risk in the Long Island Breast Cancer Study Project (LIBCSP), a population-based case-control study. Genotyping of 1,067 cases and 1,110 controls was performed by a high throughput assay with fluorescence polarization. There were no overall associations between XPC polymorphisms and breast cancer risk. A diplotype CC-CC was significantly associated with increased breast cancer risk compared with diplotype CA-CA (OR = 1.4, 95%CI: 1.0–1.9), but was not significant when compared with all other diplotypes combined (OR = 1.22, 95%CI: 0.97–1.53). No modification effects were observed for XPC genotypes by cigarette smoking status, smoking pack years or polycyclic aromatic hydrocarbons (PAH) DNA adducts. The increase in breast cancer risk was slightly more pronounced among women with detectable PAH-DNA adducts and carrying the diplotype CC-CC (OR = 1.6, 95%CI: 1.1–2.2) compared to women with non detectable PAH-DNA adducts carrying other diplotypes combined, but no statistically significant interaction was observed (P interaction = 0.69). These data suggest that XPC have neither independent effects nor interactions with cigarette smoking and PAH-DNA adducts for breast cancer risk. Further studies with multiple genetic polymorphisms in NER pathway are warranted.

Objective Colorectal cancer incidence is greater among African Americans, compared to whites in the U.S., and may be due in part to differences in diet, genetic variation at metabolic loci, and/or the joint effect of diet and genetic susceptibility. We examined whether our previously reported associations between meat-derived heterocyclic amine (HCA) intake and colon cancer were modified by N -acetyltransferase 1 (NAT1) or 2 (NAT2) genotypes and whether there were differences by race. Methods In a population-based, case-control study of colon cancer, exposure to HCAs was assessed using a food-frequency questionnaire with a meat-cooking and doneness module, among African Americans (217 cases and 315 controls) and whites (290 cases and 534 controls). Results There was no association with NAT1*10 versus NAT1-non*10 genotypes for colon cancer. Among whites, there was a positive association for NAT2-“rapid/intermediate” genotype [odds ratio (OR) = 1.4; 95% confidence interval (CI) = 1.0, 1.8], compared to the NAT2-“slow” that was not observed among African Americans. Colon cancer associations with HCA intake were modified by NAT1, but not NAT2, regardless of race. However, the “at-risk” NAT1 genotype differed by race. For example, among African Americans, the positive association with 2-amino-1-methyl-6-phenyl-imidazo[4,5- b ]pyridine (PhIP) was confined to those with NAT1*10 genotype (OR = 1.8; 95% CI = 1.0, 3.3; P for interaction = 0.02, comparing highest to lowest intake), but among whites, an association with 2-amino-3,8-dimethylimidazo[4,5- f ]quinoxaline (MeIQx) was confined to those with NAT1-non*10 genotype (OR = 1.9; 95% CI = 1.1, 3.1; P for interaction = 0.03). Conclusions Our data indicate modification by NAT1 for HCA and colon cancer associations, regardless of race. Although the at-risk NAT1 genotype differs by race, the magnitude of the individual HCA-related associations in both race groups are similar. Therefore, our data do not support the hypothesis that NAT1 by HCA interactions contribute to differences in colorectal cancer incidence between African Americans and whites.

Due to the established association between estrogen levels and breast cancer risk, polymorphic variation in genes regulating estrogen levels is thought to be related to breast cancer risk. Aromatase, the protein product of the CYP19 gene, is involved in the production of endogenous estrogens via androgen conversion. We examined whether polymorphic variation in CYP19 associated with increased breast cancer risk in a population based case-control study. We examined two single nucleotide polymorphisms (SNP), rs1008805 (A/G) and rs730154 (C/T), which have been shown to tag SNPs within two different haplotype blocks in CYP19. Among premenopausal women, the presence of at least one G allele at rs1008805 was significantly associated with an increase in the risk of breast cancer (OR = 1.72 [95% CI, 1.20-2.49]), especially with estrogen and progesterone receptor negative breast cancer (OR = 3.89 [1.74-8.70] and OR = 2.52 [1.26-5.05], respectively). No association was observed among postmenopausal women (OR = 1.06 [0.82-1.36]). There was no significant association between rs730154 and breast cancer, regardless of menopausal status. Our results suggest that premenopausal women carrying the G allele at CYP19 rs1008805 have increased risk of breast cancer. The finding supports the potential role of variation in estrogen biosynthesis genes in premenopausal breast cancer risk.

Background: Laboratory research and a growing number of epidemiologic studies have provided evidence for a reduced risk of breast cancer associated with dietary intake of certain classes of flavonoids. However, the effects of flavonoids on survival are not known. In a population-based cohort of breast cancer patients, we investigated whether dietary flavonoid intake before diagnosis is associated with subsequent survival.Methods: Women ages 25 to 98 years who were newly diagnosed with a first primary invasive breast cancer between August 1, 1996, and July 31, 1997, and participated in a population-based, case-control study (n = 1,210) were followed for vital status through December 31, 2002. At the case-control interview conducted shortly after diagnosis, respondents completed a FFQ that assessed dietary intake in the previous 12 months. All-cause mortality (n = 173 deaths) and breast cancer–specific mortality (n = 113 deaths) were determined through the National Death Index.Results: Reduced hazard ratios [age- and energy-adjusted hazard ratio (95% confidence interval)] for all-cause mortality were observed among premenopausal and postmenopausal women for the highest quintile of intake, compared with the lowest, for flavones [0.63 (0.41-0.96)], isoflavones [0.52 (0.33-0.82)], and anthocyanidins [0.64 (0.42-0.98)]. No significant trends in risk were observed. Results were similar for breast cancer–specific mortality only.Conclusion: Mortality may be reduced in association with high levels of dietary flavones and isoflavones among postmenopausal U.S. breast cancer patients. Larger studies are needed to confirm our findings. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2285–92)

Genes involved in the nucleotide excision repair (NER) pathway, which removes bulky DNA adducts, are potential low-penetrance cancer susceptibility genes. We recently reported an association between detectable polycyclic aromatic hydrocarbon (PAH)-DNA adducts and breast cancer risk. Using a population-based breast cancer case-control study on Long Island, New York, we examined whether polymorphisms in NER genes modified the association between PAH-DNA adducts and breast cancer risk. We examined polymorphisms in ERCC1 (3′-untranslated region 8092C/A), XPA (5′-untranslated region −4G/A), XPD (Asp312Asn in exon 10), XPF (Arg415Gln in exon 8), and XPG (Asp1104His in exon 15) in 1,053 breast cancer cases and 1,102 population-based controls. The presence of at least one variant allele in XPD was associated with a 25% increase in the odds ratio [OR, 1.25; 95% confidence interval (95% CI), 1.04-1.50] for breast cancer. The increase associated with homozygosity of the variant alleles for XPD and ERCC1 was stronger among those with detectable PAH-DNA adduct levels (OR, 1.83; 95% CI, 1.22-2.76 and OR, 1.92; 95% CI, 1.14-3.25 for detectable versus nondetectable adducts and homozygous wild-type genotype for XPD and ERCC1, respectively). We found no association between XPA, XPF, and XPG genotypes, PAH-DNA adducts, and breast cancer risk. When we combined genotypes for these NER pathway genes, there was a significant trend for increasing breast cancer risk with increasing number of putative high-risk alleles. Overall, this study suggests that the risk of breast cancer may be elevated among women with polymorphisms in NER pathway genes and detectable PAH-DNA adducts. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2033–41)

FAS and FAS ligand (FASL) play key roles in apoptotic signaling and down-regulation of this pathway may facilitate tumorigenesis. Alterations in apoptosis genes may affect cancer risk by influencing individual susceptibility to environmental carcinogens. Using a population-based breast cancer case-control study on Long Island, New York, we examined whether polymorphisms in FAS and FASL modified the association between breast cancer risk and a marker of environmental exposures, polycyclic aromatic hydrocarbon (PAH)-DNA adducts. We examined polymorphisms in FAS (5' UTR -1377G/A and 5' UTR -670G/A) and FASL (5' UTR -844C/T) in 1053 breast cancer cases and 1102 population-based controls. There was no significant association between these genetic polymorphisms and breast cancer risk. The presence of at least one variant allele (GA or AA) in FAS1377 was associated with a 36% increase in breast cancer risk among those with detectable PAH-DNA adduct levels [odds ratio (OR) = 1.36, 95% confidence interval (CI) = 1.01-1.83]. In addition, lactation history significantly modified the association between FAS1377 and FAS670 genetic variants and breast cancer risk (OR = 1.46, 95% CI = 1.04-2.06 and OR = 1.71, 95% CI = 1.13-1.58, respectively, in those who ever lactated compared with those who did not with the wild-type alleles). Overall, this study suggests that the risk of breast cancer may be elevated among women with polymorphisms in the FAS gene and detectable PAH-DNA adducts.

