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Background: The etiology of small intestinal cancer (SIC) is largely unknown, and there are very few epidemiological studies published to date. No studies have investigated abdominal adiposity in relation to SIC., Methods: We investigated overall obesity and abdominal adiposity in relation to SIC in the European Prospective Investigation into Cancer and Nutrition (EPIC), a large prospective cohort of approximately half a million men and women from ten European countries. Overall obesity and abdominal obesity were assessed by body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). Multivariate Cox proportional hazards regression modeling was performed to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). Stratified analyses were conducted by sex, BMI, and smoking status., Results: During an average of 13.9 years of follow-up, 131 incident cases of SIC (including 41 adenocarcinomas, 44 malignant carcinoid tumors, 15 sarcomas and 10 lymphomas, and 21 unknown histology) were identified. WC was positively associated with SIC in a crude model that also included BMI (HR per 5-cm increase = 1.20, 95 % CI 1.04, 1.39), but this association attenuated in the multivariable model (HR 1.18, 95 % CI 0.98, 1.42). However, the association between WC and SIC was strengthened when the analysis was restricted to adenocarcinoma of the small intestine (multivariable HR adjusted for BMI = 1.56, 95 % CI 1.11, 2.17). There were no other significant associations., Conclusion: WC, rather than BMI, may be positively associated with adenocarcinomas but not carcinoid tumors of the small intestine., Impact: Abdominal obesity is a potential risk factor for adenocarcinoma in the small intestine.

Purpose: The strong association between t(14;18) translocation and follicular lymphoma (FL) is well known. However, the determinants of this chromosomal aberration and their role in t(14;18) associated FL remain to be established., Methods: t(14;18) frequency within the B cell lymphoma 2 major breakpoint region was determined for 135 incident FL cases and 251 healthy controls as part of a nested case-control study within the European Prospective Investigation into Cancer cohort. Quantitative real-time PCR was performed in DNA extracted from blood samples taken at recruitment. The relationship between prevalence and frequency of the translocation with baseline anthropometric, lifestyle, and dietary factors in cases and controls was determined. Unconditional logistic regression was used to explore whether the risk of FL associated with these factors differed in t(14;18)(+) as compared to t(14;18)(-) cases., Results: Among incident FL cases, educational level (χ(2) p = 0.021) and height (χ(2) p = 0.025) were positively associated with t(14;18) prevalence, and cases with high frequencies [t(14;18)(HF)] were significantly taller (t test p value = 0.006). These findings were not replicated in the control population, although there were a number of significant associations with dietary variables. Further analyses revealed that height was a significant risk factor for t(14;18)(+) FL [OR 6.31 (95% CI 2.11, 18.9) in the tallest versus the shortest quartile], but not t(14;18)(-) cases., Conclusions: These findings suggest a potential role for lifestyle factors in the prevalence and frequency of the t(14;18) translocation. The observation that the etiology of FL may differ by t(14;18) status, particularly with regard to height, supports the subdivision of FL by translocation status.

Purpose: The relation between dietary acrylamide intake and esophageal cancer (EC) risk, including esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), has not been consistent. We evaluated the association between dietary acrylamide intake and EAC, ESCC, and overall EC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort., Methods: Multivariate Cox proportional hazards models were used to estimate the HR and 95 % confidence interval (95 % CI). Since nonlinear relations were observed, HRs were displayed for quartiles of acrylamide intake in μg per day., Results: After a mean follow-up of 11 years, 341 EC were identified, 142 of which were EAC, 176 ESCC, and 23 other histological types or not specified. An increase in EC risk was observed in the second and third quartiles (HRQ2vsQ1 1.75, 95 % CI 1.12-2.74; HRQ3vsQ1 1.66, 95 % CI 1.05-2.61), but not in the fourth quartile, and there was no evidence for a linear dose-response trend. HRs were similarly elevated but not statistically significant when ESCC and EAC were analyzed separately, due to the small number of cases observed. No associations were observed when quartiles were based on energy-adjusted acrylamide intake., Conclusions: In the EPIC cohort, an association between estimated dietary acrylamide intake and an increased risk of developing EC was observed in the middle quartiles but not in the highest quartile; however, results from other larger cohorts or consortia, and results from biomarker studies, might add to the evidence provided by this analysis, suggesting that acrylamide is not an important risk factor for EC.

