Showing papers in "Cancer Epidemiology, Biomarkers & Prevention in 2002"

Polymorphisms in DNA repair genes and associations with cancer risk.

Abstract: Common polymorphisms in DNA repair genes may alter protein function and an individual's capacity to repair damaged DNA; deficits in repair capacity may lead to genetic instability and carcinogenesis. To establish our overall understanding of possible in vivo relationships between DNA repair polymorphisms and the development of cancer, we performed a literature review of epidemiological studies that assessed associations between such polymorphisms and risk of cancer. Thirty studies of polymorphisms in OGG1, XRCC1, ERCC1, XPC, XPD, XPF, BRCA2, and XRCC3 were identified in the April 30, 2002 MEDLINE database (National Center for Biotechnology Information. PubMed Database: http://www.ncbi.nlm.nih.gov/entrez). These studies focused on adult glioma, bladder cancer, breast cancer, esophageal cancer, lung cancer, prostate cancer, skin cancer (melanoma and nonmelanoma), squamous cell carcinoma of the head and neck, and stomach cancer. We found that a small proportion of the published studies were large and population-based. Nonetheless, published data were consistent with associations between: (a) the OGG1 S326C variant and increased risk of various types of cancer; (b) the XRCC1 R194W variant and reduced risk of various types of cancer; and (c) the BRCA2 N372H variant and increased risk of breast cancer. Suggestive results were seen for polymorphisms in other genes; however, small sample sizes may have contributed to false-positive or false-negative findings. We conclude that large, well-designed studies of common polymorphisms in DNA repair genes are needed. Such studies may benefit from analysis of multiple genes or polymorphisms and from the consideration of relevant exposures that may influence the likelihood of cancer in the presence of reduced DNA repair capacity.

Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review.

Abstract: Endometrial cancer is a disease of the affluent, developed world, where epidemiological studies have shown that > or =40% of its incidence can be attributed to excess body weight. An additional proportion may be because of lack of physical activity. Alterations in endogenous hormone metabolism may provide the main links between endometrial cancer risk, and excess body weight and physical inactivity. Epidemiological studies have shown increased endometrial cancer risks among pre- and postmenopausal women who have elevated plasma androstenedione and testosterone, and among postmenopausal women who have increased levels of estrone and estradiol. Furthermore, there is evidence that chronic hyperinsulinemia is a risk factor. These relationships can all be interpreted in the light of the "unopposed estrogen" hypothesis, which proposes that endometrial cancer may develop as a result of the mitogenic effects of estrogens, when these are insufficiently counterbalanced by progesterone. In our overall synthesis, we conclude that development of ovarian hyperandrogenism may be a central mechanism relating nutritional lifestyle factors to endometrial cancer risk. In premenopausal women, ovarian hyperandrogenism likely increases risk by inducing chronic anovulation and progesterone deficiency. After the menopause, when progesterone synthesis has ceased altogether, excess weight may continue increasing risk through elevated plasma levels of androgen precursors, increasing estrogen levels through the aromatization of the androgens in adipose tissue. The ovarian androgen excess may be because of an interaction between obesity-related, chronic hyperinsulinemia with genetic factors predisposing to the development of ovarian hyperandrogenism.

Pharmacokinetics of Tea Catechins after Ingestion of Green Tea and (−)-Epigallocatechin-3-gallate by Humans: Formation of Different Metabolites and Individual Variability

Abstract: Green tea and tea polyphenols have been studied extensively as cancer chemopreventive agents in recent years. The bioavailability and metabolic fate of tea polyphenols in humans, however, are not clearly understood. In this report, the pharmacokinetic parameters of (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), and (-)-epicatechin (EC) were analyzed after administration of a single oral dose of green tea or decaffeinated green tea (20 mg tea solids/kg) or EGCG (2 mg/kg) to eight subjects. The plasma and urine levels of total EGCG, EGC, and EC (free plus conjugated forms) were quantified by HPLC coupled to an electrochemical detector. The plasma concentration time curves of the catechins were fitted in a one-compartment model. The maximum plasma concentrations of EGCG, EGC, and EC in the three repeated experiments with green tea were 77.9 +/- 22.2, 223.4 +/- 35.2, and 124.03 +/- 7.86 ng/ml, respectively, and the corresponding AUC values were 508.2 +/- 227, 945.4 +/- 438.4, and 529.5 +/- 244.4 ng x h x ml(-1), respectively. The time needed to reach the peak concentrations was in the range of 1.3-1.6 h. The elimination half-lives were 3.4 +/- 0.3, 1.7 +/- 0.4, and 2.0 +/- 0.4 h, respectively. Considerable interindividual differences and variations between repeated experiments in the pharmacokinetic parameters were noted. Significant differences in these pharmacokinetic parameters were not observed when EGCG was given in decaffeinated green tea or in pure form. In the plasma, EGCG was mostly present in the free form, whereas EGC and EC were mostly in the conjugated form. Over 90% of the total urinary EGC and EC, almost all in the conjugated forms, were excreted between 0 and 8 h. Substantial amounts of 4'-O-methyl EGC, at levels higher than EGC, were detected in the urine and plasma. The plasma level of 4'-O-methyl EGC peaked at 1.7 +/- 0.5 h with a half life of 4.4 +/- 1.1 h. Two ring-fission metabolites, (-)-5-(3',4',5'-trihydroxyphenyl)-gamma-valerolactone (M4) and (-)-5-(3',4'-dihydroxyphenyl)-valerolactone (M6), appeared in significant amounts after 3 h and peaked at 8-15 h in the urine as well as in the plasma. These results may be useful for designing the dose and dose frequency in intervention studies with tea and for development of biomarkers of tea consumption.

Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial.