To study the role of oxidative stress in breast cancer risk, we analysed plasma levels of protein carbonyls in 1050 cases and 1107 controls. We found a statistically significant trend in breast cancer risk in relation to increasing quartiles of plasma protein carbonyl levels (OR = 1.2, 95% CI = 0.9-1.5; OR = 1.5, 95% CI = 1.2-2.0; OR = 1.6, 95% CI = 1.2-2.1, for the 2(nd), 3(rd) and 4(th) quartile relative to the lowest quartile, respectively, P for trend = 0.0001). The increase in risk was similar for younger (50 years) and older women, more pronounced among women with higher physical activity levels (0.7 hrs/week for 4(th) quartile versus lowest quartile OR = 2.0, 95% CI = 1.4-3.0), higher alcohol consumption (or = 15 grams/day for 4(th) quartile versus lowest quartile OR = 2.3, 95% CI = 1.1-4.7), and hormone replacement therapy use (HRT, OR = 2.6, 95% CI = 1.6-4.4 for 4(th) quartile versus lowest quartile). The multiplicative interaction terms were statistically significant only for physical activity and HRT. The positive association between plasma protein carbonyl levels and breast cancer risk was also observed when the analysis was restricted to women who had not received chemotherapy or radiation therapy prior to blood collection. Among controls, oxidized protein levels significantly increased with cigarette smoking and higher fruit and vegetable consumption, and decreased with alcohol consumption30 grams per day. Women with higher levels of plasma protein carbonyl and urinary 15F(2t)-isoprostane had an 80% increase in breast cancer risk (OR = 1.8, 95% CI = 1.2-2.6) compared to women with levels below the median for both markers of oxidative stress. In summary, our results suggest that increased plasma protein carbonyl levels may be associated with breast cancer risk.

Alcohol increases esophageal squamous carcinoma risk but has been less consistently associated with esophageal adenocarcinoma. Alcohol dehydrogenase catalyzes the oxidation of approximately 80% of ethanol to acetaldehyde, a carcinogen. The alcohol dehydrogenase gene has several polymorphisms which may lead to faster conversion of ethanol to acetaldehyde, which may increase cancer risk. We undertook a study to examine whether a common polymorphism in the alcohol dehydrogenase 3 gene was associated with a higher risk of esophageal adenocarcinoma using data and biological samples collected for the Esophageal and Gastric Cancer Study (n = 114 esophageal and gastric cardia adenocarcinoma, n = 60 non-cardia gastric carcinoma, n = 23 cases of esophageal squamous cell carcinoma and 160 controls). Individuals homozygous for ADH 1–1 had a higher risk of each tumor type compared to individuals who had ADH 2–2 or ADH 1–2 genotype (OR = 1.7, 95% CI = 1.0–2.9 for esophageal and gastric cardia adenocarcinomas; OR = 1.7, 95% CI = 0.7–4.3 for esophageal squamous cell carcinoma; and OR = 2.8, 95% CI = 1.5–5.1 for non-cardia gastric cancer). The elevation in risk from homozygosity of the ADH 1 allele was seen in drinkers and nondrinkers, although the risk estimate was only significant for drinkers, particularly of liquor. These data suggest ADH3 genotype may be associated with risk of esophageal and gastric cardia adenocarcinomas.

p53 participates in cell cycle control, programmed cell death/apoptosis, and DNA repair, all pathways involved in carcinogenesis. TP53 variants may influence p53 function. We evaluated whether three well-characterized TP53 variants—Ex4 + 119 C > G (rs#1042522, Arg72Pro), IVS6 + 62 A > G (rs#1625895), and an IVS3 16 bp insertion/ deletion (INDEL; rs#17878362)—were associated with breast cancer risk in a population-based case-control study. Genotypes and haplotypes were determined using long-range PCR in a sample of 578 cases and 390 controls. For the Ex4 + 19 C > G SNP (rs1042522), women with the heterozygous genotype (G/C) had a 32% increase in breast cancer risk. Other variants were not associated with risk. We further examined whether these associations were modified by cigarette smoking status and detection of PAH–DNA adducts in circulating lymphocytes. Among current smokers, each copy of the minor alleles for the IVS6 + 62 A > G SNP (rs1625895) and the IVS3 INDEL polymorphism (rs17878362) was associated with lower breast cancer risk (OR = 0.49, 95% CI 0.27–0.90; OR = 0.42, 95% CI 0.22–0.78, respectively). However, among former smokers, the homozygous variant genotype for these 2 SNPs was observed among cases (4.1 and 3.2%, respectively) and not controls. Genotype associations were not modified by the presence or absence of DNA adducts in circulating lymphocytes. Three-loci haplotypes were not significantly associated with breast cancer risk. These results should be confirmed in larger studies, but suggest that cigarette smoking may influence breast cancer risk through interaction with p53.

Polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs) are carcinogens formed in or on the surface of well-done meat, cooked at high temperature.We estimated breast cancer risk in relation to intake of cooked meat in a population-based, case-control study (1508 cases and 1556 controls) conducted in Long Island, NY from 1996 to 1997. Lifetime intakes of grilled or barbecued and smoked meats were derived from the interviewer-administered questionnaire data. Dietary intakes of PAH and HCA were derived from the self-administered modified Block food frequency questionnaire of intake 1 year before reference date. Unconditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs).Modest increased risk was observed among postmenopausal, but not premenopausal, women consuming the most grilled or barbecued and smoked meats over the life course (OR = 1.47; CI = 1.12-1.92 for highest vs. lowest tertile of intake). Postmenopausal women with low fruit and vegetable intake, but high lifetime intake of grilled or barbecued and smoked meats, had a higher OR of 1.74 (CI = 1.20-2.50). No associations were observed with the food frequency questionnaire-derived intake measures of PAHs and HCAs, with the possible exception of benzo(alpha)pyrene from meat among postmenopausal women whose tumors were positive for both estrogen receptors and progesterone receptors (OR = 1.47; CI = 0.99-2.19).These results support the accumulating evidence that consumption of meats cooked by methods that promote carcinogen formation may increase risk of postmenopausal breast cancer.