Purpose: Increased physical activity (PA) is associated with a reduced risk of several cancers. PA may reduce cancer risk by changing endogenous hormones levels, but relatively little research has focused on this topic. The purpose of this study was to elucidate the relation between PA and endogenous hormone concentrations., Methods: A cross-sectional analysis of 798 pre- and 1,360 post-menopausal women included as controls in case-control studies on endogenous hormones (steroids, progesterone, sex-hormone-binding globulin (SHBG), and growth factors) levels, and cancer risk nested within European Prospective Investigation into Cancer and Nutrition cohort was performed. Multivariate regression analyses were performed to compare geometric mean levels of hormones and SHBG by categories of PA., Results: In pre-menopausal women, active women had 19 % significantly lower concentrations of androstenedione, 14 % lower testosterone, and 20 % lower free testosterone than inactive women, while no differences were observed for estrogens, progesterone, SHBG, and growth factors. In post-menopausal women, active women had 18 % significantly lower estradiol and 20 % lower free estradiol concentrations than inactive women, while no differences were observed for the other hormones and SHBG. More vigorous forms of physical activity were associated with higher insulin-like growth factor-I concentrations. Adjustment for body mass index did not alter the associations. Overall, the percentage of variance in hormone concentrations explained by PA levels was <2 %., Conclusions: Our results support the hypothesis of an influence, although small in magnitude, of PA on sex hormone levels in blood, independent of body size.

Background: Increasing evidence suggests that oral microbiota play a pivotal role in chronic diseases, in addition to the well-established role in periodontal disease. Moreover, recent studies suggest that oral bacteria may also be involved in carcinogenesis; periodontal disease has been linked to several cancers. In this study, we examined whether lifestyle factors have an impact on antibody levels to oral bacteria., Methods: Data on demographic characteristics, lifestyle factors, and medical conditions were obtained at the time of blood sample collection. For the current analysis, we measured antibody levels to 25 oral bacteria in 395 cancer-free individuals using an immunoblot array. Combined total immunoglobin G (IgG) levels were obtained by summing concentrations for all oral bacteria measured., Results: IgG antibody levels were substantially lower among current and former smokers (1,697 and 1,677 ng/mL, respectively) than never smokers (1,960 ng/mL; p trend = 0.01), but did not vary by other factors, including body mass index, diabetes, physical activity, or by dietary factors, after adjusting for age, sex, education, country, and smoking status. The highest levels of total IgG were found among individuals with low education (2,419 ng/mL)., Conclusions: Our findings on smoking are consistent with previous studies and support the notion that smokers have a compromised humoral immune response. Moreover, other major factors known to be associated with inflammatory markers, including obesity, were not associated with antibody levels to a large number of oral bacteria.

Purpose: Overweight and obesity have been suggested as a risk factor for leukemia. Impaired immune function associated with obesity, increased insulin-like growth factor-I activity and stimulating effects of leptin suggest a possible biological link between anthropometric measures and leukemia. However, evidence from epidemiological studies has been inconsistent. We examined the potential association between prospective measurements of body size and risk of leukemia among participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)., Methods: During follow-up (mean = 11.52 years, standard deviation = 2.63), 671 leukemia (lymphoid leukemia = 50.1 %, myeloid leukemia = 43.2 %) cases were identified. Anthropometric measures including weight, height, body mass index (BMI), waist circumference (WC), hip circumference, and waist-to-hip ratio (WHR) were measured. Cox proportional hazard models were used to explore the association between anthropometric measures and risk of leukemia., Results: No associations were observed between anthropometric measures and total leukemia, and lymphoid leukemia. Risk of myeloid leukemia significantly increased for higher categories of BMI and WC among women. Analyses by subtype of myeloid leukemia showed an increased risk of acute myeloid leukemia (AML) for higher categories of WHR among women. This association seemed to be reversed for chronic myeloid leukemia. No association between anthropometric measures and myeloid leukemia were observed among men except an increased risk of AML with height., Conclusion: The study showed no associations between anthropometric measures and total leukemia, and lymphoid leukemia among men and women. A possible association between BMI as general obesity and WC as abdominal obesity and increased risk of myeloid leukemia among women were observed.

Purpose: The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed., Methods: Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (<0.02) were followed up in 2,323 cases and 2,340 controls from eight case-control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition., Results: When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95 %CI 1.04-1.23), rs1552462 (SYT9) (OR 1.27, 95 %CI 1.02-1.59), and rs7074891 (CUBN) (OR 1.91, 95 %CI 1.12-3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers., Conclusions: This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case-control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis.

Purpose: Diabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan)., Methods: The pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case-control study design. Subjects who were diagnosed with diabetes near the time (<2 years) of pancreatic cancer diagnosis were excluded from all analyses. All analyses were adjusted for age, race, gender, study, alcohol use, smoking, BMI, and family history of pancreatic cancer., Results: Self-reported diabetes was associated with a forty percent increased risk of pancreatic cancer (OR = 1.40, 95 % CI: 1.07, 1.84). The association differed by duration of diabetes; risk was highest for those with a duration of 2-8 years (OR = 1.79, 95 % CI: 1.25, 2.55); there was no association for those with 9+ years of diabetes (OR = 1.02, 95 % CI: 0.68, 1.52)., Conclusions: These findings provide support for a relationship between diabetes and pancreatic cancer risk. The absence of association in those with the longest duration of diabetes may reflect hypoinsulinemia and warrants further investigation.