Abstract: The Nutritional Prevention of Cancer Trial was a randomized, clinical trial designed to evaluate the efficacy of selenium as selenized yeast (200 microg daily) in preventing the recurrence of nonmelanoma skin cancer among 1312 residents of the Eastern United States. Original secondary analyses through December 31, 1993 showed striking inverse associations between treatment and the incidence of total [hazard ratio (HR) = 0.61, 95% confidence interval (CI) = 0.46-0.82], lung, prostate, and colorectal cancer and total cancer mortality. This report presents results through February 1, 1996, the end of blinded treatment. Effect modification by baseline characteristics is also evaluated. The effects of treatment overall and within subgroups of baseline age, gender, smoking status, and plasma selenium were examined using incidence rate ratios and Cox proportional hazards models. Selenium supplementation reduced total (HR = 0.75, 95% CI = 0.58-0.97) and prostate (HR = 0.48, 95% CI = 0.28-0.80) cancer incidence but was not significantly associated with lung (HR = 0.74, 95% CI = 0.44-1.24) and colorectal (HR = 0.46, 95% CI = 0.21-1.02) cancer incidence. The effects of treatment on other site-specific cancers are also described. The protective effect of selenium was confined to males (HR = 0.67, 95% CI = 0.50-0.89) and was most pronounced in former smokers. Participants with baseline plasma selenium concentrations in the lowest two tertiles (<121.6 ng/ml) experienced reductions in total cancer incidence, whereas those in the highest tertile showed an elevated incidence (HR = 1.20, 95% CI = 0.77-1.86). The Nutritional Prevention of Cancer trial continues to show a protective effect of selenium on cancer incidence, although not all site-specific cancers exhibited a reduction in incidence. This treatment effect was restricted to males and to those with lower baseline plasma selenium concentrations.

Metabolism of the Cancer Chemopreventive Agent Curcumin in Human and Rat Intestine

Abstract: Curcumin, the yellow pigment in turmeric, prevents malignancies in the intestinal tract of rodents. It is under clinical evaluation as a potential colon cancer chemopreventive agent. The systemic bioavailability of curcumin is low, perhaps attributable, at least in part, to metabolism. Indirect evidence suggests that curcumin is metabolized in the intestinal tract. To investigate this notion further, we explored curcumin metabolism in subcellular fractions of human and rat intestinal tissue, compared it with metabolism in the corresponding hepatic fractions, and studied curcumin metabolism in situ in intact rat intestinal sacs. Analysis by high-performance liquid chromatography, with detection at 420 or 280 nm, permitted characterization of curcumin conjugates and reduction products. Chromatographic inferences were corroborated by mass spectrometry. Curcumin glucuronide was identified in intestinal and hepatic microsomes, and curcumin sulfate, tetrahydrocurcumin, and hexahydrocurcumin were found as curcumin metabolites in intestinal and hepatic cytosol from humans and rats. The extent of curcumin conjugation was much greater in intestinal fractions from humans than in those from rats, whereas curcumin conjugation was less extensive in hepatic fractions from humans than in those from rats. The curcumin-reducing ability of cytosol from human intestinal and liver tissue exceeded that observed with the corresponding rat tissue by factors of 18 and 5, respectively. Curcumin sulfate was identified in incubations of curcumin with intact rat gut sacs. Curcumin was sulfated by human phenol sulfotransferase isoenzymes SULT1A1 and SULT1A3. Equine alcohol dehydrogenase catalyzed the reduction of curcumin to hexahydrocurcumin. The results show that curcumin undergoes extensive metabolic conjugation and reduction in the gastrointestinal tract and that there is more metabolism in human than in rat intestinal tissue. The pharmacological implications of the intestinal metabolism of curcumin should be taken into account in the design of future chemoprevention trials of this dietary constituent.

Risk of Renal and Colonic Neoplasms and Spontaneous Pneumothorax in the Birt-Hogg-Dubé Syndrome

Abstract: The Birt-Hogg-Dube syndrome, a genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal and colonic neoplasms and spontaneous pneumothorax, but the risk of developing these disorders is unknown. We identified risk factors for renal tumors and spontaneous pneumothorax in 98 patients affected with the Birt-Hogg-Dube syndrome, in 13 Birt-Hogg-Dube haplotype carriers, and in 112 unaffected family members. Development of renal tumors was strongly associated with the Birt-Hogg-Dube syndrome and age. The odds ratio for renal tumor in BHD-affected family members adjusted for age was 6.9 (95% confidence interval, 1.5–31.6) and ∼9.0 for the other risk factors considered. Chromophobe renal carcinoma, an uncommon type of renal cancer, was the predominant type of renal cancer found. Spontaneous pneumothorax was also strongly associated with the Birt-Hogg-Dube syndrome and age. The odds ratio for pneumothorax in BHD-affected individuals, adjusted for age, was 50.3 (95% confidence interval, 6.4–392), and about 32 times higher adjusting for the other risk variables. Colon cancer and colon polyps were not related to the Birt-Hogg-Dube syndrome. The Birt-Hogg-Dube syndrome confers an increased risk for the development of renal tumors and spontaneous pneumothorax. We found no increase in risk for the development of colon polyps or colon carcinomas.

Lifestyle Correlates of Plasma Insulin-like Growth Factor I and Insulin-like Growth Factor Binding Protein 3 Concentrations

Abstract: Plasma levels of insulin-like growth factor I (IGF-I) have been associated with risk of several cancers. Although protein-calorie malnutrition is known to decrease IGF-I levels, few published studies have related diet to IGF-I levels in well-nourished humans. We examined the cross-sectional association of plasma IGF-I and IGF-binding protein 3 (IGFBP-3) levels with intakes of alcohol, energy, macronutrients, micronutrients, and specific foods in 1037 healthy women. Adjusted mean hormone levels across categories of dietary variables were calculated by linear regression. Results were adjusted for non-dietary factors found to be associated with IGF levels. Total energy intake was positively associated with IGF-I levels when adjusted for covariates. Adjusted mean levels of IGF-I (ng/ml) across increasing quintiles of energy intake were 181, 185, 191, 199, and 195 (P for the linear trend = 0.006). In other multivariate analyses, energy-adjusted fat and carbohydrate intake had no association with IGF-I levels. The most consistent finding was a positive association between protein intake with circulating IGF-I concentration (174, 188, 201, 192, and 196 ng/ml across quintiles of protein intake; P = 0.002), which was largely attributable to milk intake. Adjusted mean levels of IGF-I (ng/ml) across increasing quartiles of milk intake were 183, 189, 188, and 200 (P = 0.01). Higher fat intake, in particular saturated fat, was associated with lower levels of IGFBP-3. We conclude that higher energy, protein, and milk intakes were associated with higher levels of IGF-I. These associations raise the possibility that diet could affect cancer risk through influencing IGF-I level.

