Serum C-peptide, IGFBP-1 and IGFBP-2 and risk of colon and rectal cancers in the European Prospective Investigation into Cancer and Nutrition

Western style diets and lifestyles are associated with increasing rates of obesity, diabetes and insulin resistance. Higher circulating insulin levels may modulate cell proliferation and apoptosis either directly or indirectly by increasing the bioactivity of IGF-I and decreasing the bioactivity of some of its binding proteins. The objective of this study was to determine the association of increasing levels of serum C-peptide, a biomarker of pancreatic insulin secretion, and IGF binding proteins (IGFBP) -1 and -2 with colorectal cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), a large cohort involving 10 Western European countries. A total of 1,078 colorectal cancer cases were matched (age, date of blood donation, fasting status, gender, study center) to an equal number of control subjects. Relative cancer risks were estimated using conditional logistic regression models. Serum C-peptide concentration was positively associated with an increased colorectal cancer risk for the highest versus the lowest quintile (OR=1.56, 95% CI=1.16-2.09, p(trend)<0.01), which was slightly attenuated after adjustment for BMI and physical activity (OR=1.37, 95% CI=1.00-1.88, p(trend)=0.10). When stratified by anatomical site, the cancer risk was stronger in the colon (OR=1.67, 95% CI=1.14-2.46, p(trend)<0.01) than in the rectum (OR=1.42, 95% CI=0.90-2.25, p(trend)=0.35). The cancer risk estimates were not heterogeneous by gender or fasting status. No clear colorectal cancer risk associations were observed for IGFBP-1 or -2. This large prospective study confirms that hyperinsulinemia, as determined by C-peptide levels, is associated with an increased colorectal cancer risk.     

Serum C-peptide levels and breast cancer risk: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)

It has been hypothesized that chronic hyperinsulinemia, a major metabolic consequence of physical inactivity and excess weight, might increase breast cancer risk by direct effects on breast tissue or indirectly by increasing bioavailable levels of testosterone and estradiol. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), we measured serum levels of C-peptide--a marker for pancreatic insulin secretion--in a total of 1,141 incident cases of breast cancer and 2,204 matched control subjects. Additional measurements were made of serum sex hormone binding globulin (SHBG) and sex steroids. Conditional logistic regression models were used to estimate breast cancer risk for different levels of C-peptide. C-peptide was inversely correlated with SHBG and hence directly correlated with free testosterone among both pre and postmenopausal women. C-peptide and free estradiol also correlated positively, but only among postmenopausal women. Elevated serum C-peptide levels were associated with a nonsignificant reduced risk of breast cancer diagnosed up to the age of 50 years [odds ratio (OR)=0.70, (95% confidence interval (CI), 0.39-1.24); ptrend=0.05]. By contrast, higher levels of C-peptide were associated with an increase of breast cancer risk among women above 60 years of age, however only among those women who had provided a blood sample under nonfasting conditions [OR=2.03, (95% CI, 1.20-3.43); ptrend=0.01]. Our results do not support the hypothesis that chronic hyperinsulinemia generally increases breast cancer risk, independently of age. Nevertheless, among older, postmenopausal women, hyperinsulinemia might contribute to increasing breast cancer risk.     

Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer

Conditions related to chronic hyperinsulinemia, such as obesity, noninsulin dependent diabetes mellitus and polycystic ovary syndrome, are associated with an increased risk of endometrial cancer. Elevated plasma IGF‐I and decreased levels of IGF‐binding proteins have been shown to be associated with increased risk of several cancer types that are frequent in affluent societies. We investigated for the first time in a prospective study the association of pre‐diagnostic blood concentrations of C‐peptide (a marker of pancreatic insulin production), IGF‐I, IGFBP‐1, ‐2 and ‐3 with endometrial cancer risk. A case‐control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). It included 166 women with primary invasive endometrial cancer and 315 matched controls, of which 44 case and 78 control subjects were premenopausal at recruitment. Endometrial cancer risk increased with increasing levels of C‐peptide (p_trend = 0.0002), up to an odds ratio (OR) of 4.76 [95% confidence interval (CI) = 1.91–11.8] for the highest quintile. This association remained after adjustment for BMI and other confounders [OR for the top quintile = 4.40 (1.65–11.7)]. IGFBP‐1 levels were inversely related to endometrial cancer [p_trend = 0.002; OR in the upper quintile = 0.30 (0.15–0.62)], but the association was weakened and lost statistical significance after adjustment for confounders [p_trend = 0.06; OR in the upper quintile = 0.49 (0.22–1.07)]. Risk was unrelated to levels of IGF‐I, IGFBP‐2 and IGFBP‐3. Chronic hyperinsulinemia, as reflected by increased circulating C‐peptide, is associated with increased endometrial cancer risk. Decrease in the prevalence of chronic hyperinsulinemia, through changes in lifestyle or medication, is expected to prevent endometrial cancer. © 2003 Wiley‐Liss, Inc.     