Background: Several studies have suggested an increased risk of bladder cancer among hairdressers, who are occupationally exposed to hair dyes. There has also been concern about a possible increased risk of bladder cancer among users of hair dyes. However, the association between personal hair dye use and bladder cancer risk remains inconclusive., Objective: In this study, we examined associations between personal use of permanent and temporary hair dyes and bladder cancer risk in a population-based case-control study involving 1,385 cases (n = 246 women) and 4,754 controls (n = 2,587 women)., Methods: Participants filled out a questionnaire with regard to history of personal hair dye use and risk factors for bladder cancer. Unconditional logistic regression was used to calculate odds ratios (OR) and 95 % confidence intervals (CI), adjusted for age, smoking status, duration of smoking and intensity of smoking., Results: Analyses were restricted to women as less than 5 % of all men in the study ever used hair dyes. About 50 % of the women ever used hair dyes. Use of temporary hair dyes (OR, 0.77; 95 % CI, 0.58-1.02) or use of permanent hair dyes (OR, 0.87; 95 % CI, 0.65-1.18) was not associated with bladder cancer risk. No clear association between hair dyes and bladder cancer risk was found when dye use was defined by type, duration or frequency of use, dye color, or extent of use. Also, results were similar for aggressive- and non-aggressive bladder cancer. Age, educational level, and smoking status did not modify the association between hair dye use and bladder cancer risk., Conclusions: The present study does not support an association between personal hair dye use and bladder cancer risk. Also, various types of hair dye, intensity of exposure to hair dyes or dye color do not appear to be important factors for bladder cancer development.

Purpose: Data from prospective epidemiological studies in Asian populations and from experimental studies in animals and cell lines suggest a possible protective association between dietary isoflavones and the development of prostate cancer. We examined the association between circulating concentrations of genistein and prostate cancer risk in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition., Methods: Concentrations of the isoflavone genistein were measured in prediagnostic plasma samples for 1,605 prostate cancer cases and 1,697 matched control participants. Relative risks (RRs) for prostate cancer in relation to plasma concentrations of genistein were estimated by conditional logistic regression., Results: Plasma genistein concentrations were not associated with prostate cancer risk; the multivariate relative risk for men in the highest fifth of genistein compared with men in the lowest fifth was 1.00 (95 % confidence interval: 0.79, 1.27; p linear trend = 0.82). There was no evidence of heterogeneity in this association by age at blood collection, country of recruitment, or cancer stage or histological grade., Conclusion: Plasma genistein concentration was not associated with prostate cancer risk in this large cohort of European men.

The association between menopausal hormone therapy (HT) and risk of ovarian cancer was assessed among 126,920 post-menopausal women recruited into the European Prospective Investigation into Cancer and Nutrition. After an average of 9-year follow-up, 424 incident ovarian cancers were diagnosed. Cox models adjusted for body mass index, smoking status, unilateral ovariectomy, simple hysterectomy, age at menarche, number of full-term pregnancies, and duration of oral contraceptives were used. Compared with baseline never use, current use of any HT was positively associated with risk (HR [hazard ratio], 1.29; 95% CI [confidence interval], 1.01-1.65), while former use was not (HR, 0.96; 95% CI, 0.70-1.30). Current estrogen-only HT was associated with a 63% higher risk (HR, 1.63; 95% CI, 1.08-2.47), while current estrogen plus progestin was associated with a smaller and non-significant higher risk (HR, 1.20; 95% CI, 0.89-1.62). Use of tibolone was associated with a twofold greater risk (HR, 2.19; 95% CI, 1.06-4.50), but was based on small numbers. In conclusion, women who currently use HT have a moderate increased risk of ovarian cancer, and which may be stronger for estrogen-only than estrogen plus progestin preparations.

Objective: To examine the association between fruit and vegetable consumption and risk of different histological subtypes of lung cancer among participants of the European Prospective Investigation into Cancer and Nutrition study., Methods: Multivariable Cox proportional hazard models were used to analyze the data. A calibration study in a subsample was used to reduce dietary measurement errors., Results: During a mean follow-up of 8.7 years, 1,830 incident cases of lung cancer (574 adenocarcinoma, 286 small cell, 137 large cell, 363 squamous cell, 470 other histologies) were identified. In line with our previous conclusions, we found that after calibration a 100 g/day increase in fruit and vegetables consumption was associated with a reduced lung cancer risk (HR 0.94; 95% CI 0.89-0.99). This was also seen among current smokers (HR 0.93; 95% CI 0.90-0.97). Risks of squamous cell carcinomas in current smokers were reduced for an increase of 100 g/day of fruit and vegetables combined (HR 0.85; 95% CI 0.76-0.94), while no clear effects were seen for the other histological subtypes., Conclusion: We observed inverse associations between the consumption of vegetables and fruits and risk of lung cancer without a clear effect on specific histological subtypes of lung cancer. In current smokers, consumption of vegetables and fruits may reduce lung cancer risk, in particular the risk of squamous cell carcinomas.