Point: Population Stratification: A Problem for Case-Control Studies of Candidate-Gene Associations?

Abstract: The case-control design is a widely used approach for investigating associations between candidate genes and dichotomous disease traits. As mostcommonly implemented, cases are drawn from a population-baseddisease registry and unrelated controls from their source population, perhaps matching on age,

Chemopreventive Efficacy and Pharmacokinetics of Curcumin in the Min/+ Mouse, a Model of Familial Adenomatous Polyposis

Abstract: Curcumin, the major yellow pigment in turmeric, prevents the development of adenomas in the intestinal tract of the C57Bl/6J Min/+ mouse, a model of human familial APC. To aid the rational development of curcumin as a colorectal cancer-preventive agent, we explored the link between its chemopreventive potency in the Min/+ mouse and levels of drug and metabolites in target tissue and plasma. Mice received dietary curcumin for 15 weeks, after which adenomas were enumerated. Levels of curcumin and metabolites were determined by high-performance liquid chromatography in plasma, tissues, and feces of mice after either long-term ingestion of dietary curcumin or a single dose of [(14)C]curcumin (100 mg/kg) via the i.p. route. Whereas curcumin at 0.1% in the diet was without effect, at 0.2 and 0.5%, it reduced adenoma multiplicity by 39 and 40%, respectively, compared with untreated mice. Hematocrit values in untreated Min/+ mice were drastically reduced compared with those in wild-type C57Bl/6J mice. Dietary curcumin partially restored the suppressed hematocrit. Traces of curcumin were detected in the plasma. Its concentration in the small intestinal mucosa, between 39 and 240 nmol/g of tissue, reflects differences in dietary concentration. [(14)C]Curcumin disappeared rapidly from tissues and plasma within 2-8 h after dosing. Curcumin may be useful in the chemoprevention of human intestinal malignancies related to Apc mutations. The comparison of dose, resulting curcumin levels in the intestinal tract, and chemopreventive potency suggests tentatively that a daily dose of 1.6 g of curcumin is required for efficacy in humans. A clear advantage of curcumin over nonsteroidal anti-inflammatory drugs is its ability to decrease intestinal bleeding linked to adenoma maturation.

Fasting glucose is a risk factor for breast cancer: a prospective study.

Abstract: There is some evidence that glucose and other factors related to glucose metabolism, such as insulin and insulin-like growth-factors (IGFs) may contribute to breast cancer development. The present study analyzed the hypothesis that serum glucose, insulin levels, and IGF-I pattern are associated with breast cancer using a nested case-control study. Between 1987 and 1992, 10,786 women ages 35-69 were recruited in a prospective study in Italy. Women with history of cancer and on hormone therapy were excluded at baseline. At recruitment, blood samples were collected after a 12-h fast between 7:30 and 9:00 a.m. from all of the study participants. After 5.5 years, 144 breast cancer cases were identified among the participants of the cohort. Four matched controls were chosen for each breast cancer case from members of the cohort who did not develop breast cancer during the follow-up period. In premenopausal women, glucose was associated with breast cancer risk: the age, body mass index, and reproductive variable adjusted relative risk (RR) for the highest quartile of serum glucose versus the lowest was 2.8 [95% confidence interval (CI), 1.2-6.5], and P for trend was 0.02. Insulin showed a weaker association with breast cancer, the adjusted RR of the highest quartile versus the lowest was 1.7 (95% CI, 0.7-4.1), and P for trend was 0.14, whereas the adjusted RR of the highest quartile of IGF-I was 3.1 (95% CI, 1.1-8.6), and P for trend was 0.01. Increased levels of insulin-like growth factor binding protein-3 (IGFBP)-3 were related to breast cancer risk: the adjusted RR for the highest quartile was 2.1 (95% CI, 0.95-4.75), and P for trend was 0.02. In postmenopausal women, the associations of glucose, insulin, and IGF-1 pattern were associated with breast cancer risk in heavier subjects characterized by a body mass index higher than 26. These results indicate that chronic alteration of glucose metabolism is related to breast cancer development.

Cigarette smoking and the risk of breast cancer in women: a review of the literature.

Abstract: Animal experiments and in vitro studies have shown that compounds found in tobacco smoke, such as polycyclic hydrocarbons, aromatic amines, and N-nitrosamines, may induce mammary tumors. The findings of smoking-specific DNA adducts and p53 gene mutations in the breast tissue of smokers also support the biological plausibility of a positive association between cigarette smoking and breast cancer, as does the detection of carcinogenic activity in breast fluid. However, epidemiological studies conducted over the past few decades have variably shown positive, inverse, or null associations. To help reconcile the discrepant findings, epidemiologists have paid increasing attention to measures of exposure to tobacco smoke that might be of the greatest etiological importance, to aspects of the smoker that might modify the association between smoking and breast cancer risk, and to the potentially different associations that might exist with different types of breast tumors, such as those with and without estrogen or progesterone receptors. Overall, the results of these studies suggest that smoking probably does not decrease the risk and indeed suggest that there may be an increased breast cancer risk with smoking of long duration, smoking before a first full-term pregnancy, and passive smoking. These findings require confirmation in future studies, as do suggestions of increased risk among women with certain genotypes.