Physical activity and risk of endometrial cancer: the European prospective investigation into cancer and nutrition

The etiologic role of physical activity in endometrial cancer risk remains unclear given the few epidemiologic studies that have been conducted. To investigate this relation more fully, an analysis was undertaken in the European prospective investigation into cancer and nutrition (EPIC). During an average 6.6 years of follow-up, 689 incident endometrial cancer cases were identified from an analytic cohort within EPIC of 253,023 women. Cox proportional hazards models were used to estimate the associations between type of activity (total, occupational, household, recreational) and endometrial cancer risk. For total activity, women in the highest compared with the lowest quartile of activity had a risk of 0.88 (95% confidence interval (95% CI=0.61-1.27). No clear associations between each type of activity and endometrial cancer risk were found for the total study population combined. Associations were more evident in the stratified results, with premenopausal women who were active versus inactive experiencing a risk of 0.66 (95% CI=0.38-1.14) overall. Among premenopausal women, for household and recreational activities the risk estimates in the highest as compared with the lowest quartiles were, respectively, 0.48 (95% CI=0.23-0.99) and 0.78 (95% CI=0.44-1.39). No effect modification by body mass index, hormone replacement therapy, oral contraceptive use or energy intake was found. This study provides no evidence of a protective effect of increased physical activity in endometrial cancer risk in all women but some support for a benefit among premenopausal women. The relative risk reductions are most apparent for household activities.     

Circulating levels of insulin-like growth factor I,its binding proteins -1,-2, -3, C-peptide and risk of postmenopausal breast cancer

Higher levels of circulating Insulin-like Growth Factor (IGF)-I may be associated with higher risks for premenopausal breast cancer. We investigate the associations between circulating levels of IGF-I, its binding proteins (IGFBPs) -1, -2, -3, C-peptide and postmenopausal breast cancer. This is a prospective study nested in 2 Dutch cohorts. The study population included women who were postmenopausal at baseline. Breast cancer cases were identified through linkage with cancer registries. Controls were matched to cases by cohort, age, date of blood donation and place of residence. In total, 149 breast cancer cases and 333 healthy controls were included. Plasma levels of IGF-I, IGFBP-1, -2, -3 and C-peptide were measured by radioimmunoassays. Estimates of the relative risk for breast cancer associated with the quartiles of the peptides' circulating levels were obtained by conditional logistic regression. Models were adjusted for BMI, age at menarche and age at first full-term delivery. For IGF-I, the adjusted OR (95% CI) of the top vs. bottom quartile was 1.1 (0.6; 2.1); for IGFBP-1 it was 0.7 (0.3; 1.3); for IGFBP-2, 1.1 (0.5; 2.4); for IGFBP-3, 1.6 (0.7; 3.5), for C-peptide, 1.3 (0.7; 2.7) and for IGF-I/IGFBP-3 ratio, 1.0 (0.5; 1.8). Our data do not support an association between postmenopausal circulating levels of IGF-I, IGFBP-1, -2, -3, C-peptide and postmenopausal breast cancer.     

Serum insulin‐like,growth factor binding protein‐related protein 1 (IGFBP‐rP1) and endometrial cancer risk in Chinese women

Hyperinsulinemia and the metabolic syndrome confer increased risks of endometrial carcinoma. The roles of insulin, and, insulin‐like growth factor‐binding proteins (IGFBPs) in the etiology of endometrial carcinoma, remain unclear. We recruited 206 patients with endometrial carcinoma and 350 healthy women to a case–control study of fasting insulin and IGFBP‐related protein 1 (IGFBP‐rP1) in a Chinese tertiary centre. Patients with endometrial carcinoma had higher insulin concentrations (14.8 ± 16.7 vs. 8.1 ± 9.4 μU/mL; p < 0.001) and lower IGFBP‐rP1 levels (17.5 ± 17.2 vs. 22.4 ± 22.8 μg/L; p = 0.018) than controls. High insulin and IGFBP‐rP1 levels were both positively and negatively associated with endometrial cancer (odds ratio for the highest tertile versus the lowest tertile: insulin: 4.11; 95% CI = 2.61–6.47; IGFBP‐rP1: 0.38; 95% CI = 0.24–0.60). Logistic regression analysis confirmed the associations between endometrial carcinoma and fasting insulin or IGFBP‐rP1 after adjustments for age, BMI, serum glucose, cholesterol, triglycerides and high‐density lipoprotein cholesterol (odds ratio for the highest tertile versus the lowest tertile: insulin: 2.13; 95% CI = 1.30–3.49; IGFBP‐rP1: 0.57; 95% CI = 0.34–0.94). Hyperinsulinemia and high IGFBP‐rP1 levels confer altered risks for endometrial carcinoma.     