We conducted a population-based case-control study on the relation of menstrual and reproductive factors and hormone use with pancreatic cancer risk among female participants of the SEARCH program study. We evaluated 367 cases of ductal adenocarcinoma and 821 controls for associations between pancreatic cancer and age at menarche, age at menopause, number of pregnancies, exogenous hormone use, and history of gynaecologic surgery. Among directly interviewed and proxy participants, we found a statistically significant association for having age of menarche at 11 years or younger compared with menarche at ages 12-13 years (OR = 1.8, 95% CI = 1.1-3.1). This result was consistent, but not statistically significant, among three of the four studies analyzed, and when the data were analyzed separately by response status (direct vs. proxy interviews). No other menstrual or reproductive factors were associated with pancreatic cancer risk in this study. In conclusion, earlier age at menarche may be weakly associated with pancreatic cancer, but it seems unlikely that menstrual and reproductive factors play more than only a minor role in pancreatic cancer. Additional analyses in large prospective study populations and in pooled studies may help to clarify remaining inconsistencies.

Objective: To evaluate the association between lifestyle and dietary factors and serum concentrations of androgens in middle-aged healthy men., Methods: We conducted a cross-sectional analysis of the association of lifestyle factors with circulating concentrations of androstenedione (A-dione), 3-alpha-androstanediol glucuronide (A-diol-g), testosterone (T), SHBG (sex hormone-binding globulin), and free testosterone (FT) among 636 men in the European Prospective Investigation into Cancer and Nutrition., Results: Compared with the youngest age group (40-49 years), the oldest (70-79 years) had a higher mean concentration of SHBG (by 44%) and lower mean concentrations of A-diol-g (by 29%) FT (19%). Men in the highest BMI group (> or =29.83 kg/m(2)) had a higher mean A-diol-g concentration (by 38%) and lower mean concentration of T (by 20%) SHBG (29%) compared with the lowest (<24.16 kg/m(2)). Current smokers had higher mean concentrations of T (by 13%), SHBG (14%), and A-dione (15%) compared with never smokers. Physical activity and dietary factors were not associated with androgen concentrations, although men in the highest fifth of alcohol intake had higher mean concentrations of A-dione (by 9%), FT (11%) compared with the lowest., Conclusion: Our results suggest that age, body weight, smoking, and alcohol intake are associated with circulating androgen concentrations in men.

Objective: To examine the association of baseline and lifetime ethanol intake with cancer of the pancreas in the European Prospective Investigation into Cancer and Nutrition (EPIC)., Methods: Included in this analysis were 478,400 subjects, of whom detailed information on the intake of alcoholic beverages at baseline and over lifetime was collected between 1992 and 2000. During a median follow-up time of 8.9 years, 555 non-endocrine pancreatic cancer cases were observed. Multivariate Cox proportional hazard models were used to examine the association of ethanol intake at recruitment and average lifetime ethanol intake and pancreatic cancer adjusting for smoking, height, weight, and history of diabetes., Results: Overall, neither ethanol intake at recruitment (relative risk (RR) = 0.94, 95% confidence interval (CI) 0.69-1.27 comparing 30+ g/d vs. 0.1-4.9 g/d) nor average lifetime ethanol intake (RR = 0.95, 95% CI 0.65-1.39) was associated with pancreatic cancer risk. High lifetime ethanol intake from spirits/liquor at recruitment tended to be associated with a higher risk (RR = 1.40, 95% CI 0.93-2.10 comparing 10+ g/d vs. 0.1-4.9 g/d), but no associations were observed for wine and beer consumption., Conclusion: These results suggest no association of alcohol consumption with the risk of pancreatic cancer.