Counterpoint: Bias from Population Stratification Is Not a Major Threat to the Validity of Conclusions from Epidemiological Studies of Common Polymorphisms and Cancer

Abstract: In their Point, Thomas and Witte [(1)][1] forcefully lay out their case for seriously considering the impact of population stratification in so-called “association” studies of genetic factors and cancer. In our Counterpoint, we discuss the nature of population stratification; the conditions that

Colorectal cancer mortality and factors related to the insulin resistance syndrome.

Abstract: It has been proposed that hyperinsulinemia is involved in colon carcinogenesis. An association between post-load plasma glucose (PLG) levels and risk of colorectal cancer mortality would be consistent with this hypothesis. We used data from the Chicago Heart Association Detection Project in Industry to examine the associations of nonfasting PLG and other variables related to the insulin resistance syndrome ( i.e. , systolic blood pressure, body mass index, uric acid, and resting heart rate) with colorectal cancer mortality. After excluding participants reporting a history of diabetes, 191 and 126 colorectal cancer deaths occurred among 20,433 men and 15,149 women, respectively. In multivariate Cox regression analysis, there was a positive relationship between PLG levels and colorectal cancer mortality for women ( P for trend = 0.08) but not for men. When men and women were combined, a trend ( P = 0.05) for PLG remained. Examination of clustering of insulin resistance syndrome-related risk factors revealed that men with at least 3 of 4 risk factors ( i.e. , in the highest quartile of the sex-specific distribution for PLG, systolic blood pressure, body mass index, or resting heart rate) had a relative risk (RR) of 1.67 [95% confidence interval (CI), 1.04–2.70] as compared with men who were not in the upper quartile for any of these factors. For women, the RR was 1.29 (95% CI, 0.70–2.37). For men and women combined, the RR was 1.50 (95% CI, 1.03–2.19). These findings provide evidence for a modest association of PLG and insulin resistance syndrome with colorectal cancer mortality and support the insulin hypothesis.

Validity of Free Testosterone and Free Estradiol Determinations in Serum Samples from Postmenopausal Women by Theoretical Calculations

Abstract: In this study, we validated measurements of free testosterone (fT) and free estradiol (fE(2)) concentrations calculated from total serum concentrations of testosterone (T), estradiol (E(2)), and sex hormone-binding globulin (SHBG), measured by direct, commercial radioimmunoassays, by comparison with reference measurements obtained by dialysis plus an in-house radioimmunoassay after extraction and chromatographic purification. The study was conducted in serum samples from 19 postmenopausal women who were part of an ongoing prospective cohort study. We also performed sensitivity analyses to examine the robustness of the theoretical calculations. Sensitivity analyses showed that in this population, competitive binding of dihydrotestosterone and total T could be ignored in the calculation of fE(2), and competitive binding by dihydrotestosterone does not need to be taken into account for calculation of fT. Furthermore, variations in albumin and SHBG concentrations had negligible effects on fT and fE(2) calculations. Values of fT and fE(2), calculated from total T and E(2) concentrations obtained by the same in-house radioimmunoassay used for the dialysis method, correlated highly with the measurements by dialysis (Pearson's coefficients of correlation above 0.97). When calculating fT and fE(2) using total T and total E(2) concentrations obtained by different direct radioimmunoassays, almost all kits gave good correlations with the reference method for fT (Pearson's r > 0.83), but only a few gave good correlations for fE(2) (Diagnostic System Laboratories and DiaSorin; r > 0.80). The direct radioimmunoassays giving the best correlation for fT and fE(2) with the dialysis method were those that best measured total concentrations of T and E(2). Furthermore, mean values of fT and fE(2) corresponded well to mean values by the reference method if SHBG measurements were also well calibrated. We conclude that in postmenopausal women, theoretical calculations are valid for the determination of fT and fE(2) concentrations and can give reliable estimation of cancer risk in epidemiological studies when the total concentrations of T, E(2), and SHBG are measured accurately.

The Effectiveness of Interventions To Promote Mammography among Women with Historically Lower Rates of Screening

Abstract: This study examines mammography-enhancing intervention studies that focus on women in groups with historically lower rates of mammography use than the general population. These groups consist of women who are disproportionately older, poorer, of racial-ethnic minorities, have lower levels of formal education, and live in rural areas. We refer to them as diverse populations. The purpose of this report is to determine which types of mammography-enhancing interventions are most effective for these diverse populations. For this report, United States and international studies with concurrent controls that reported actual receipt of mammograms (usually based on self-report) as an outcome were eligible for inclusion. Intervention effects were measured by differences in intervention and control group screening rates postintervention and were weighted to reflect the certainty of each study's contribution. These effects differed significantly (Q = 218, 34 df), and the variation between studies was best explained by indicators of the use of access-enhancing approaches. Combined intervention effects were estimated for different categories of intervention types using random effects models for subgroups of studies. The strongest combination of approaches used access-enhancing and individual-directed strategies and resulted in an estimated 27% increase in mammography use (95% confidence interval, 9.9-43.9, nine studies). Additionally impressive was the access-enhancing and system-directed combination (20% increase and 95% confidence interval, 8.2-30.6, five studies). Access-enhancing strategies are an important complement to individual- and system-directed interventions for women with historically lower rates of screening.

Association of the hOGG1 Ser326Cys polymorphism with lung cancer risk.