Plasma insulin,IGF-binding proteins-1 and -2 and risk of colorectal cancer: a prospective study in northern Sweden

Chronically elevated plasma insulin levels have been postulated to increase colon cancer risk, either directly through colonic insulin receptors or indirectly through downregulation of IGFBP-1 and/or IGFBP-2, thus increasing IGF activity. Our aim was to examine the relationships of plasma insulin and IGFBPs-1 and -2 with risks of colon and rectal cancers. We conducted a case-control study nested within the prospective Northern Sweden Health and Disease Cohort. Insulin and IGFBPs were measured in prediagnostic plasma samples from 168 men and women who developed cancers of the colon (n = 110) or rectum (n = 58) and from 336 matched controls. Conditional logistic regression analyses showed no significant relationship of plasma insulin with risk of colon or rectal cancer. In subjects whose blood samples had been collected after more than 4 hr of fasting, insulin showed a moderate but still nonsignificant association with colorectal cancer risk [ORs over quartiles: 1.00, 0.70 (95% CI 0.35-1.39), 1.06 (95% CI 0.55-2.07), 1.63 (95% CI 0.82-3.24); p(trend) = 0.10]. Plasma IGFBP-1 and IGFBP-2 showed no association with risk of colon and/or rectal cancer, either in the full study population or among the fasting subjects. Our results only moderately support a possible relationship of chronic hyperinsulinemia with colon cancer risk.     

Smoking and the risk of endometrial cancer: results from the Nurses' Health Study

An inverse association between smoking and endometrial cancer has generally been observed, primarily among current smokers. To assess this association, we analyzed data from the prospective Nurses' Health Study. From 1976 to 2000, 702 cases of invasive endometrial cancer were identified during 1.8 million person-years of follow-up. Smoking status was assessed in 1976 and updated every 2 years. Cox proportional hazards models were used to calculate multivariate relative risks (RRs), controlling for endometrial cancer risk factors. Compared to never smokers, the multivariate RR of endometrial cancer was significantly lower among both current smokers (RR = 0.63; 95% CI = 0.50-0.79) and past smokers (RR = 0.73; 95% CI = 0.62-0.87). When additionally adjusting for body mass index (BMI), the RR for current smokers was attenuated (RR = 0.72; 95% CI = 0.57-0.90), but the RR for past smokers did not change. Risk was lower among women who smoked 35 or more cigarettes a day (RR = 0.60; 95% CI = 0.39-0.91) and among those who smoked for 40 or more years (RR = 0.63; 95% CI = 0.45-0.87). Tests for trend, which excluded never smokers, were not statistically significant for any of the smoking variables analyzed. These data indicate that both current and past smoking are associated with a lower risk of endometrial cancer. The findings provide insight into disease etiology and suggest that the influence of smoking on endometrial cancer risk occurs even in early adulthood, is long-lasting, and may not be attributed solely to short-term hormonal modulation.     

Prediagnostic plasma IGFBP‐1, IGF‐1 and risk of prostate cancer

Insulin‐like growth factor (IGF)?1 is associated with a higher risk of prostate cancer. IGF‐binding protein (IGFBP)?1, a marker for insulin activity, also binds IGF‐1 and inhibits its action. Data on IGFBP‐1 and prostate cancer risk are sparse and whether the IGF and insulin axes interact to affect prostate cancer carcinogenesis is unknown. We evaluated the independent and joint influence of prediagnostic plasma levels of IGFBP‐1 (fasting) and IGF‐1 on risk of prostate cancer among 957 cases and 1,021 controls with fasting levels of IGFBP‐1 and 1,709 cases and 1,778 controls with IGF‐1 nested within the Health Professionals Follow‐up Study. Unconditional logistic regression adjusting for matching factors was used to estimate the odds ratio (OR) and 95% confidence interval (CI). Higher prediagnostic fasting IGFBP‐1 levels were associated with lower risk of prostate cancer (highest vs. lowest quartile OR = 0.67, 95% CI 0.52–0.86, p_trend = 0.003), which remained similar after adjusting for IGF‐1. Prediagnostic IGF‐1 was associated with increased risk of prostate cancer (highest vs. lowest quartile OR = 1.28, 95% CI = 1.05–1.56, p_trend = 0.01). The associations with each marker were primarily driven by lower‐grade and non‐advanced prostate cancer. Being low in IGFBP‐1 and high in IGF‐1 did not confer appreciable additional risk (p_interaction = 0.42). In summary, prediagnostic fasting IGFBP‐1 may influence prostate cancer carcinogenesis. Being low in IGFBP‐1 or high in IGF‐1 is sufficient to elevate the risk of prostate cancer.     