Background: The suspect carcinogens, heterocyclic amines (HAAs), found in well-done meat require host-mediated metabolic activation before inducing DNA mutations. The role of SULT1A1 and of NAT2 on the activation of HAAs suggests that NAT2 rapid acetylator genotype and SULT1A1 allele variants can have an effect on HAA carcinogenicity., Methods: Data were collected as part of a case-control study nested within the EPIC cohort, the Gen Air investigation. EPIC is a prospective study designed to investigate the relationship between nutrition and cancer. Information was collected through a non-dietary questionnaire on lifestyle variables and through a dietary questionnaire. The subjects were restricted to non-smokers. We calculated the matched odds ratio for bladder cancer risk using logistic regression, controlling for potential confounders., Results: There were 227 bladder cases and 612 controls matched 1:3. Meat intake and NAT2 genotype were not independently associated with bladder cancer risk. A significant relationship was observed between bladder cancer risk and consumption of meat only among subjects with the rapid NAT2 genotype (odds ratios [OR] 2.9, 95% CI 1.0-7.9 for the 2nd quartile of meat intake; 3.6, 95% CI 1.3-9.7 for the 3rd quartile; and 3.5, 95% CI 1.2-9.7 for the 4th quartile), and was not present among subjects with the slow genotype. An interaction between NAT2 and meat intake was found in logistic regression (P = 0.034). No association was observed for SULT1A *1/2 genotype (1.0; 95% CI 0.7-1.5) and for SULT1A1 *2/2 genotype (0.9; 95% CI 0.5-1.7)., Conclusions: These results are suggestive of a role of meat intake and NAT2 on bladder cancer risk. They support the hypothesis that among subjects with the rapid NAT2 acetylation genotype higher levels of HAAs exposure are a bladder cancer risk factor. We did not observe an effect of SULT1A1 allele variants on this cancer. The present study adds new information on the possible long-term adverse effects of diets with high meat intake.

Introduction: Lymphomas are a heterogeneous group of malignant diseases of cells of the immune system. The best-established risk factors are related to dys-regulation of immune function, and evidence suggests that factors such as dietary or lifestyle habits may be involved in the etiology., Material and Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 849 lymphoma cases were identified in a median follow-up period of 6.4 years. Fruit and vegetable consumption was estimated from validated dietary questionnaires. Cox proportional hazard models were used to examine the association between fruit and vegetable intake with the risk of lymphomas overall and subentities., Results: There was no overall association between total fruit and vegetable consumption and risk of lymphoma [hazard ratio (HR)=0.95, 95% confidence interval (CI) 0.78-1.15 comparing highest with lowest quartile]. However, the risk of diffuse large B-cell lymphomas (DLBCL) tended to be lower in participants with a high intake of total vegetables (HR=0.49, 95% CI 0.23-1.02)., Conclusion: In this large prospective study, an inverse associations between fruit and vegetable consumption and risk of lymphomas overall could not be confirmed. Associations with lymphoma subentities such as DLBCL warrant further investigation.

Objective: Most epidemiologic studies have suggested an increased risk of breast cancer with increasing alcohol intake. Using data from 274,688 women participating in the European Prospective Investigation into Cancer and Nutrition study (EPIC), we investigated the relation between alcohol intake and the risk of breast cancer., Methods: Incidence rate ratios (IRRs) based on Cox proportional hazard models were calculated using reported intake of alcohol, recent (at baseline) and lifetime exposure. We adjusted for known risk factors and stratified according to study center as well as potentially modifying host factors., Results: During 6.4 years of follow up, 4,285 invasive cases of breast cancer within the age group 35-75 years were identified. For all countries together the IRR per 10 g/day higher recent alcohol intake (continuous) was 1.03 (95% confidence interval (CI): 1.01-1.05). When adjusted, no association was seen between lifetime alcohol intake and risk of breast cancer. No difference in risk was shown between users and non-users of HRT, and there was no significant interaction between alcohol intake and BMI, HRT or dietary folate., Conclusion: This large European study supports previous findings that recent alcohol intake increases the risk of breast cancer.

Objective: To examine the association between anthropometry and endometrial cancer, particularly by menopausal status and exogenous hormone use subgroups., Methods: Among 223,008 women in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, there were 567 incident endometrial cancer cases during 6.4 years of follow-up. The analysis was performed with Cox proportional hazards modeling., Results: Weight, body mass index (BMI), waist and hip circumferences and waist-hip ratio (WHR) were strongly associated with increased risk of endometrial cancer. The relative risk (RR) for obese (BMI 30- < 40 kg/m(2)) compared to normal weight (BMI < 25) women was 1.78, 95% CI = 1.41-2.26, and for morbidly obese women (BMI > or = 40) was 3.02, 95% CI = 1.66-5.52. The RR for women with a waist circumference of > or =88 cm vs. <80 cm was 1.76, 95% CI = 1.42-2.19. Adult weight gain of > or =20 kg compared with stable weight (+/-3 kg) increased risk independent of body weight at age 20 (RR = 1.75, 95% CI = 1.11-2.77). These associations were generally stronger for postmenopausal than premenopausal women, and oral contraceptives never-users than ever-users, and much stronger among never-users of hormone replacement therapy compared to ever-users., Conclusion: Obesity, abdominal adiposity, and adult weight gain were strongly associated with endometrial cancer risk. These associations were particularly evident among never-users of hormone replacement therapy.