Abstract: Oxidative stress may be one mechanism by which tobacco smoke causes lung cancer. A common oxidative damage to DNA is the highly mutagenic 7,8-dihydro-8-oxoguanine adduct, which can be repaired by 8-oxoguanine glycosylase I (OGG1). A Ser326Cys substitution polymorphism in the hOGG1 gene has been suggested, based on in vitro data, to reduce the activity of the enzyme. We tested the association of this polymorphism with lung cancer in a population-based, case control study of 298 cases and 405 controls of Caucasian, Japanese, or Native Hawaiian ancestry in Hawaii. Subjects were genotyped with a PCR-RFLP assay, and odds ratios were estimated by logistic regression after adjustment for other observed risk factors, including smoking and vegetable intake. We found marked differences in the frequencies of the hOGG1 Cys variant allele among ethnic groups (45% in Hawaiians, 42% in Japanese, and 22% in Caucasians). The homozygous Cys/Cys genotype was also found to be more common in cases than controls ( P = 0.008), with an odds ratio of 2.1 (95% confidence interval: 1.2–3.7) for this genotype compared with the Ser/Ser genotype. Heterozygous individuals were not at increased risk. This association with the Cys/Cys genotype was observed for each sex, ethnic group, and lung cancer cell type. There was also the suggestion that vegetable intake may not be protective against lung cancer among subjects with the Cys/Cys genotype. These data suggest that the presence of two hOGG1 326 Cys alleles confers a 2-fold increased risk of lung cancer. Additional studies need to be conducted to confirm this association.

Environmental toxins and breast cancer on Long Island. II. Organochlorine compound levels in blood.

Abstract: Whether environmental contaminants increase breast cancer risk among women on Long Island, NY, is unknown. The study objective is to determine whether breast cancer risk is increased in relation to organochlorines, compounds with known estrogenic characteristics that were extensively used on Long Island and other areas of the United States. Recent reports do not support a strong association, although there are concerns with high risks observed in subgroups of women. Blood samples from 646 case and 429 control women from a population-based case-control study conducted on Long Island were analyzed. No substantial elevation in breast cancer risk was observed in relation to the highest quintile of lipid-adjusted serum levels of p,p'-bis(4-chlorophenyl)-1,1-dichloroethene (DDE) [odds ratio (OR), 1.20 versus lowest quintile; 95% confidence interval (CI), 0.76-1.90], chlordane (OR, 0.98; 95% CI, 0.62-1.55), dieldrin (OR, 1.37; 95% CI, 0.69-2.72), the sum of the four most frequently occurring PCB congeners (nos. 118, 153, 138, and 180; OR, 0.83; 95% CI, 0.54-1.29), and other PCB congener groupings. No dose-response relations were apparent. Nor was risk increased in relation to organochlorines among women who had not breastfed or were overweight, postmenopausal, or long-term residents of Long Island; or with whether the case was diagnosed with invasive rather than in situ disease, or with a hormone receptor-positive tumor. These findings, based on the largest number of samples analyzed to date among primarily white women, do not support the hypothesis that organochlorines increase breast cancer risk among Long Island women.

Environmental toxins and breast cancer on Long Island. I. Polycyclic aromatic hydrocarbon DNA adducts

Abstract: Polycyclic aromatic hydrocarbons (PAH) are potent mammary carcinogens in rodents, but their effect on breast cancer development in women is not clear. To examine whether currently measurable PAH damage to DNA increases breast cancer risk, a population-based case-control study was undertaken on Long Island, NY. Cases were women newly diagnosed with in situ and invasive breast cancer; controls were randomly selected women frequency matched to the age distribution of cases. Blood samples were donated by 1102 (73.0%) and 1141 (73.3%) of case and control respondents, respectively. Samples from 576 cases and 427 controls were assayed for PAH-DNA adducts using an ELISA. The geometric mean (and geometric SD) of the log-transformed levels of PAH-DNA adducts on a natural scale was slightly, but nonsignificantly, higher among cases [7.36 (7.29)] than among controls [6.21 (4.17); P = 0.51]. The age-adjusted odds ratio (OR) for breast cancer in relation to the highest quintile of adduct levels compared with the lowest was 1.51 [95% confidence interval (CI), 1.04-2.20], with little or no evidence of substantial confounding (corresponding multivariate-adjusted OR, 1.49; 95% CI, 1.00-2.21). There was no consistent elevation in risk with increasing adduct levels, nor was there a consistent association between adduct levels and two of the main sources of PAH, active or passive cigarette smoking or consumption of grilled and smoked foods. These data indicate that PAH-DNA adduct formation may influence breast cancer development, although the association does not appear to be dose dependent and may have a threshold effect.

Differences in Breast Cancer Hormone Receptor Status and Histology by Race and Ethnicity among Women 50 Years of Age and Older

Abstract: Numerous studies have demonstrated differences in certain biological breast cancer characteristics associated with survival, including hormone receptor status and histology, among women of different racial and ethnic groups. However, women classified as "Asian or Pacific Islanders" or "Hispanic whites" represent heterogeneous populations, and few studies have separately evaluated subgroups of these populations with respect to these breast tumor characteristics. Using data obtained from 11 cancer registries that participate in the Surveillance, Epidemiology, and End Results (SEER) Program, the tumor characteristics of 93,317 women in whom invasive breast cancer was diagnosed from 1992 to 1998 were compared by race and ethnicity using unconditional and polytomous logistic regression. The study consisted of 75,978 non-Hispanic whites, 6,915 African Americans, 203 Native Americans, 5,750 Asians/Pacific Islanders, and 4,471 Hispanic whites. Eight Asian/Pacific Islander and four Hispanic white subgroups were also analyzed separately. Relative to non-Hispanic whites, African Americans, Native Americans, Filipinos, Chinese, Koreans, Vietnamese, Indians/Pakistanis, Mexicans, South/Central Americans, and Puerto Ricans living in the United States had 1.4- to 3.1-fold elevated risks of presenting with estrogen receptor-negative/progesterone receptor-negative breast cancer. Numerous differences by histological type, including lobular, ductal/lobular, mucinous, comedocarcinoma, tubular, and medullary histologies, were also observed by race/ethnicity. Breast cancer tumor characteristics differ by race/ethnicity in the United States. Both biological and lifestyle factors likely contribute to these findings. Our results may explain, to some extent, the differences in breast cancer stage and survival observed by race/ethnicity. Understanding the factors underlying these differences may provide further insight into breast cancer etiology in different populations.

Serum androgen concentrations in young men: a longitudinal analysis of associations with age, obesity, and race. The CARDIA male hormone study.