Background: Dihydrofolate reductase (DHFR) converts dihydrofolate (DHF) into tetrahydrofolate (THF) and plays an essential role in cell metabolism and cellular growth. Folic acid from multivitamins needs to be reduced by DHFR before it participates in cellular reactions. Objectives: We examined the relation of a 19-base pair (bp) deletion polymorphism of the DHFR gene with the risk of breast cancer by using data from the Long Island Breast Cancer Study Project, a population-based case-control study. We also investigated the transcriptional effect of this deletion polymorphism. Design: Dietary data and habitual use of multivitamins were assessed from a modified Block food-frequency questionnaire (FFQ). Genotypes of DHFR were ascertained from 1062 case subjects and 1099 control subjects by allele-specific polymerase chain reaction. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% CIs. Result: Although the DHFR 19-bp deletion polymorphism was not associated with overall breast cancer risk, we observed a borderline significant additive interaction (P = 0.06) between the DHFR genotype and multivitamin use. The-19-bp allele was associated with greater breast cancer risk in multivitamin users (51.2% of the study population) with an OR of 1.26 (95% CI: 0.96, 1.66) and 1.52(95% CI: 1.08, 2.13) for the +/- and -/- genotypes, respectively (P for trend = 0.02) than in multivatimin nonusers. A dose-dependent relation (P for trend < 0.001) between DHFR expression and the deletion genotype was observed. Compared with the subjects with the 19-bp +/+ genotype, subjects with the -/- genotype had 4.8-fold DHFR mRNA levels. Conclusions: The DHFR 19-bp deletion polymorphism affects the transcription of DHFR gene in humans. Multivitamin supplements may place a subgroup of women (ie, those with the - 19-bp allele) at elevated risk of developing breast cancer.

Isothiocyanates (ITC) are potentially anticarcinogenic phytochemicals formed from the metabolism of glucosinolates and are found in cruciferous vegetables as well as a select number of other foods. ITC are both substrates for and inducers of glutathione S-transferase (GST) phase II metabolizing enzymes involved in carcinogen detoxification as well as effectors of phase I pathways. Previous studies report mixed results on the interaction between cruciferous vegetable intake, GST polymorphisms, and risk of cancer. We conducted a study of 114 healthy human subjects between 18 and 50 y of age to examine the biologic mechanism underlying the associations, specifically, to assess whether GST genotype is associated with urinary ITC metabolites following a known dose of broccoli. After 48 h of abstaining from all sources of glucosinolates, participants provided a blood sample, consumed 1 meal containing 2.5 g broccoli/kg body weight, and collected urine for 24 h. ITC metabolites were measured in the urine using a HPLC cyclocondensation assay. DNA was extracted from blood samples, and GSTM1 deletion, GSTT1 deletion, GSTP1 Ile105Val, and GSTA1*A/*B were genotyped by matrix-assisted laser desorption/ionization time-of-flight. A chi-square test was used to compare high and low ITC excretion levels across genotypes. ITC levels were regressed on genotype, adjusting for gender. There were no substantial differences in ITC levels among genotypes, either individually or in combination. Contrary to our hypothesis, a higher proportion of GSTM1 null individuals had high ITC excretion (62%) compared with the proportion of GSTM1 present with high ITC excretion (39%) (P = 0.03). These results are in agreement with another feeding study, and lend support to the idea of alternative routes of ITC metabolism.

BACKGROUND AND AIMS: TLR4 is a cell-surface signaling receptor involved in the recognition and host response to Helicobacter pylori. The TLR4+896A>G polymorphism linked with impaired reactivity to bacterial lipopolysaccharide may play a role in gastric carcinogenesis. METHODS: We assessed associations with premalignant gastric changes in 149 relatives of gastric cancer patients, including 45 with hypochlorhydria and gastric atrophy. We also genotyped 2 independent Caucasian population-based case-control studies of upper gastrointestinal tract cancer, initially in 312 noncardia gastric carcinoma cases and 419 controls and then in 184 noncardia gastric carcinomas, 123 cardia carcinomas, 159 esophageal cancers, and 211 frequency-matched controls. Odds ratios were computed from logistic models and adjusted for potential confounding factors. RESULTS: TLR4+896G carriers had an 11-fold (95% confidence interval [CI], 2.5-48) increased odds ratio (OR) for hypochlorhydria; the polymorphism was unassociated with gastric acid output in the absence of H pylori infection. Carriers also had significantly more severe gastric atrophy and inflammation. Seventeen percent of gastric carcinoma patients in the initial study and 15% of the noncardia gastric carcinoma patients in the replication study had 1 or 2 TLR4 variant alleles vs 8% of both control populations (combined OR = 2.3; 95% CI = 1.6-3.4). In contrast, prevalence of TLR4+896G was not significantly increased in esophageal squamous cell (2%, OR = 0.2) or adenocarcinoma (9%, OR = 1.4) or gastric cardia carcinoma (11%, OR = 1.4). CONCLUSIONS: Our data suggest that the TLR4+896A>G polymorphism is a risk factor for noncardia gastric carcinoma and its precursors. The findings underscore the role of the host innate immune response in outcome of H pylori infection.

The catechol-O-methyltransferase (COMT) gene encodes enzymes that inactivate catechol estrogens and may have a protective role in estrogen-induced tumorigenesis, such as uterine leiomyoma (fibroids). Val158Met is a common single-nucleotide polymorphism of the COMT gene (Ex4-12 GA; rs4680) that results in a lower activity enzyme, increasing susceptibility to tumorigenesis. The purpose of this study was to evaluate the relation between the COMTVal158Met polymorphism and uterine fibroids. Participants were 972 premenopausal African American (n = 576) and white (n = 396) women from a cross-sectional sample of women in the National Institute of Environmental Health Science's Uterine Fibroid Study. Blood was collected from participants for DNA, and telephone interviews and questionnaires were completed to gather demographic and reproductive history. Prevalence ratios and 95% confidence intervals were estimated using race-specific log-risk regression models. Effect measure modification by age, body mass index, oral contraceptive use, full-term births, smoking, and alcohol use were also evaluated. Distributions of genotypes and fibroid prevalence varied by race. No associations between fibroids and Val158Met were observed among African American or white participants. This study suggests that variation in this polymorphism alone does not affect fibroid prevalence. Additional research is needed to examine other variations and haplotypes within the COMT gene.

Pesticides, common environmental exposures, have been examined in relation to breast cancer primarily in occupational studies or exposure biomarker studies. No known studies have focused on self-reported residential pesticide use. The authors investigated the association between reported lifetime residential pesticide use and breast cancer risk among women living on Long Island, New York. They conducted a population-based case-control study of 1,508 women newly diagnosed with breast cancer between August 1996 and July 1997 and 1,556 randomly selected, age-frequency-matched controls. Comprehensive residential pesticide use and other risk factors were assessed by using an in-person, interviewer-administered questionnaire. Unconditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Breast cancer risk was associated with ever lifetime residential pesticide use (odds ratio = 1.39, 95% confidence interval: 1.15, 1.68). However, there was no evidence of increasing risk with increasing lifetime applications. Lawn and garden pesticide use was associated with breast cancer risk, but there was no dose response. Little or no association was found for nuisance-pest pesticides, insect repellents, or products to control lice or fleas and ticks on pets. This study is the first known to suggest that self-reported use of residential pesticides may increase breast cancer risk. Further investigation in other populations is necessary to confirm these findings.