Objective: Most studies on tobacco smoking have focused on daily-smokers. Occasional smokers, who have never smoked daily, have often been included in the reference group of never-smokers. We have investigated the association between occasional smoking and cancer of the bladder, kidney, pancreas, upper aero-digestive tract and lung., Methods: The study population consisted of 158,488 persons, who provided information on occasional smoking, within the European Prospective Investigation into Cancer and Nutrition (EPIC), 780 of whom developed a smoking-related cancer. We used Cox proportional hazard model, stratified by gender and country to estimate incidence rate ratios (IRR) for smoking-related cancers., Results: The results suggest that occasional smokers have a higher risk of bladder cancer (IRR: 1.92, 95% confidence interval (CI) 0.93-3.98) and of the major smoking-related cancers combined (IRR: 1.24, 95% CI 0.80-1.94) than true never-smokers. Including occasional smokers in the reference group resulted in a lower risk estimate for former and current smokers., Conclusions: Occasional smoking should be discouraged.

Objective: Women with a moderate intake of alcohol have higher concentrations of sex steroids in serum, and higher risk of developing breast cancer, compared to non-drinkers. In the present study, we investigate the relationships between alcohol consumption and serum levels of sex steroids and sex-hormone binding globulin (SHBG) in 790 pre- and 1,291 post-menopausal women, who were part of the European Prospective Investigation into Cancer and Nutrition (EPIC)., Methods: Serum levels of testosterone (T), androstenedione (Delta4), dehydroepiandrosterone sulphate (DHEAS), estrone (E1), estradiol (E2) and SHBG were measured by direct immunoassays. Free T (fT) and free E2 (fE2) were calculated according to mass action laws. Current alcohol intake exposure to alcohol was assessed from dietary questionnaires., Results: Pre-menopausal women who consumed more than 25 g/day of alcohol had about 30% higher DHEAS, T and fT, 20% higher Delta4 and about 40% higher E1, concentrations compared to women who were non-consumers. E2, fE2 and SHBG concentrations showed no association with current alcohol intake. In post-menopausal women, DHEAS, fT, T, Delta4, and E1 concentrations were between 10% and 20% higher in women who consumed more than 25 g/day of alcohol compared to non-consumers. E2 or fE2 were not associated with alcohol intake at all. SHBG levels were about 15% lower in alcohol consumers compared to non-consumers., Conclusion: This study supports the hypothesis of an influence of alcohol intake on sex hormone concentrations in blood.

Epidemiologic studies suggest that a high intake of fruits and vegetables is associated with decreased risk of cancers of the upper aero-digestive tract. We studied data from 345,904 subjects of the prospective European Investigation into Cancer and Nutrition (EPIC) recruited in seven European countries, who had completed a dietary questionnaire in 1992-1998. During 2,182,560 person years of observation 352 histologically verified incident squamous cell cancer (SCC) cases (255 males; 97 females) of the oral cavity, pharynx, larynx, and esophagus were identified. Linear and restricted cubic spline Cox regressions were fitted on variables of intake of fruits and vegetables and adjusted for potential confounders. We observed a significant inverse association with combined total fruits and vegetables intake (estimated relative risk (RR) = 0.91; 95% confidence interval (95% CI) 0.83-1.00 per 80 g/d of consumption), and nearly significant inverse associations in separate analyses with total fruits and total vegetables intake (RR: 0.97 (95% CI: 0.92-1.02) and RR = 0.89 (95% CI: 0.78-1.02) per 40 g/d of consumption). Overall, vegetable subgroups were not related to risk with the exception of intake of root vegetables in men. Restricted cubic spline regression did not improve the linear model fits except for total fruits and vegetables and total fruits with a significant decrease in risk at low intake levels (<120 g/d) for fruits. Dietary recommendations should consider the potential benefit of increasing fruits and vegetables consumption for reducing the risk of cancers of the upper aero-digestive tract, particularly at low intake.

Variants in the metabolic genes NAT1, NAT2, GSTM1 or GSTT1, may cause differences in individual detoxifying capacity of possible carcinogens. We examined the cumulative effect of putative at risk genotypes on breast cancer risk and we examined the extent to which these polymorphisms modify the association between smoking and breast cancer. A case cohort study was conducted in the DOM cohort with 676 breast cancer cases and a random sample of 669 individuals. No effect of the NAT1, NAT2 or GSTM1 genotypes on breast cancer risk was observed. However, women with GSTT1 null genotype had a 30% increased breast cancer risk compared to women with GSTT1 present (RR = 1.30 (95% confidence interval (CI) 1.04-1.64)). Smoking did not influence breast cancer risk nor did genetic variations in NAT1, NAT2 or GSTM1 in combination with smoking. Compared to women who never smoked with GSTT1 present, women with GSTT1 null genotype and who formerly smoked showed an increased breast cancer risk (RR = 2.55 (95% CI 1.10-5.90)), but current smokers who smoked 20 cigarettes or more per day did not (RR = 1.06 (95% CI 0.51-2.18)). Increasing numbers of putative at risk genotypes increased breast cancer risk in a dose dependent manner (p for trend 0.01). The risk was more than doubled in women with all four risk genotypes, RR = 2.45 (95% CI 1.24-4.86), compared to women with zero putative at risk genotypes. In conclusion, the results of this study suggest that presence of three or more putative at risk genotypes increases breast cancer risk.