Abstract: Serum testosterone concentration appears to be higher in black men than white men, particularly at younger ages. The higher incidence of prostate cancer in blacks has been attributed, at least in part, to this difference. Other factors associated with androgen levels in men include age and obesity. However, most of the studies of adult androgen levels are limited by their cross-sectional design. We conducted longitudinal analyses (Generalized Estimating Equation) of the associations of age, body mass index (BMI), and waist circumference with total and free testosterone and sex hormone-binding globulin (SHBG) concentrations during an 8-year period and compared these hormonal factors between black (n = 483) and white (n = 695) male participants of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. For men ages 24 years and older at the time of the first hormone measurement, increasing age was associated with a statistically significant decrease in serum total and free testosterone and an increase in SHBG (P < 0.05). BMI and waist circumference were inversely associated with total testosterone and SHBG, but only BMI was inversely associated with free testosterone. After adjustment for age and BMI, total testosterone was higher in blacks (0.21 ng/ml; P = 0.028) than whites, an approximately 3% difference. However, after further adjustment for waist circumference, there was no black-white difference (0.05 ng/ml; P = 0.62). These results indicate that the age-associated decrease in circulating testosterone and increase in SHBG begin during the 3rd decade of life, and that increasing obesity, particularly central obesity, is associated with decreasing total testosterone and SHBG. Results also suggest that the previously observed difference in total testosterone between black and white men could be attributed, for the most part, to racial differences in abdominal obesity.

Risk Factors for Hyperplastic and Adenomatous Polyps Evidence for Malignant Potential

Abstract: Recent studies have suggested that hyperplastic polyps may be benign precursor lesions for a distinct subset of colorectal tumors. We conducted a clinic-based case-control study to evaluate risk factors for hyperplastic polyps. Cases with hyperplastic polyps (n = 219), adenomas (n = 437), and both types of polyps (n = 138), along with colonoscopy-negative controls (n = 708), were identified at a gastroenterology practice in the Minneapolis area during 1991-1994. A self-administered questionnaire was used to collect risk factor information. Risk factors for hyperplastic and adenomatous polyps were generally similar to those for colorectal cancer. Male sex, smoking, and alcohol consumption were associated with increased risk of all polyp groups; nonsteroidal anti-inflammatory drug use, hormone replacement therapy use, and calcium intake were associated with reduced risk. There was no apparent association between increasing age and hyperplastic polyp risk (P = 0.21) in this analysis, although it was a strong risk factor for adenoma (P 25 pack-years of smoking was 4.1 [95% confidence interval (CI), 2.2-7.6], whereas the OR for adenoma alone was 1.3 (95% CI, 0.8-2.3). The OR estimate for individuals diagnosed with both polyp types was 4.2 (95% CI, 1.9-9.3). These results suggest, as one possibility, that the consistent association of adenoma and smoking observed in previous studies may be partially attributable to the inclusion of individuals with both adenomas and hyperplastic polyps in the adenoma case group. To the contrary, individuals with both polyp types may be expressing a phenotype distinct from those who have only adenomas and should be considered separately. Further studies are necessary to establish which polyp phenotypes are related to smoking. Overall, the similarity of the risk profiles of colorectal hyperplastic polyps, adenoma, and cancer provides additional support for the growing body of evidence that some hyperplastic polyps may have neoplastic potential.

Selenium supplementation and lung cancer incidence: an update of the nutritional prevention of cancer trial.

Abstract: Interest in the chemopreventive effects of the trace element selenium has spanned the past three decades. Of >100 studies that have investigated the effects of selenium in carcinogen-exposed animals, two-thirds have observed a reduction in tumor incidence and/or preneoplastic endpoints (G. F. Combs and S. B. Combs, The Role of Selenium in Nutrition Chapter 10, pp. 413-462. San Diego, CA: Academic Press, 1986, and B. H. Patterson and O. A. Levander, Cancer Epidemiol. Biomark. Prev., 6: 63-69, 1997). The Nutritional Prevention of Cancer Trial, a randomized clinical trial reported by Clark et al. (L. C. Clark et al., JAMA, 276: 1957-1963, 1996), showed as a secondary end point, a statistically significant decrease in lung cancer incidence with selenium supplementation. The adjusted hazard ratio (HR) was 0.56 [95% confidence interval (CI), 0.31-1.01; P = 0.05]. These results were based on active follow-up of 1312 participants. This reanalysis used an extended Nutritional Prevention of Cancer Trial participant follow-up through the end of the blinded clinical trial on February 1, 1996. The additional 3 years added 8 cases to the selenium-treated group and 4 cases to the placebo group, and increased follow-up to 7.9 years. The relative risk of 0.70 (95% CI, 0.40-1.21; P = 0.18) is not statistically significant. Whereas the overall adjusted HR is not significant (HR = 0.74; 95% CI, 0.44-1.24; P = 0.26), and the HR for current and former smokers was not significant, the trend is toward a reduction in risk of incident lung cancer with selenium supplementation. In a subgroup analysis there was a nominally significant HR among subjects with baseline plasma selenium in the lowest tertile (HR = 0.42; 95% CI, 0.18-0.96; P = 0.04). The analysis for the middle and highest tertiles of baseline showed HRs of 0.91 and 1.25. The current reanalysis indicates that selenium supplementation did not significantly decrease lung cancer incidence in the full population, but a significant decrease among individuals with low baseline selenium concentrations was observed.

A Longitudinal Study of the Effects of Menopause on Mammographic Features

Abstract: Menopause has an important influence on risk of breast cancer. We have examined longitudinally the effect of menopause on mammographic densities, a strong risk factor for the disease, in women in the Canadian National Breast Screening Study. Baseline mammograms from women in the National Breast Screening Study, who were premenopausal at entry and had undergone menopause after entry, were compared with the mammogram that most closely followed menopause, using a computer-assisted method of measurement. The changes seen in the mammograms of these subjects were compared with those in an age-matched group of women who were also premenopausal at entry, had been followed for the same length of time, and had not experienced menopause. The results of this longitudinal study show that menopause has effects on characteristics of the mammogram that, over the same period of time, are greater than the effects of age. These effects are a reduction in the area of radiologically dense tissue, an increase in the area of nondense tissue, and a decrease in the percentage of density. However, these changes do not fully account for the effects of age on mammographic densities seen in cross-sectional data. Menopause is associated with distinct changes in the mammogram that account for some, but not all, of the observed association of increasing age with decreasing percentage of mammographic density. The observed changes in the morphology of the breast may explain some of the effect that menopause has on breast cancer risk.