Background: Factors underlying a possible excess of amyotrophic lateral sclerosis (ALS) among military veterans remain unidentified. Limitations of previous studies on this topic include reliance on ALS mortality as a surrogate for ALS incidence, low statistical power, and sparse information on military-related factors. Objectives: We evaluated associations between military-related factors and ALS using data from a case-control study of U.S. military veterans. Methods: From 2005 to 2010, we identified medical record-confirmed ALS cases via the National Registry of Veterans with ALS and controls via the Veterans Benefits Administration's Beneficiary Identification and Records Locator System database. In total, we enrolled 621 cases and 958 frequency-matched controls in the Genes and Environmental Exposures in Veterans with Amyotrophic Lateral Sclerosis study. We collected information on military service and deployments and 39 related exposures. We used unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). We used inverse probability weighting to adjust for potential bias from confounding, missing covariate data, and selection arising from a case group that disproportionately included long-term survivors and a control group that may or may not differ from U.S. military veterans at large. Results: The odds of ALS did not differ for veterans of the Air Force, Army, Marines, and Navy. We found higher odds of ALS for veterans whose longest deployment was World War II or the Korean War and a positive trend with total years of all deployments (OR = 1.27; 95% CI: 1.06, 1.52). ALS was positively associated with exposure to herbicides for military purposes, nasopharyngeal radium, personal pesticides, exhaust from heaters or generators, high-intensity radar waves, contaminated food, explosions within one mile, herbicides in the field, mixing and application of burning agents, burning agents in the field, and Agent Orange in the field, with ORs between 1.50 and 7.75. Conclusions: Although our results need confirmation, they are potentially important given the large number of U.S. military veterans, and they provide clues to potential factors underlying the apparent increase of ALS in veteran populations. Keywords: Amyotrophic lateral sclerosis, Case-control, Deployment, Etiology, Military

Background Breast cancer patients commonly report using >1 form of complementary and alternative medicine (CAM). However, few studies have attempted to analyze predictors and outcomes of multiple CAM modalities. We sought to group breast cancer patients by clusters of type and intensity of complementary and alternative medicine (CAM) use following diagnosis. Methods Detailed CAM use following breast cancer diagnosis was assessed in 2002–2003 among 764 female residents of Long Island, New York diagnosed with breast cancer in 1996–1997. Latent class analysis (LCA) was applied to CAM modalities while taking into account frequency and intensities. Results Four distinct latent classes of CAM use emerged: 1) “Low-dose supplement users” (40 %), who used only common nutritional supplements; 2) “Vitamin/mineral supplement users” (39 %), using an abundance of supplements in addition to other practices; 3) “Mind-body medicine users” (12 %), with near-universal use of supplements, mind-body medicine techniques, and massage; and 4) “Multi-modality high-dose users” (9 %), who were highly likely to use nearly all types of CAM. Predictors of membership in classes with substantial CAM use included younger age, more education, higher income, Jewish religion, ideal body mass index, higher fruit and vegetable intake, higher levels of physical activity, receipt of adjuvant chemotherapy, and prior use of oral contraceptives. Conclusions LCA identified important subgroups of breast cancer patients characterized by varying degrees of complementary therapy use. Further research should explore the reproducibility of these classes and investigate the association between latent class membership and breast cancer outcomes.

Background: Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus. Methods: We examined the associations between risks of EA and Barrett's esophagus and 387 SNPs that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 Barrett's esophagus) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn. Results: After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or Barrett's esophagus. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed. Conclusions: Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or Barrett's esophagus. Impact: To our knowledge, this is the first investigation of pleiotropic genetic associations with risks of EA and Barrett's esophagus. Cancer Epidemiol Biomarkers Prev; 24(11); 1801–3. ©2015 AACR.

Despite the overlap between the clinical symptoms/sequelae of polycystic ovarian syndrome (PCOS) and many known reproductive risk factors for breast cancer, the relationship between PCOS and breast cancer remains unclear, possibly because of the complex heterogeneity and challenges in diagnosing PCOS over time. We hypothesized that PCOS, specific PCOS-related symptoms/sequelae, or clusters of PCOS-related symptoms/sequelae may be differentially associated with pre- versus postmenopausal breast cancer risk. Cases were 1,508 women newly diagnosed with a first primary in situ or invasive breast, and the 1,556 population-based controls were frequency-matched by age. History of physician-diagnosed PCOS was reported by 2.2 % (n = 67), among whom oral contraceptive (OC) use, irregular menstruation, and infertility due to ovulatory dysfunction were common. Using unconditional logistic regression, adjusted odds ratios (95 % CI) for PCOS were increased for premenopausal [2.74 (1.13, 6.63)], but not postmenopausal breast cancer [0.87 (0.44, 1.71)]. We used cluster analysis to investigate whether risk among all women varied by PCOS-related symptoms/sequelae, such as reproductive irregularities, OC use, and components of insulin resistance. In the cluster analysis, odds ratios were elevated among premenopausal women who had a history of OC use and no ovulatory dysfunction [1.39 (1.03, 1.88)], compared to those with fewer number of PCOS-related symptoms/sequelae. PCOS and associated PCOS-related symptoms/sequelae including OC use may play a role in the development of premenopausal breast cancer. Our findings require confirmation in studies with a larger number of premenopausal women with systematically applied diagnostic criteria for PCOS.

Incidence of esophageal adenocarcinoma (EA) has increased substantially in recent decades. Multiple risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), such as reflux, European ancestry, male sex, obesity, and tobacco smoking, and several germline genetic variants were recently associated with disease risk. Using data from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), small non-coding RNAs implicated in post-transcriptional gene regulation, and deregulated in many cancers, including EA. Polymorphisms in three classes of genes were examined for association with risk of EA or BE: miRNA biogenesis genes (157 SNPs, 21 genes); miRNA gene loci (234 SNPs, 210 genes); and miRNA-targeted mRNAs (177 SNPs, 158 genes). Nominal associations (P0.50), and we did not find evidence for interactions between variants analyzed and two risk factors for EA/BE (smoking and obesity). This analysis provides the most extensive assessment to date of miRNA-related SNPs in relation to risk of EA and BE. While common genetic variants within components of the miRNA biogenesis core pathway appear unlikely to modulate susceptibility to EA or BE, further studies may be warranted to examine potential associations between unassessed variants in miRNA genes and targets with disease risk.

Esophageal adenocarcinoma (EA) incidence is among the most rapidly increasing of any cancer type in the U.S., and prognosis is poor. Prevalence of the potential precursor lesion, Barrett's esophagus (BE), is also increasing. Candidates for safe and effective risk reduction strategies are needed, potentially including dietary components. In this qualitative review, we summarize recently published epidemiologic studies, in context of earlier work, on dietary intake and BE-EA outcomes. Potential cohort study/intervention trial candidates which could be increased to reduce BE-EA development include intake of: (1) fruits and vegetables; vegetables; fruit (EA only); (2) β-carotene and vitamins C and E; (3) folate (EA only); and (4) total fiber (EA only). Also, (5) red and processed meat intake could be targeted for dietary reduction/omission to reduce EA development. Few dietary constituents have been evaluated among EA patients to examine associations with mortality, thus interventions conducted among EA patients are premature.

Esophageal (EA) and esophagogastric junction (EGJA) adenocarcinoma have been steadily increasing in frequency in younger people; however, the etiology of these cancers is poorly understood. We therefore investigated associations of body mass index (BMI), cigarette smoking, alcohol consumption, gastroesophageal reflux and use of nonsteroidal anti-inflammatory drugs (NSAIDs) in relation to age-specific risks of EA and EGJA. We pooled individual participant data from eight population-based, case-control studies within the international Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). The analysis included 1,363 EA patients, 1,472 EGJA patients and 5,728 control participants. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for age-specific (50, 50-59, 60-69, ≥70 years) cancer outcomes, as well as interactions by age. BMI, smoking status and pack-years, recurrent gastroesophageal reflux and frequency of gastroesophageal reflux were positively associated with EA and EGJA in each age group. Early-onset EA (50 years) had stronger associations with recurrent gastroesophageal reflux (OR = 8.06, 95% CI: 4.52, 14.37; peffect modification = 0.01) and BMI (ORBMI ≥ 30 vs .25 = 4.19, 95% CI: 2.23, 7.87; peffect modification = 0.04), relative to older age groups. In contrast, inverse associations of NSAID use were strongest in the oldest age group (≥70 years), although this apparent difference was not statistically significant. Age-specific associations with EGJA showed similar, but slightly weaker patterns and no statistically significant differences by age were observed. Our study provides evidence that associations between obesity and gastroesophageal reflux are stronger among earlier onset EA cancers.

