Susan E. McCann

Detection of epithelial ovarian cancer using 1H-NMR-based metabonomics

Currently available serum biomarkers are insufficiently reliable to distinguish patients with epithelial ovarian cancer (EOC) from healthy individuals. Metabonomics, the study of metabolic processes in biologic systems, is based on the use of 1H‐NMR spectroscopy and multivariate statistics for biochemical data generation and interpretation and may provide a characteristic fingerprint in disease. In an effort to examine the utility of the metabonomic approach for discriminating sera from women with EOC from healthy controls, we performed 1H‐NMR spectroscopic analysis on preoperative serum specimens obtained from 38 patients with EOC, 12 patients with benign ovarian cysts and 53 healthy women. After data reduction, we applied both unsupervised Principal Component Analysis (PCA) and supervised Soft Independent Modeling of Class Analogy (SIMCA) for pattern recognition. The sensitivity and specificity tradeoffs were summarized for each variable using the area under the receiver‐operating characteristic (ROC) curve. In addition, we analyzed the regions of NMR spectra that most strongly influence separation of sera of EOC patients from healthy controls. PCA analysis allowed correct separation of all serum specimens from 38 patients with EOC (100%) from all of the 21 premenopausal normal samples (100%) and from all the sera from patients with benign ovarian disease (100%). In addition, it was possible to correctly separate 37 of 38 (97.4%) cancer specimens from 31 of 32 (97%) postmenopausal control sera. SIMCA analysis using the Coomans plot demonstrated that sera classes from patients with EOC, benign ovarian cysts and the postmenopausal healthy controls did not share multivariate space, providing validation for the class separation. ROC analysis indicated that the sera from patients with and without disease could be identified with 100% sensitivity and specificity at the 1H‐NMR regions 2.77 parts per million (ppm) and 2.04 ppm from the origin (AUC of ROC curve = 1.0). In addition, the regression coefficients most influential for the EOC samples compared to postmenopausal controls lie around δ3.7 ppm (due mainly to sugar hydrogens). Other loadings most influential for the EOC samples lie around δ2.25 ppm and δ1.18 ppm. These findings indicate that 1H‐NMR metabonomic analysis of serum achieves complete separation of EOC patients from healthy controls. The metabonomic approach deserves further evaluation as a potential novel strategy for the early detection of epithelial ovarian cancer.

Type I and II Endometrial Cancers: Have They Different Risk Factors?

PURPOSE Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors. PATIENTS AND METHODS Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors. RESULTS Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m(2) increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (P heterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar. CONCLUSION The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.

Association between global DNA hypomethylation in leukocytes and risk of breast cancer

Background: Global DNA hypomethylation may result in chromosomal instability and oncogene activation, and as a surrogate of systemic methylation activity, may be associated with breast cancer risk. Methods: Samples and data were obtained from women with incident early-stage breast cancer (I–IIIa) and women who were cancer free, frequency matched on age and race. In preliminary analyses, genomic methylation of leukocyte DNA was determined by measuring 5-methyldeoxycytosine (5-mdC), as well as methylation analysis of the LINE-1-repetitive DNA element. Further analyses used only 5-mdC levels. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of breast cancer in relation to amounts of methylation. Results: In a subset of samples tested (n = 37), 5-mdC level was not correlated with LINE-1 methylation. 5-mdC level in leukocyte DNA was significantly lower in breast cancer cases than healthy controls (P = 0.001), but no significant case–control differences were observed with LINE-1 methylation (P = 0.176). In the entire data set, we noted significant differences in 5-mdC levels in leukocytes between cases (n = 176) and controls (n = 173); P value < 0.001. Compared with women in the highest 5-mdC tertile (T3), women in the second (T2; OR = 1.49, 95% CI = 0.84–2.65) and lowest tertile (T1; OR = 2.86, 95% CI = 1.65–4.94) had higher risk of breast cancer (P for trend ≤0.001). Among controls only and cases and controls combined, only alcohol intake was found to be inversely associated with methylation levels. Conclusion: These findings suggest that leukocyte DNA hypomethylation is independently associated with development of breast cancer.

Diet in the epidemiology of endometrial cancer in western New York (United States).