Urinary Excretion of Phytoestrogens and Risk of Breast Cancer among Chinese Women in Shanghai

Abstract: Although the majority of ecological and experimental studies have suggested a potential role of phytoestrogens in breast cancer prevention, findings from epidemiological studies have been inconsistent. Part of the inconsistencies may be attributable to the difficulty in measuring intake levels of phytoestrogens. Overnight urine samples from 250 incident breast cancer cases and their individually matched controls were analyzed for urinary excretion rates of isoflavonoids, mammalian lignans, and citrus flavonoids. The study subjects were a subset of the participants in the Shanghai Breast Cancer Study, a large population-based case-control study conducted in Shanghai from 1996-1998. To minimize potential influence of treatment on the exposure of interest, urine samples from breast cancer cases were collected before cancer therapy. Urinary excretion of total isoflavonoids and mammalian lignans was substantially lower in breast cancer cases than in controls. The median excretion rate of total isoflavonoids was 13.97 nmol/mg creatinine in cases and 23.09 in controls (P = 0.01), and the median excretion rate of total lignans was 1.77 in cases and 4.16 in controls (P < 0.01). The risk of breast cancer was reduced with increasing excretion of total isoflavonoids (P for trend, 0.04) and total lignans (P for trend, <0.01), with adjusted odds ratios of 0.62 (95% confidence interval, 0.39-0.99) and 0.40 (95% confidence interval, 0.24-0.64) observed for the highest versus the lowest tertile of total isoflavonoid and lignan excretion, respectively. The adjusted odds ratio was 0.28 (95% confidence interval, 0.15-0.50) for women who had a high excretion rate of both total lignans and isoflavonoids compared with those with a low excretion of both groups of phytoestrogens. No association was observed with citrus flavonoids. The results from this study suggest that high intake of certain phytoestrogens may reduce the risk of breast cancer.

Variation in BRCA1 Cancer Risks by Mutation Position

Abstract: Previous studies have reported variation in BRCA1 breast and ovarian cancer risks with mutation position, suggesting that mutations toward the 3' end of the gene are associated with lower ovarian cancer risks. We evaluated the evidence for genotype-phenotype correlations in 356 families with protein-truncating BRCA1 mutations. In contrast to previous reports, the ovarian:breast cancer ratio associated with mutations in a central region of the gene (nucleotides 2401-4190) was significantly higher than for other mutations [odds ratio, 1.70 (P = 0.017) compared with nucleotides 1-2400; odds ratio, 1.89 (P = 0.02) compared with nucleotides 4191-end]. The risks of breast and ovarian cancer conferred by mutations in different regions of the gene were estimated separately by conditional maximum likelihood. According to the best fitting model, the breast cancer risk associated with mutations in the central region was found to be significantly lower than for other mutations (relative risk, 0.71; 95% confidence interval, 0.58-0.86; P = 0.0002), whereas the ovarian cancer risk associated with mutations 3' to nucleotide 4191 was significantly reduced relative to the rest of the gene (relative risk, 0.81; 95% confidence interval, 0.66-1.00; P = 0.044). The cancer risks associated with missense mutations in the RING domain in exon 5 appear to be similar to those associated with protein-truncating mutations toward the 3' end of BRCA1, based on nine additional families.

Eight-Year Follow-Up of the 90,000-Person Haimen City Cohort: I. Hepatocellular Carcinoma Mortality, Risk Factors, and Gender Differences

Abstract: In an 8-year follow-up of a prospective cohort study in Haimen City, China, we sought to identify hepatocellular carcinoma (HCC) risk factors in addition to hepatitis B virus (HBV) infection. Two cohorts of adults between ages 25 and 64 years at study entry were followed from 1992-1993 to 2000. The male cohort included 58,545 men, 15.0% of whom were HBV carriers. The female cohort included 25,340 women, 10.7% of whom were HBV carriers. 434,718 person-years of follow-up were accumulated, and 1092 deaths from HCC occurred. The relationship of potential risk factors measured at study entry to HCC mortality was analyzed using Cox proportional hazards models. For males, HCC mortality was significantly associated with HBV infection [relative risk (RR) 18.8; 95% confidence interval (CI), 15.7-22.5], history of acute hepatitis (RR, 2.3; 95% CI, 2.0-2.7), family history of HCC (RR, 2.3; 95% CI, 1.9-2.7), and occupation as a peasant (RR, 1.5; 95% CI, 1.3-1.8). For females, HCC mortality was significantly associated with HBV infection (RR, 33.5; 95% CI, 17.1-65.5) and acute hepatitis history (RR, 4.7; 95% CI, 3.0-7.5). HCC risk was not significantly associated with alcohol consumption, water source, or staple foods in either sex. There was no association with smoking in males, but there was a positive association for females. Environmental and genetic risk factors besides HBV infection play a significant role in HCC mortality in this extremely high-risk population. Gender differences in HCC mortality and known risk factors are substantial and warrant further study. Identification of risk factors amenable to intervention should be a high priority in the prevention of HCC.

Perceived Barriers and Benefits to Colon Cancer Screening among African Americans in North Carolina: How Does Perception Relate to Screening Behavior?