Anthropometric factors and risk of endometrial cancer: the European prospective investigation into cancer and nutrition

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/m²) compared to normal weight (BMI < 25) women was 1.78, 95% CI = 1.41–2.26, and for morbidly obese women (BMI ≥ 40) was 3.02, 95% CI = 1.66–5.52. The RR for women with a waist circumference of ≥88 cm vs. <80 cm was 1.76, 95% CI = 1.42–2.19. Adult weight gain of ≥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.     

Serum concentrations of IGF-I, IGFBP-3 and c-peptide and risk of hyperplasia and cancer of the breast in postmenopausal women

Experimental evidence suggests that insulin and insulin-related growth factors may play a role in breast pathology through their mitogenic and anti-apoptotic effects on breast cells. Our objective was to assess the relationship between serum concentrations of insulin-like growth factor-I (IGF-I), its major binding protein (IGFBP-3), the ratio IGF-I:IGFBP-3, c-peptide (a marker of insulin secretion) and the ratio c-peptide:fructosamine (a marker of insulin resistance) and the risk of epithelial hyperplasia (an established breast cancer risk factor) and localized breast cancer among postmenopausal women. Study subjects were patients who provided serum before breast biopsy or mastectomy in 3 hospitals in Grand Rapids, MI between 1977 and 1987. Two case groups, 186 subjects with epithelial hyperplasia of the breast and 185 subjects with localized breast cancer, were compared to 159 subjects with nonproliferative breast changes that have not been associated with increased breast cancer risk. Serum concentrations of IGF-I, IGFBP-3 and the ratio IGF-I:IGFBP-3 were not related to risk of either hyperplasia or breast cancer. For women in the highest quartile of c-peptide or of c-peptide:fructosamine compared to those in the lowest quartile, the odds ratios (ORs) for hyperplasia were 3.0 (95% confidence interval [CI] 1.4-6.5) and 3.3 (95% CI 1.5-7.3), respectively (p trend = 0.02 and 0.02, respectively). The corresponding ORs for breast cancer were 1.5 (95% CI 0.7-3.0) and 1.6 (95% CI 0.8-3.2), respectively (p trend = 0.35 and 0.25, respectively). Our results suggest that insulin and insulin resistance may play a role in breast pathology in postmenopausal women.     

Dietary flavonoid intake and colorectal cancer risk in the European prospective investigation into cancer and nutrition (EPIC) cohort

Flavonoids have been shown to inhibit colon cancer cell proliferation in vitro and protect against colorectal carcinogenesis in animal models. However, epidemiological evidence on the potential role of flavonoid intake in colorectal cancer (CRC) development remains sparse and inconsistent. We evaluated the association between dietary intakes of total flavonoids and their subclasses and risk of development of CRC, within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. A cohort of 477,312 adult men and women were recruited in 10 European countries. At baseline, dietary intakes of total flavonoids and individual subclasses were estimated using centre‐specific validated dietary questionnaires and composition data from the Phenol‐Explorer database. During an average of 11 years of follow‐up, 4,517 new cases of primary CRC were identified, of which 2,869 were colon (proximal = 1,298 and distal = 1,266) and 1,648 rectal tumours. No association was found between total flavonoid intake and the risk of overall CRC (HR for comparison of extreme quintiles 1.05, 95% CI 0.93–1.18; p‐trend = 0.58) or any CRC subtype. No association was also observed with any intake of individual flavonoid subclasses. Similar results were observed for flavonoid intake expressed as glycosides or aglycone equivalents. Intake of total flavonoids and flavonoid subclasses, as estimated from dietary questionnaires, did not show any association with risk of CRC development.     