AbstractObjectives: We examined diet and risk of endometrial cancer among women in the Western New York Diet Study (1986–1991). Methods: Self-reported frequency of use of 172 foods and beverages during the 2 years before the interview and other relevant data were collected by detailed interviews from 232 endometrial cancer cases and 639 controls, frequency-matched for age and county of residence. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by unconditional logistic regression, adjusting for age, education, body mass index (BMI), smoking history, hypertension, diabetes, age at menarche, parity, oral contraceptive use, menopausal status, menopausal estrogen use, and energy. Results: Risks were reduced for women in the highest quartiles of intake of protein (OR 0.4, 95% CI: 0.2–0.9), dietary fiber (OR 0.5, 95% CI: 0.3–1.0), phytosterols (OR 0.6, 95% CI: 0.3–1.0), vitamin C (OR 0.5, 95% CI: 0.3–0.8) folate (OR 0.4, 95% CI: 0.2–0.7), alpha-carotene (OR 0.6, 95% CI: 0.4–1.0), beta-carotene (OR 0.4, 95% CI: 0.2–0.6), lycopene (OR 0.6, 95% CI: 0.4–1.0), lutein + zeaxanthin (OR 0.3, 95% CI: 0.2–0.5) and vegetables (OR 0.5, 95% CI: 0.3–0.9), but unrelated to energy (OR 0.9, 95% CI: 0.6–1.5) or fat (OR 1.6, 95% CI: 0.7–3.4). Conclusions: Our results support previous findings of reduced endometrial cancer risks associated with a diet high in plant foods.

Intakes of Selected Nutrients, Foods, and Phytochemicals and Prostate Cancer Risk in Western New York

Abstract: A number of epidemiological studies have suggested that diet may affect the etiology of prostate cancer, but few have investigated the impact of phytochemical intakes on this cancer. We conducted a case-control study of diet and prostate cancer in western New York involving 433 men with primary, histologically confirmed prostate cancer and 538 population-based controls, frequency matched to cases on age and county of residence. Diet was assessed with a detailed food-frequency questionnaire. We calculated daily intakes of nutrients and the phytochemicals β-sitosterol, campesterol, stigmasterol, total phytosterols, total lignan precursors, quercetin, and kaempferol based on published food composition data. Odds ratios (ORs) and 95% confidence intervals (CIs) describing the association of prostate cancer risk with selected nutrients, phytochemicals, and food groups were estimated with unconditional logistic regression. Compared with men in the lowest quartile of intake, reduced risks were observed for men in the highest quartile of intake of vitamin C (OR = 0.49; 95% CI = 0.33-0.74), β-carotene (OR = 0.53; 95% CI = 0.36-0.79), α-carotene (OR = 0.67; 95% CI = 0.47-0.97), lutein (OR = 0.55; 95% CI = 0.37-0.81), lycopene (OR = 0.62; 95% CI = 0.42-0.92), total lignan precursors (OR = 0.66; 95% CI = 0.47-0.94), quercetin (OR = 0.64; 95% CI = 0.44-0.92), and total vegetables (OR = 0.53; 95% CI = 0.36-0.79), but weak increased risks were observed for snacks and sweets (OR = 1.46; 95% CI = 0.95-2.23). Estimates associated with nutrients and phytochemicals were attenuated after adjustment for total vegetable intake. Nevertheless, our results support the hypothesis that a phytochemical-rich, plant-based diet is of importance in reducing risks of hormone-related neoplasms.

Analysis of patterns of food intake in nutritional epidemiology: food classification in principal components analysis and the subsequent impact on estimates for endometrial cancer

OBJECTIVE To assess the effect of different methods of classifying food use on principal components analysis (PCA)-derived dietary patterns, and the subsequent impact on estimation of cancer risk associated with the different patterns. METHODS Dietary data were obtained from 232 endometrial cancer cases and 639 controls (Western New York Diet Study) using a 190-item semi-quantitative food-frequency questionnaire. Dietary patterns were generated using PCA and three methods of classifying food use: 168 single foods and beverages; 56 detailed food groups, foods and beverages; and 36 less-detailed groups and single food items. RESULTS Classification method affected neither the number nor character of the patterns identified. However, total variance explained in food use increased as the detail included in the PCA decreased (approximately 8%, 168 items to approximately 17%, 36 items). Conversely, reduced detail in PCA tended to attenuate the odds ratio (OR) associated with the healthy patterns (OR 0.55, 95% confidence interval (CI) 0.35-0.84 and OR 0.77, 95% CI 0.49-1.20, 168 and 36 items, respectively) but not the high-fat patterns (OR 0.95, 95% CI 0.57-1.58 and OR 0.85, 0.51-1.40, 168 and 36 items, respectively). CONCLUSIONS Greater detail in food-use information may be desirable in determination of dietary patterns for more precise estimates of disease risk.