Abstract: This study investigated perceived barriers and benefits, as conceptualized by the Health Belief Model,in relation to screening for colorectal cancer (CRC) among African-American adults participating in a church-based health promotion program. CRC is one of the most common cancers and is the second leading cause of cancer death for men and women. Screening can be effective at detecting cancer at treatable stages, but a large proportion of people at risk have not been screened or are not screened regularly, as recommended by national guidelines. In this study, logistic regression was used to assess the relation of barriers and benefits to self-reported history of fecal occult blood testing (FOBT), flexible sigmoidoscopy, and colonoscopy. Barriers were significantly negatively related to recent FOBT and recent sigmoidoscopy. Benefits were significantly related to having a recent sigmoidoscopy and a recent colonoscopy but not to recent FOBT. Results suggest that the way people perceive sigmoidoscopy and colonoscopy may differ from FOBT with respect to the relative importance of perceived benefits versus barriers. Findings are discussed within the context of these Health Belief Model constructs and implications for health promotion programming.

Polymorphism of the DNA Repair Gene XRCC1 and Risk of Primary Lung Cancer

Abstract: DNA repair plays a critical role in protecting the genome of the cell from insults of cancer-causing agents, such as those found in tobacco smoke. Reduced DNA repair capacity, therefore, can increase the susceptibility to smoking-related cancers. Recently, three coding polymorphisms in X-ray cross-complementing group 1 (XRCC1) DNA repair gene have been identified, and it is possible that these polymorphisms may affect DNA repair capacity and thus modulate cancer susceptibility. We investigated the relationship between the codon 399 polymorphism in XRCC1 gene and lung cancer risk in male smokers. The study population consisted of 192 lung cancer patients and 135 healthy controls. The distribution of XRCC1 genotypes was not significantly different between cases and controls. When the cases were categorized by histological type, however, the presence of at least one Gln allele was associated with a significant increased risk for squamous cell carcinoma [crude odds ratio (OR) = 1.77, 95% confidence interval (CI) = 1.06-2.93 and adjusted OR = 1.66, 95% CI = 0.99-2.79]. The risk for the disease increased as the number of Gln alleles increased (Arg/Gln genotype: adjusted OR = 1.45, 95% CI = 0.84-2.5; Gln/Gln genotype: adjusted OR = 3.26, 95% CI = 1.17-9.15). When the subjects dichotomized by cigarette consumption into two pack-year groups ( 40 pack-years), the Gln allele was associated with an increased risk for squamous cell carcinoma only in the group of individuals having < or =40 pack-years of smoking (Arg/Gln genotype: adjusted OR = 1.48, 95% CI = 0.78-2.8; Gln/Gln genotype: adjusted OR = 5.75, 95% CI = 1.46-22.69). These results suggest that XRCC1 codon 399 polymorphism may be an important genetic determinant of squamous cell carcinoma of the lung in persons with lower degrees of cigarette use.

Use of Oral Contraceptives and Breast Cancer Risk The Norwegian-Swedish Women’s Lifestyle and Health Cohort Study

Abstract: Current use of oral contraceptives (OCs) has been reported to increase breast cancer risk slightly. In 1991/1992, a prospective cohort study specifically designed to examine the role of hormonal contraceptives in relation to breast cancer was conducted in Norway and Sweden. This study was entitled Women's Lifestyle and Health. Of 196,000 invited women aged 30-49 years, 106,844 women answered a 4-page questionnaire. Altogether, 103,027 women providing information on contraceptive use were included in the analysis presented here, and 1,008 primary invasive breast cancers were diagnosed throughout 1999 (end of follow-up). Proportional hazard regression was used to calculate relative risks (RRs) with adjustment for age and other possible confounders. An increased breast cancer risk was observed among women who were current/recent users of OCs of any type at the start of follow-up [RR, 1.6; 96% confidence interval (CI), 1.2-2.1]. Current/recent use (i.e., use in the year preceding cohort enrolment) of combined OCs (RR, 1.5; 95% CI, 1.0-2.0) and progestin-only pills (RR, 1.6; 95% CI, 1.0-2.4) entailed similar levels of increased risk. An increased risk of borderline significance was found among short-term (i.e., less than 13 months) users before age 20 years (RR, 1.3; 95% CI, 1.0-1.7) and before first full-term pregnancy (RR, 1.4; 95% CI, 1.0-1.8). Long-term users of OCs were at a higher risk of breast cancer than never users (test for trend, P = 0.005). Current/recent use of OCs is associated with an increased breast cancer risk. Use of combined OCs and progestin-only pills seem to increase the risk at the same level.

Postmenopausal Estrogen and Progestin Use in Relation to Breast Cancer Risk

Abstract: Epidemiological evidence now consistently supports a modest increase in breast cancer risk among women using postmenopausal hormones, usually estrogens. Less is known regarding how the addition of progestin affects breast cancer risk. The objective of this study was to investigate the type and duration of postmenopausal therapy and breast cancer risk. We performed a multicenter population-based case-control study set in Massachusetts, New Hampshire, and Wisconsin. The subjects were 5298 postmenopausal women (age range, 50-79 years) with a new diagnosis of invasive breast cancer from statewide tumor registries. For comparison, 5571 controls were randomly selected from population lists. Participants completed a structured telephone interview covering hormone use and breast cancer risk factors. Multivariable regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). The RR for breast cancer increased with longer durations of hormone use, about 2%/year for estrogen alone (RR, 1.02; 95% CI, 1.01-1.03) and 4%/year for estrogen-progestin use (RR, 1.04; 95% CI, 1.01-1.08). Estrogen-progestin use that was both recent and long term (>5 years in duration) was more strongly associated with breast cancer risk (RR, 1.57; 95% CI, 1.15-2.14) than similar use of estrogen alone (RR, 1.39; 95% CI, 1.17-1.65). In estrogen-progestin users, risks were similar for sequential and continuous use regimens but perhaps stronger for lobular than ductal breast cancer. Use of progestin alone was associated with a doubling of risk (RR, 2.09; 95% CI, 1.07-4.07 for ever use versus nonuse). Estrogen-progestin use, both sequential and continuous, appears to be more strongly associated with risk of breast cancer than use of estrogen alone.