Objectives: The risk of some cancers is positively associated with body weight, which may influence circulating levels of sex-steroid hormones, insulin and IGF-I. Interrelationships between these hormones and the associations with adiposity were evaluated in healthy women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC)., Methods: A cross-sectional analysis was performed on anthropometric and hormonal data from 743 pre- and 1217 postmenopausal women. Body mass index (BMI) and waist circumference were used as indicators of adiposity. C-peptide, Insulin Growth Factor (IGF)-I, Insulin Growth Factor binding protein (IGFBP)-3, androgens, estrogens and sex hormone binding globulin (SHBG) were measured by immunoassays; free sex steroid concentrations were calculated., Results: BMI and waist circumference were positively correlated with estrogens in postmenopausal women and with C-peptide, free testosterone and inversely with SHBG in all women. C-peptide and IGF-I were inversely correlated with SHBG, and positively with free sex steroids in postmenopausal women. IGF-I was positively associated with postmenopausal estrogens and androgen concentrations in all women., Conclusions: Sex-steroid concentrations appear to be regulated along several axes. Adiposity correlated directly with estrogens in postmenopausal women and with insulin, resulting in lower SHBG and increased levels of free sex steroids. Independent of adiposity and insulin, IGF-I was associated with decreased SHBG levels, and increased concentrations of androgens and postmenopausal estrogens.

Objective: Epidemiological studies suggest that individuals with elevated plasma concentrations of insulin-like growth factor (IGF-I) are at increased risk of developing cancer. We assessed whether dietary intake of total energy, protein, alcohol, phytoestrogens and related foods, and tomatoes and lycopene was associated with plasma levels of IGF-I and IGF binding proteins (IGFBPs) in Dutch women., Methods: A cross-sectional study was conducted in 224 premenopausal and 162 postmenopausal women, aged 49-69, participating in the Prospect-EPIC study in the Netherlands. Diet was assessed using a food frequency questionnaire., Results: In postmenopausal women, higher alcohol intake was associated with lower plasma IGFBP-1 concentrations (alcohol 1.4 to 20 g/day: 20% decrease in IGFBP-1; p = 0.04), and higher intake of plant lignans was associated with higher IGFBP-1 concentrations (plant lignans 0 to 1 mg/day: 59% increase in IGFBP-1; p =0.02). Higher soy intake was associated with higher plasma IGFBP-2 concentrations in premenopausal women (soy 0 to 2.5 g/day: 3% increase in IGFBP-2; p = 0.04). No independent associations of dietary factors with IGF-I or IGFBP-3 concentrations were observed. However, in premenopausal women alcohol intake was inversely associated with IGF-I and positively associated with IGFBP-3 after mutual adjustment., Conclusions: In this study population, with limited variation in dietary intake, total energy, protein, phytoestrogens and lycopene were not associated with IGF-I and IGFBP-3. Alcohol was inversely, and some measures of phytoestrogen intake were positively associated with plasma IGFBP-1 or -2 concentrations. The roles of IGFBP-1 and -2 in relation to IGF-I bioactivity and cancer deserve further investigation.

Objective: We studied whether polymorphisms in N-acetyltransferase 1 and 2 and Glutathione S-transferase M1 and T1 genes modify the association between meat consumption and breast cancer., Methods: A nested case control was conducted in a Dutch prospective cohort. Breast cancer cases (229) and controls (264) were frequency matched on age, town and menopausal status., Results: There is no relation between any type of meat consumption ( i.e., total meat, processed meat, fresh meat, red meat and white meat) and breast cancer risk. Neither presence of NAT1 or NAT2 rapid genotype, or GSTT1 null genotype, alone or in combination with meat consumption affects breast cancer risk. Absence of GSTM1 shows 46% increased breast cancer risk (OR = 1.46 (95% confidence interval, 95% CI = 1.02-2.09)). When stratifying according to combined 'GSTM1 genotype-meat consumption' categories, breast cancer risk is slightly increased with consumption of red meat both in women with genotype GSTM1 presence (OR = 1.49 and 1.75 for intermediate and high versus low consumption) and in GSTM1 null genotype (OR = 1.18 and 1.02). These increases are statistically not significant. In postmenopausal women a suggestion of an effect of red meat consumption is observed: effects are slightly stronger, although still not statistically significant and without a clear dose-response relation: OR = 1.79 (95% CI = 0.92-3.50) and 1.46 (1.46 (95% CI = 0.76-2.82) for intermediate and high compared to low red meat consumption respectively. Reliable evaluation of interaction is not possible due to the small number of cancers., Conclusion: GSTM1 null genotype increases breast cancer risk. Red meat consumption slightly increases breast cancer risk, but the relation is not statistically significant and GSTM1, NAT1, NAT2 and GSTT1 polymorphisms do not modify this relation., (Copyright 2004 Kluwer Academic Publishers)