Purpose Obesity is associated with increased bioavailability of estrogen, hyperinsulinemia, and chronic inflammation, all of which may promote tumor growth. Given DNA repair and oxidative stress pathways may work together with these mechanisms to influence carcinogenesis, we hypothesized that genetic variation in these pathways may modify the obesity-postmenopausal breast cancer (BC) association. Methods Resources from a population-based case-control study (990 cases and 970 controls) were used to construct logistic regression models. Body mass index (BMI, weight [kilogram]/height [square meter]) was assessed 1 year before reference date. We characterized interactions between BMI and 29 genetic polymorphisms in oxidative stress and DNA repair pathways. Results Age-adjusted odds ratios (95% confidence intervals) for postmenopausal BC were 1.24 (1.00–1.52) and 1.35 (1.09–1.71) for 25 ≥ BMI 2 , respectively. We observed multiplicative interactions ( P ≤ .05) for eight gene polymorphisms in DNA repair and oxidative stress pathways. For example, among MPO variant allele carriers, obesity was associated with a twofold increased risk of postmenopausal BC (2.13 [1.35–3.36]); however, in wild-type homozygotes, the relationship was less pronounced (1.33 [0.93–1.89]). Our findings were no longer significant after Bonferroni correction. Conclusions Obesity may be particularly deleterious for postmenopausal BC development in the presence of biologically plausible DNA repair or oxidative stress genotypes.

Background: Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear. Methods: We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5 216 302 women, including 113 178 events. In a consortium with individual-level data from 46 325 case patients and 42 482 control subjects, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16 003 case patients and 41 335 control subjects. Results: The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10 cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10 cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5 × 10-8. Conclusions: Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.

Polycyclic aromatic hydrocarbon (PAH)–DNA adducts have been associated with breast cancer incidence. Aberrant changes in DNA methylation may be an early event in carcinogenesis. However, possible relations between PAH–DNA adducts, methylation, and breast cancer are unknown. The objectives of this study were to (1) assess associations between PAH–DNA adducts, and breast cancer, stratified by DNA methylation markers and (2) examine interactions between adducts and DNA methylation in association with breast cancer and tumor subtype. In a population-based case–control study, promoter methylation of 13 breast cancer-related genes was measured in tumor tissue (n = 765–851 cases). Blood DNA from breast cancer cases (n = 873) and controls (n = 941) was used to assess PAH–DNA adducts and global methylation. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95 % confidence intervals (CI); and the ratio of the OR (ROR) was used to assess heterogeneity. Women with detectable PAH–DNA adducts and methylated RARβ (ROR 2.69, 95 % CI 1.02–7.12; p for interaction = 0.03) or APC (ROR 1.76, 95 % CI 0.87–3.58; p for interaction = 0.09) genes were more likely to have hormone receptor-positive tumors than other subtypes. Interactions with other methylation markers were not apparent (p ≥ 0.10). The association between adducts and breast cancer did not vary by methylation status of the tumor nor did adducts associate with global methylation in the controls. Gene-specific methylation of RARβ, and perhaps APC, may interact with PAH–DNA adducts to increase risk of hormone receptor-positive breast cancer. There was little evidence that adducts were associated with or interacted with other methylation markers of interest.

The hypothesized association between breast cancer and circadian disruption was evaluated in the Electromagnetic Fields and Breast Cancer on Long Island Study. Participants included 576 women with breast cancer diagnosed from August 1996 to June 1997 and 585 population-based controls (87% and 83% participation rates, respectively) aged75 years and living in the same Long Island, New York, home foror = 15 years. An in-person interview ascertained light-at-night exposure histories through shift work (previous 15 years) and at home (previous 5 years). Odds ratios and 95% confidence intervals were estimated by unconditional multivariate logistic regression. Breast cancer was not associated with overall shift work (odds ratio (OR) = 1.04, 95% confidence interval (CI): 0.79, 1.38) or evening shift work (OR = 1.08, 95% CI: 0.81, 1.44). However, overnight shift workers were at lower risk than women never working shifts (OR = 0.55, 95% CI: 0.32, 0.94). Women who frequently turned on lights at home during sleep hours (or = twice/week andor = twice/night) had increased risks (OR = 1.65, 95% CI: 1.02, 2.69). The latter results suggest positive associations with residential light-at-night exposure, or they could reflect response biases. Furthermore, overall and evening shift work were not significant factors, and analyses of overnight shift workers yielded reduced risk estimates. The study thus provides mixed evidence for the light-at-night hypothesis.

The gene encoding catechol-O-methyltransferase (COMT), critical to the inactivation of reactive catechol estrogens, has several single nucleotide polymorphisms (SNPs) that influence enzyme activity. A 3-SNP haplotype (IVS1+255 C>T; Ex4-12 G>A; 3′UTR-521 A>G), which has been shown to reduce COMT expression in the human brain, has been identified. To evaluate the influence of genetic variation of COMT on breast cancer risk, these 3-SNPs were genotyped in 1052 cases and 1098 controls. We estimated the associations between breast cancer and individual SNPs, as well as, multilocus haplotypes. We also examined surrogates of hormone exposure as potential modifiers of the putatively functional Ex4-12 SNP-breast cancer association. Odds ratios (OR) and 95% confidence intervals (CI) were based on age-adjusted unconditional logistic regression models. We found no association between the individual SNPs alone and breast cancer. When examining the association between breast cancer and the 3-SNP haplotypes, we observed a 19% increase in risk associated with each copy of the TGG haplotype (OR=1.19, 95% CI 0.96–1.49), relative to the common TAA haplotype, which was statistically significant when assuming a dominant model (OR=1.32, 95% CI 1.05–1.67, p-value=0.02). In this report of COMT haplotypes and breast cancer, we found some evidence that additional genetic variability beyond the Ex4-12 G>A SNP contributes to risk of breast cancer among a small subgroup of women; however, these results need to be replicated in additional studies.

To evaluate the role of oxidative stress in breast cancer, we measured urinary levels of 15-F2t-isoprostane (15-F2t-IsoP) and 8-oxodeoxyguanosine (8-oxodG) in 400 cases and 401 controls, participants of the Long Island Breast Cancer Study Project. We also analyzed the effect of different factors that are associated with oxidative stress and might influence 15-F2t-IsoP and 8-oxodG levels. We observed a statistically significant trend in breast cancer risk with increasing quartiles of 15-F2t-IsoP levels [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 0.81-1.94; OR, 1.53; 95% CI, 0.99-2.35; OR, 1.88; 95% CI, 1.23-2.88, for the 2nd, 3rd, and 4th quartile relative to the lowest quartile, respectively; Ptrend = 0.002]. Although it is possible that increased levels may reflect the stress associated with recent treatment, the positive association was also observed when the analyses were restricted to case women for whom chemotherapy and radiation therapy had not yet been initiated at the time of the urine collection. The association with the highest quartile compared with lowest quartile of 15-F2t-IsoP was similar across strata of age, physical activity, fruit and vegetable intake, alcohol intake, cigarette smoking, body mass index, and menopausal status. We did not observe any association of breast cancer risk with 8-oxodG levels, but when cases with radiation treatment were removed from the analysis, a significant inverse trend (P = 0.04) was observed. Among controls, levels of 15-F2t-IsoP were higher among current cigarette smokers but did not differ by the amount of physical activity, fruit and vegetable intake, alcohol intake, body mass index, and menopausal status. Among controls, levels of 8-oxodG were higher among postmenopausal women and current and former cigarette smokers but did not differ by the other factors. In summary, our results suggest that urinary markers of lipid peroxidation and oxidative DNA damage may be associated with breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(4):639-44)