Consumption of Raw Cruciferous Vegetables is Inversely Associated with Bladder Cancer Risk

Cruciferous vegetables contain isothiocyanates, which show potent chemopreventive activity against bladder cancer in both in vitro and in vivo studies. However, previous epidemiologic studies investigating cruciferous vegetable intake and bladder cancer risk have been inconsistent. Cooking can substantially reduce or destroy isothiocyanates, and could account for study inconsistencies. In this hospital-based case-control study involving 275 individuals with incident, primary bladder cancer and 825 individuals without cancer, we examined the usual prediagnostic intake of raw and cooked cruciferous vegetables in relation to bladder cancer risk. Odds ratios (OR) and 95% confidence intervals (CI) were estimated with unconditional logistic regression, adjusting for smoking and other bladder cancer risk factors. We observed a strong and statistically significant inverse association between bladder cancer risk and raw cruciferous vegetable intake (adjusted OR for highest versus lowest category = 0.64; 95% CI, 0.42-0.97), with a significant trend (P = 0.003); there were no significant associations for fruit, total vegetables, or total cruciferous vegetables. The associations observed for total raw crucifers were also observed for individual raw crucifers. The inverse association remained significant among current and heavy smokers with three or more servings per month of raw cruciferous vegetables (adjusted ORs, 0.46 and 0.60; 95% CI, 0.23-0.93 and 0.38-0.93, respectively). These data suggest that cruciferous vegetables, when consumed raw, may reduce the risk of bladder cancer, an effect consistent with the role of dietary isothiocyanates as chemopreventive agents against bladder cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(4):938–44)

Antioxidants, oxidative stress, and pulmonary function in individuals diagnosed with asthma or COPD.

Objective:The objective of this study was to investigate the association between antioxidant nutrients and markers of oxidative stress with pulmonary function in persons with chronic airflow limitation.Design:Cross-sectional study exploring the association of antioxidant nutrients and markers of oxidative stress with forced expiratory volume in the first second (FEV1%) and forced vital capacity (FVC%).Setting/Subjects:The study data included 218 persons with chronic airflow limitation recruited randomly from the general population of Erie and Niagara counties, New York State, USA.Results:After adjustment for covariates, multiple linear regression analysis showed that serum β-cryptoxanthin, lutein/zeaxanthin, and retinol, and dietary β-carotene, β-cryptoxanthin, lutein/zeaxanthin, vitamin C, and lycopene were positively associated with FEV1% (P<0.05, all associations). Serum vitamins β-cryptoxanthin, lutein/zeaxanthin, and lycopene, and dietary β-cryptoxanthin, β-carotene, vitamin C, and lutein/zeaxanthin were positively associated with FVC% (P<0.05, all associations). Erythrocytic glutathione was negatively associated with FEV1%, while plasma thiobarbituric acid-reactive substances (TBARS) were negatively associated with FVC% (P<0.05).Conclusion:These results support the hypothesis that an imbalance in antioxidant/oxidant status is associated with chronic airflow limitation, and that dietary habits and/or oxidative stress play contributing roles.

Dietary lignan intakes and risk of pre- and postmenopausal breast cancer

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.

Associations between Catalase Phenotype and Genotype: Modification by Epidemiologic Factors

Catalase is an endogenous antioxidant enzyme that neutralizes hydrogen peroxide and is induced by oxidative challenge. A −262C → T polymorphism in the promoter region of the gene (CAT) is associated with risk of several conditions related to oxidative stress. We sought to determine the functional effects of the CAT polymorphism on enzyme activity in erythrocytes and the potential modifying effects of demographic and lifestyle factors on genotype/phenotype relationships, using specimens and data from controls from breast and prostate cancer studies in Arkansas (n = 420). There was a dose-response reduction in catalase activity by genotype, with geometric means of 115.4 units/mg hemoglobin for those with CC genotypes, 82.1 units/mg for those with CT genotypes, and 73.5 units/mg for those with TT genotypes. Associations were only observed among Caucasians (P < 0.0001), with no effects among African Americans (P = 0.91), and were stronger among women than men, although numbers in stratified analyses were small. Differences in catalase activity by genotype were most pronounced among those in the highest tertiles of consumption of fruits and vegetables (−35%, P = 0.003), with weaker relationships among those who were lower consumers (−21.8%, P = 0.16). Among those with CC genotypes, there was no change in activity by consumption, but there were notable decreases in activity by tertiles of consumption for those with at least one T allele. These data indicate that the CAT −262C → T polymorphism predicts a portion of catalase phenotype, which may be limited to Caucasians. Associations between genotype and phenotype were modified by dietary factors, illustrating the biochemical complexity of studies of genetic polymorphisms and disease risk. (Cancer Epidemiol Biomarkers Prev 2006;15(6):1217-22)