Objective: The relationship between smoking and colorectal cancer risk and whether such effect is modified by variations in the NAT2 genotype is investigated., Methods: In the prospective DOM (Diagnostisch Onderzoek Mammacarcinoom; 27,722 women) cohort follow-up from 1976 until 1987 revealed 54 deaths due to colon or rectal cancer, and follow-up from 1987 to 01-01-1996 revealed 204 incident colorectal cancer cases. A random sample (n = 857) from the baseline cohort was used as controls. Four NAT2 restriction fragment length polymorphisms (RFLPs) were analysed using DNA extracted from urine samples. Rapid or slow acetylator phenotype status was attributed to individuals., Results: Smoking may increase the risk for colon cancer (RR = 1.36, 95% CI 0.97-1.92) as well as for rectal cancer (RR = 1.31, 95% CI 0.76-2.25), although not statistically significant. Rapid NAT2 acetylation did not increase colorectal cancer risk, but in combination with smoking the risk was statistically significant increased, compared to women who had a slow NAT2 imputed phenotype and never smoked (RR = 1.56, 95% CI 1.03-2.37). For colon cancer, but not for rectal cancer the increased risk was statistically significant (RR = 1.67, 95% CI, 1.05-2.67 versus RR = 1.30 95% CI 0.63-2.68)., Conclusions: Our study points to smoking as a risk factor for colon and rectal cancer and, in addition, especially in women with rapid NAT2 imputed phenotype.

Objective: We evaluated the effect of meat consumption and cigarette smoking in combination with N-acetyltransferases 1 and 2 (NAT1 and NAT2), and glutathione S-transferase M1 (GSTM1) genotypes on colorectal cancer., Methods: From a Dutch prospective study, after 8.5 years of follow-up, data of 102 incident colorectal cancer cases and a random sample of 537 controls frequency-matched for gender and age were analyzed. Baseline information on dietary and smoking habits, as well as blood samples for DNA isolation and genotyping, were available., Results: Red meat intake increased colorectal cancer risk among men (OR 2.7; 95% CI 1.1-6.7 highest vs. lowest intake), whereas poultry and fish decreased risk among women (OR 0.5; 95% CI 0.2-1.07). Cigarette smoking for at least 16 years increased colorectal cancer risk among former smokers only (OR 2.7; 95% CI 1.0-7.4), compared to those having smoked for 15 years or less. NAT1 and NAT2 polymorphisms did not significantly modify these associations. High consumption of poultry and fish was inversely associated with colorectal cancer only in the presence of GSTM1., Conclusions: In this study meat consumption and former long-term smoking were associated with colorectal cancer. Associations of colorectal cancer with different types of meat were modified by gender and GSTM1 genotype.

Objective: Epidemiologic studies suggest that subjects with elevated plasma concentrations of insulin-like growth factor (IGF)-I are at increased risk of developing cancer. The objective of our study was to assess whether cancer risk factors such as lack of physical activity, obesity, and central body fat distribution are associated with plasma levels of IGF-I and related proteins (i.e. IGF binding proteins 1-3 and C-peptide)., Methods: A cross-sectional study was conducted in a population of 225 premenopausal women, aged 49-57, participating in the Prospect-EPIC study in the Netherlands. Plasma concentrations of IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, and C-peptide were determined. On the day of blood collection height, weight, and waist and hip circumference were measured. Habitual physical activity was assessed using a validated self-administered questionnaire., Results: Mean concentrations of plasma IGF-I, IGFBP-1, IGFBP-2, IGFBP-3, and C-peptide were 156.1, 14.3, 434.4, 3062, and 2.86 ng/ml, respectively. Women in the highest tertile for physical activity had lower plasma concentrations of IGF-I, IGFBP-3, and C-peptide, and higher concentrations of IGFBP-1 and IGFBP-2, as compared to women in the lowest tertile. However, these differences were not statistically significant. BMI and related measures were significantly inversely associated with IGFBP-1 and IGFBP-2, and positively with IGFBP-3 and C-peptide. Linear regression analyses showed that the non-significant association of physical activity with components of the plasma IGF system was further attenuated by adjusting for obesity and central body fat distribution., Conclusions: Our data suggest that an active lifestyle is not independently associated with the plasma IGF system. We did confirm that a lean body shape is associated with higher concentrations of IGFBP-1 and IGFBP-2, and possibly also with lower concentrations of IGF-I and IGFBP-3.