The role of oxidative stress in breast cancer risk is still unclear. OGG1 encodes an 8-oxoguanine DNA glycosylase/AP lyase that catalyzes the removal of 8-oxodeoxyguanosine from DNA. 8-Oxodeoxyguanosine, the most abundant lesion generated by oxidative stress, is highly mutagenic. Environmental sources of oxidative stress, such as alcohol consumption, cigarette smoking, high body mass index (BMI), and low fruits and vegetables intake, may modify the association of genetic polymorphisms with breast cancer risk. We investigated the association between three genetic polymorphisms in OGG1 (Ser326Cys, 7143A/G, and 11657A/G) and breast cancer risk among 1,058 cases and 1,102 controls participating in the Long Island Breast Cancer Study Project. No associations were observed between individual OGG1 polymorphisms, haplotypes, or diplotypes and breast cancer. The association between having at least one variant allele and breast cancer risk was stronger among moderate alcohol drinkers for Ser326Cys [odds ratio (OR), 1.82; 95% confidence interval (95% CI), 1.06-3.10] relative to nondrinkers with the wild-type genotype and among those with higher BMI for 7143A/G (OR, 1.47; 95% CI, 1.10-1.96) and for 11657A/G (OR, 1.41; 95% CI, 1.05-1.88), relative to women with BMI < 25 kg/m2 and the wild-type genotype. However, the patterns were not seen for all three single nucleotide polymorphisms (SNP) nor were there any clear allele dose associations; only one interaction was statistically significant, assuming a multiplicative model (11657A/G, Pinteraction = 0.04). In summary, although we found some differences between the three OGG1 SNPs and breast cancer risk among moderate alcohol drinkers and women with higher BMI, replication of these results is needed to rule out spurious findings. In addition, data on functionality of these polymorphisms are crucial to understand if these modest differences are important. (Cancer Epidemiol Biomarkers Prev 2006;15(4):811–5)

Moderate alcohol intake of one to two drinks per day has been consistently associated with a 30-50% increase in breast cancer. Despite the consistency in the overall association, several important questions remain, including whether the association between alcohol intake and breast cancer risk is affected by the timing of alcohol exposure, modified by other risk factors such as body mass index (BMI), menopausal status, and hormone replacement therapy (HRT), or more pronounced among hormone receptor positive tumors or invasive rather than in situ disease.To address these questions, we conducted a large population-based study (1508 cases and 1556 controls) that collected detailed information on alcohol and other exposures throughout the lifecourse.Consumption of 15-30 grams/day (approximately one to two drinks) throughout life was associated with a modest 33% increase in risk (odds ratio [OR] = 1.33, 95% confidence interval (CI) = 1.01-1.74), but heavier consumption (or = 30 grams per day) was not. Risk did not vary with alcohol type (beer, wine, or hard liquor) or by patterns of use, such as recent use, intake prior to age 20 years, or whether use began at an early age. The association with lifetime intake was limited to women with a BMI25 (OR = 2.13, 95% CI = 1.29-3.54). Alcohol consumption of approximately one drink per day was associated with estrogen receptor positive tumors among women with a BMI25, but not among women BMIor = 25. Also, the elevated OR was observed only among women diagnosed with invasive (OR = 1.56, 95% CI = 1.11-2.18), but not in situ breast tumors.These data give added support that moderate alcohol consumption over the life course increases breast cancer risk, particularly among women with low BMI and those diagnosed with estrogen receptor positive tumors or with invasive rather than in situ disease. Risk is confined to moderate intake and does not vary with the timing of use, with heavier doses, or with the type of alcohol consumed.

Carbonated soft drinks (CSDs) have been associated with gastroesophageal reflux, an established risk factor for esophageal adenocarcinoma. As both CSD consumption and esophageal adenocarcinoma incidence have sharply increased in recent decades, we examined CSD as a risk factor for esophageal and gastric cancers in a U.S. multicenter, population-based case-control study. Associations between CSD intake and risk were estimated by adjusted odds ratios (ORs), comparing the highest versus lowest quartiles of intake. All statistical tests were two-sided. Contrary to the proposed hypothesis, CSD consumption was inversely associated with esophageal adenocarcinoma risk (highest versus lowest quartiles, OR = 0.47, 95% confidence interval = 0.29 to 0.76; Ptrend = .005), due primarily to intake of diet CSD. High CSD consumption did not increase risk of any esophageal or gastric cancer subtype in men or women or when analyses were restricted to nonproxy interviews. These findings indicate that CSD consumption (especially diet CSD) is inversely associated with risk of esophageal adenocarcinoma, and thus it is not likely to have contributed to the rising incidence rates.

BACKGROUND Most epidemiologic studies report a reduced risk of developing breast cancer associated with higher levels of recreational physical activity, but little is known regarding its effect on prognosis. METHODS In this study, the authors investigated whether activity undertaken prior to diagnosis influenced breast cancer survival in a population-based cohort. A follow-up study was conducted among 1264 women ages 20 to 54 years who were diagnosed with invasive breast cancer between 1990 and 1992. Women in the study were interviewed within several months of diagnosis and were asked about their average frequency of moderate and vigorous activity at age 13 years, age 20 years, and during the year before diagnosis. With 8 to 10 years of follow-up, all-cause mortality status was determined by using the National Death Index (n = 290 deaths). RESULTS A modest reduction in the hazards ratio (HR) was observed for the highest quartile of activity in the year before diagnosis compared with the lowest quartile (stage-adjusted and income-adjusted HR, 0.78; 95% confidence interval [95% CI], 0.56–1.08). High activity was associated with a reduced HR among women who were overweight or obese at the time of diagnosis (HR, 0.70; 95% CI, 0.49–0.99) but not among ideal weight or underweight women (HR, 1.08; 95% CI, 0.77–1.52). A reduced HR was not evident for activity at age 13 years or 20 years or for average activity across the 3 periods studied. CONCLUSIONS The results of this study provided some suggestive evidence for a beneficial effect on survival of recreational physical activity undertaken in the year before diagnosis, particularly among women who are overweight or obese near the time of diagnosis. Cancer 2006. Published 2006 by the American Cancer Society.

Background Previous studies suggest that polycyclic aromatic hydrocarbons (PAHs) may adversely affect breast cancer risk. Indoor air pollution from use of indoor stoves and/or fireplaces is an important source of ambient PAH exposure. However, the association between indoor stove/fireplace use and breast cancer risk is unknown. We hypothesized that indoor stove/fireplace use in a Long Island, New York study population would be positively associated with breast cancer and differ by material burned, and the duration and timing of exposure. We also hypothesized that the association would vary by breast cancer subtype defined by p53 mutation status, and interact with glutathione S-transferases GSTM1, T1, A1 and P1 polymorphisms. Methods Population-based, case-control resources (1,508 cases/1,556 controls) were used to conduct unconditional logistic regression to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Results Breast cancer risk was increased among women reporting ever burning synthetic logs (which may also contain wood) in their homes (OR = 1.42, 95% CI 1.11, 1.84), but not for ever burning wood alone (OR = 0.93, 95% CI 0.77, 1.12). For synthetic log use, longer duration >7 years, older age at exposure (>20 years; OR = 1.65, 95% CI 1.02, 2.67) and 2 or more variants in GSTM1, T1, A1 or P1 (OR = 1.71, 95% CI 1.09, 2.69) were associated with increased risk. Conclusions Burning wood or synthetic logs are both indoor PAH exposure sources; however, positive associations were only observed for burning synthetic logs, which was stronger for longer exposures, adult exposures, and those with multiple GST variant genotypes. Therefore, our results should be interpreted with care and require replication. Electronic supplementary material The online version of this article (doi:10.1186/1476-069X-13-108) contains supplementary material, which is available to authorized users.

Multivariate methods were used to predict levels of dichlorodiphenyldichloroethene (DDE) and polychlorinated biphenyl (PCB) concentrations in plasma from characteristics that included age, diet, race, reproductive history, socioeconomic status, and reported body mass index (BMI) at several decades of life before blood collection. Measurements were available for organochlorine compound (organochlorines), cholesterol, and triglycerides in plasma from 1,008 women participants in a population-based case-control study of breast cancer undertaken in 1996 to 1997 on Long Island, NY. Organochlorine compound levels were associated with age, race, lactation history, body size characteristics, and plasma lipids. PCB predictors also included fish consumption. DDE was correlated with current BMI, BMI at every decade of age from ages 20 to 60 years, and BMI-gain (from ages 20 or 30 years to 1997). In contrast, PCBs were correlated inversely with both BMI (fifth to seventh decades of age) and BMI-gain. After adjusting for covariates, DDE and PCB were both positively associated with BMI and inversely with BMI-gain; they were lowest with low BMI, high BMI-gain, and longer lactation. This pattern is consistent with a pharmacokinetic model that predicts higher body burdens during windows of highest uptake, faster elimination of organochlorine compounds in leaner women, and lowered levels accompanying BMI-gain. As a result, lifetime intake for specific organochlorine compound may lead to different plasma levels dependent on changes in body size, absolute intensity of intake, and whether exposure is ongoing (i.e., PCB) or long discontinued (i.e., DDE).

The detection of polycyclic aromatic hydrocarbon (PAH)-DNA adducts in human lymphocytes may be useful as a surrogate end point for individual cancer risk prediction. In this study, we examined the relationship between environmental sources of residential PAH, as well as other potential factors that may confound their association with cancer risk, and the detection of PAH-DNA adducts in a large population-based sample of adult women. Adult female residents of Long Island, New York, aged at least 20 years were identified from the general population between August 1996 and July 1997. Among 1556 women who completed a structured questionnaire, 941 donated sufficient blood (25+ ml) to allow use of a competitive ELISA for measurement of PAH-DNA adducts in peripheral blood mononuclear cells. Ambient PAH exposure at the current residence was estimated using geographic modeling (n=796). Environmental home samples of dust (n=356) and soil (n=360) were collected on a random subset of long-term residents (15+ years). Multivariable regression was conducted to obtain the best-fitting predictive models. Three separate models were constructed based on data from : (A) the questionnaire, including a dietary history; (B) environmental home samples; and (C) geographic modeling. Women who donated blood in summer and fall had increased odds of detectable PAH-DNA adducts (OR=2.65, 95% confidence interval (CI)=1.69, 4.17; OR=1.59, 95% CI=1.08, 2.32, respectively), as did current and past smokers (OR=1.50, 95% CI=1.00, 2.24; OR=1.46, 95% CI=1.05, 2.02, respectively). There were inconsistent associations between detectable PAH-DNA adducts and other known sources of residential PAH, such as grilled and smoked foods, or a summary measure of total dietary benzo-[a]-pyrene (BaP) intake during the year prior to the interview. Detectable PAH-DNA adducts were inversely associated with increased BaP levels in dust in the home, but positively associated with BaP levels in soil outside of the home, although CIs were wide. Ambient BaP estimates from the geographic model were not associated with detectable PAH-DNA adducts. These data suggest that PAH-DNA adducts detected in a population-based sample of adult women with ambient exposure levels reflect some key residential PAH exposure sources assessed in this study, such as cigarette smoking.

Risk factors for subtypes of esophageal and gastric cancer recently have been identified, but their effect on survival is unknown.Incident cases (n = 1142) from a population-based case-control study were followed-up from diagnosis (1993-1995) until 2000. Cox regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for esophageal and gastric cancer in relation to prediagnostic factors.Relative to distant stage, esophageal adenocarcinoma (EA) patients with localized disease had a decreased risk for death (HR, .22; 95% CI, .15-.31), followed by those with regional spread (HR, .32; 95% CI, .23-.45). Similar patterns were seen for the other tumor types. Except for other (non-cardia) gastric adenocarcinomas (OGA), higher household income (or =15,000 US dollars/y vs.15,000 US dollars/y) was associated with a 33%-38% decrease in risk for death. Prediagnosis body mass index (BMI) between 25 and 29.9 kg/m 2 was associated with longer survival for EA and OGA patients (EA: HR, .67; 95% CI, .51-.88) vs. BMI25 kg/m(2). Women with esophageal squamous cell carcinoma (ES) and OGA experienced longer survival compared with men. Age, education, cigarette smoking, alcohol intake, gastroesophageal reflux disease, and nonsteroidal anti-inflammatory drug use did not consistently predict survival.Predictors of lengthened esophageal and gastric cancer survival included higher income (except in OGA), overweight (among EA and OGA patients), and female sex (among ES and OGA patients).

DNA repair is essential to an individual's ability to respond to damage caused by environmental carcinogens. Alterations in DNA repair genes may affect cancer risk by influencing individual susceptibility to environmental exposures. XPD, a gene involved in nucleotide excision repair, may influence individual DNA repair capacity particularly of bulky adducts. Using a population-based breast cancer case-control study that was specifically conducted to examine markers of environmental exposures, such as polycyclic aromatic hydrocarbons (PAH), on Long Island, NY, we examined whether XPD genotype modified the associations among PAH-DNA adducts, cigarette smoking, and breast cancer risk. Specifically, we examined the XPD polymorphism at exon 23, position 751 in 1,053 breast cancer cases and 1,102 population-based controls. The presence of at least one variant allele (Lys/Gln or Gln/Gln) was associated with a 20% increase in risk of breast cancer [odds ratio (OR), 1.21; 95% confidence interval (95% CI), 1.01-1.44]. The increase in risk for homozygosity of the variant allele (Gln/Gln) seemed limited to those with PAH-DNA adduct levels above the median(OR, 1.61; 95% CI, 0.99-2.63 for adducts above the median versus OR, 1.05; 95% CI, 0.64-1.74 for adductsbelow the median), although the multiplicative interaction was not statistically significant. The increasein risk for homozygosity of the variant allele (Gln/Gln) was only seen among current smokers (OR, 1.97; 95% CI, 1.02-3.81 for current smokers versus OR, 0.87; 95% CI, 0.57-1.32 for never smokers); the multiplicative interaction was statistically significant. Overall, this study suggests that those individuals with this polymorphism in the XPD gene may face an increased risk of breast cancer from PAH-DNA adducts and cigarette smoking.

Myeloperoxidase (MPO), an antimicrobial enzyme in the breast, generates reactive oxygen species (ROS) endogenously. An MPO G463A polymorphism exists in the promoter region, with the variant A allele conferring lower transcription activity than the common G allele. Because oxidative stress may play a role in breast carcinogenesis, we evaluated MPO genotypes in relation to breast cancer risk among 1,011 cases and 1,067 controls from the Long Island Breast Cancer Study Project (1996–1997). We also assessed the potential modifying effects of dietary antioxidants and hormonally related risk factors on these relationships. Women over 20 years with incident breast cancer who were residents of Nassau and Suffolk Counties, NY, were identified as potential cases. Population-based controls were frequency matched by 5-year age groups. Genotyping was performed with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) technology, and suspected breast cancer risk factors and usual dietary intake were assessed during an in-person interview. Unconditional logistic regression was used to estimate odds ratios and 95% confidence intervals. Having at least one A allele was associated with an overall 13% reduction in breast cancer risk. When consumption of fruits and vegetables and specific dietary antioxidants were dichotomized at the median, inverse associations with either GA or AA genotypes were most pronounced among women who consumed higher amounts of total fruits and vegetables (odds ratio, 0.75; 95% confidence interval, 0.58–0.97); this association was not noted among the low-consumption group (P for interaction = 0.04). Relationships were strongest among premenopausal women. Results from this first study of MPO genotypes and breast cancer risk indicate that MPO variants, related to reduced generation of ROS, are associated with decreased breast cancer risk, and emphasize the importance of fruit and vegetable consumption in reduction of breast cancer risk.

To evaluate whether environmental tobacco smoke (ETS) influences breast cancer incidence, data from a population-based case-control study were analyzed. Respondents with available ETS information assessed by in-person questionnaires included 1356 newly diagnosed cases and 1383 controls. Relative to nonsmokers who reported no residential ETS exposure throughout the life course, the odds ratios (OR) for breast cancer were not substantially elevated in relation to ETS exposure, active smoking, or a joint measure of active and passive smoking (OR, 1.15, 95% CI, 0.90, 1.48). An increased OR, however, was noted among nonsmokers who lived with a smoking spouse for over 27 years (2.10, 95% CI, 1.47, 3.02), although no dose-response was evident. Also, among women with hormone-receptor-positive tumors only, the OR for both active and passive smoking was increased (1.42 for ER+ PR+, 95% CI, 1.00, 2.00). Our data suggest that if there is an effect for ETS on breast cancer, that effect is restricted to selected subgroups of women, such as those with long-term exposure from a smoking spouse.

This study was undertaken to determine whether selected risk factors for esophageal and gastric cancer are associated with tumors that overexpress cyclin D1. Archived tumor tissue was available for 630 esophageal and gastric cancer patients who participated in a population-based case-control study. Patients were categorized into case groups based on whether protein overexpression of the cyclin D1 gene, as assessed by immunohistochemistry, was present (cyclin D1+, n = 285) or not (cyclin D1−, n = 345) in the tumor. The distribution of risk factors in each of these case groups was then compared with the distribution among the 695 controls. Multivariate-adjusted odds ratios (OR) for esophageal adenocarcinoma were reduced in relation to use of aspirin and other nonsteroidal anti-inflammatory drug (NSAID) use but only among patients with cyclin D1+ tumors (0.45, 95% confidence interval [CI] = 0.26, 0.79) and not among those with cyclin D1− tumors (1.12, 95% CI = 0.67, 1.86). A similar pattern was observed for gastric cardia adenocarcinomas. In contrast, ORs for esophageal squamous cell carcinoma and noncardia gastric adenocarcinomas in relation to NSAID use were reduced, regardless of cyclin D1 status. ORs did not vary with cyclin D1 status in relation to alcohol, body size, or cigarette smoking, with the following exception; for noncardia gastric adenocarcinomas the cyclin D1− tumors showed a 2-fold elevation in the OR with ever smoking. These data suggest that the reduction in risk associated with NSAID use may be restricted to those esophageal and gastric cardia adenocarcinomas that overexpress cyclin D1.

The Electromagnetic Fields and Breast Cancer on Long Island Study (EBCLIS) is a large population-based case-control study investigating possible associations between magnetic fields and breast cancer, and includes a comprehensive set of in-home measurements. We investigated the reproducibility of wire codes, their relation to 24-h measurements of residential magnetic fields, and potential influences, such as housing characteristics, in homes of the 1161 EBCLIS participants. Replicate wire coding was performed in homes originally categorized as having very high current configurations (VHCC) in the Wertheimer-Leeper (W-L) wire coding scheme, and a random sample of other homes (235 residences). Reproducibility was very high, with a kappa statistic of 0.83 (95% confidence interval (CI)=0.77-0.89) for the five-category W-L wire codes and 0.91 (95% CI=0.86-0.95) for the three-category Kaune-Savitz (K-S) codes. As levels of W-L and K-S wire codes increased, the mean and median 24-h levels of broadband and harmonic fields in the residences also increased, indicating an association between wire codes and magnetic fields measurements. Regions of Long Island with the highest percentage of homes built before 1950 had the highest percentage of higher current configuration homes, as well as the highest average 24-h broadband and harmonic measurements. Adjustment for age of the home and region did not affect the relation between wire codes and measured magnetic fields. Our results indicate that: (a). a high reproducibility in wire coding was achieved, (b). wire codes were correlated with magnetic fields, and (c). wire code levels were related to the age of the home. The high level of reproducibility suggests that, in our case-control analyses, there will be minimal bias due to misclassification of wire code categories. Results also suggest that wire codes are a proxy measure, to some degree, for current in-home magnetic field measurements in this study.

Breast cancer is one of the major cancers around the world but its etiology is still not well understood. Only approximately 50% of the disease is associated with known risk factors including highly penetrant genes and lifestyle factors. Thus, environmental carcinogens may play an important role in the etiology of breast cancer. The arylamine 4-aminobiphenyl (4-ABP) is a tobacco smoke constituent, an environmental contaminant, and a well-established bladder carcinogen in rodents and humans. In this study, we investigated the role of 4-ABP in the etiology of human breast cancer by measuring 4-ABP-DNA adducts using a monoclonal antibody based immunoperoxidase method that had been validated by comparison with gas chromatography/mass spectroscopy analysis of liver tissues from 4-ABP-treated mice. Adducts were analyzed in 150 paraffin-embedded breast tumors and in 55 adjacent normal tissues collected from cases in the Long Island Breast Cancer Study Project. The role of polymorphisms in genes involved in the metabolism of 4-ABP including N-acetyl transferase 2 (NAT2), cytochrome P4501A2 (CYP1A2) and glutathione S-transferase M1 (GSTM1) and the nucleotide excision repair gene XPD was also explored in the same patients. The mean log-transformed relative staining intensity for 4-ABP-DNA adducts was higher in normal (5.93 +/- 0.54) than in the corresponding tumor (5.44 +/- 0.62, P < 0.0001) tissues. However, a highly significant positive correlation was observed between the levels of 4-ABP-DNA in both tissues (r = 0.72, P < 0.0001). Smoking status was correlated with the levels of 4-ABP-DNA in tumor adjacent normal tissues with a significant linear trend (P = 0.04) for current, former and never smokers; adducts were not related to smoking status in tumor tissues. No correlation was observed between the levels of 4-ABP-DNA and polymorphisms in the genes analyzed even when subjects were stratified by smoking status. These results demonstrate that smoking is associated with increased levels of 4-ABP-DNA adducts in human mammary tissue. In this study, genetic polymorphisms did not significantly affect the formation of 4-ABP-DNA adducts in breast cancer cases, perhaps due to the small number of samples.

Objective: To evaluate the potential etiologic heterogeneity of breast cancer by examining whether associations with reproductive and other personal characteristics differed by p53 protein expression status. Methods: Data from the Carolina Breast Cancer Study, a population-based, case–control study of 861 cases and 790 controls, were utilized. Immunohistochemical staining for the p53 protein was performed on 638 archived tumor specimens; 46% of cases were classified as p53+. Two separate unconditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for p53+ and p53− breast cancer relative to controls for reproductive and other personal characteristics. Analyses were performed separately for younger (≤45 years) and older (>45 years) women. Results: Risk factor profiles largely overlapped for p53+ and p53− breast cancer, with the exception of oral contraceptive (OC) use among younger women and a family history of breast cancer. Prolonged OC use was more strongly associated with p53+ breast cancer [OR 3.1 (95% CI: 1.2–8.1) than p53− breast cancer (OR 1.3 (95% CI: 0.6–3.2)] among younger women only. A first-degree family history of breast cancer was associated with p53+ breast cancer among younger women [OR 1.5 (95% CI: 1.0–2.2)] and older women [OR 1.4 (95% CI: 0.9–2.3)], but not p53− breast cancer in either age-group. Conclusions: These results provide little evidence of breast cancer heterogeneity as classified by p53 expression status. However, although not statistically significant, OC use among younger women and family history of breast cancer may operate through a pathway involving p53 alterations to increase risk of breast cancer.

Objective: To assess risk factors for breast cancer among very young compared to older premenopausal women. Methods: Between 1990 and 1992 a population-based case–control study conducted in Atlanta, GA, Seattle/Puget Sound, WA, and central NJ interviewed 3307 premenopausal women aged 20–54 years. Logistic regression models estimated adjusted relative risks (RR) and 95% confidence intervals (CI) for each of three 10-year age groups. Results: Among the youngest age group (