Dietary intake of heme iron and risk of gastric cancer in the European prospective investigation into cancer and nutrition study

Even though recent studies suggest that a high intake of heme iron is associated with several types of cancer, epidemiological studies in relation to gastric cancer (GC) are lacking. Our previous results show a positive association between red and processed meat and non cardia gastric cancer, especially in Helicobacter pylori infected subjects. The aim of the study is to investigate the association between heme iron intake and GC risk in the European prospective investigation into cancer and nutrition (EURGAST-EPIC). Dietary intake was assessed by validated center-specific questionnaires. Heme iron was calculated as a type-specific percentage of the total iron content in meat intake, derived from the literature. Antibodies of H. pylori infection and vitamin C levels were measured in a sub-sample of cases and matched controls included in a nested case-control study within the cohort. The study included 481,419 individuals and 444 incident cases of GC that occurred during an average of 8.7 years of followup. We observed a statistically significant association between heme iron intake and GC risk (HR 1.13 95% CI: 1.01-1.26 for a doubling of intake) adjusted by sex, age, BMI, education level, tobacco smoking and energy intake. The positive association between heme iron and the risk of GC was statistically significant in subjects with plasma vitamin C <39 mmol/l only (log2 HR 1.54 95% CI (1.01-2.35). We found a positive association between heme iron intake and gastric cancer risk.     

Plasma insulin,C‐peptide and blood glucose and the risk of gastric cancer: The Japan Public Health Center‐based prospective study

To date, the association between diabetes mellitus (DM) and gastric cancer has been controversial, including the underlying mechanism. We investigated the association between plasma diabetic biomarkers (insulin, C‐peptide, and blood glucose) and gastric cancer risk. In addition, homeostasis model assessment of insulin resistance (HOMA‐IR) and homeostasis model assessment of β‐cell function (HOMA‐β) were calculated. A total of 36,745 subjects aged 40–69 years in the Japan Public Health Center‐based prospective study (JPHC) who returned the baseline questionnaire and provided blood samples were followed from 1990 to 2004. In the present analysis, 477 cases and 477 matched controls were used. The odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) for developing gastric cancer were calculated using conditional logistic regression models. Plasma insulin was positively associated with increased risk of gastric cancer; compared to tertile 1, ORs were 1.69 (95% CI = 1.11–2.59) and 2.01 (1.19–3.38) for tertiles 2 and 3, respectively (p for trend = 0.009). In men, C‐peptide was also positively associated with a significant risk; corresponding ORs were 1.42 (0.85–2.38) and 1.91 (1.03–3.54), respectively (p for trend = 0.04). These findings were confirmed for blood samples from the fasting group (≥8 hr after a meal). Higher HOMA‐IR was also associated with increased risk, whereas no association was observed for blood glucose. Our findings suggest that Japanese population with higher insulin and C‐peptide levels derived from insulin resistance have an elevated risk of gastric cancer.     

Alcohol and endometrial cancer risk in the NIH‐AARP diet and health study

Previous investigations have provided conflicting results regarding whether alcohol consumption affects endometrial cancer risk, although in many of these studies the highest category of alcohol intake examined was limited. Further, most were unable to resolve how alcohol associations are affected by beverage type, the presence of other endometrial cancer risk factors, or tumor characteristics. To address these issues, we prospectively evaluated the association between alcohol intake and incident endometrial cancer (n = 1,491) in a cohort of 114,414 US women enrolled in the NIH‐AARP Diet and Health Study. We calculated relative risks (RR) and 95% confidence intervals (CI) using Cox proportional hazards regression. After adjustment for age, body mass index (BMI), smoking and other potential confounders, the multivariable RRs (and 95% CIs) compared with nondrinkers were 0.97 (0.87–1.09) for >0–<12 g of alcohol/day, 1.06 (0.87–1.31) for 12–<24 g/day and 0.93 (0.71–1.20) for ≥24 g/day (p trend = 0.90). There was, however, some suggestion of higher risks associated with alcohol consumption among lean women (BMI, <25) and users of menopausal hormone therapy, with significant interactions with both parameters (respective interaction p‐values of 0.002 and 0.005). The relationship was also enhanced, albeit nonsignificantly so, for low grade cancers. Our results do not support that alcohol is a strong contributor to endometrial cancer risk, but slight risk increases may prevail among some users or for selected tumor characteristics.     

Risk of endometrial cancer in relationship to cigarette smoking: results from the EPIC study

Current epidemiologic evidence indicates that cigarette smoking reduces the risk of endometrial cancer. We examined data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to analyze further aspects of the smoking-endometrial cancer relationship, such as possible modifying effects of menopausal status, HRT use, BMI and parity. In a total of 249,986 women with smoking exposure and menopausal status information, 619 incident endometrial cancer cases were identified during 1.56 million person-years of follow-up. Among postmenopausal women, the hazard ratio (HR) for current smokers versus never smokers was 0.70 (95% CI = 0.53-0.93), while it was 1.75 (95% CI = 1.13-2.70) among premenopausal women at recruitment. After adjustment for risk factors, the HR for postmenopausal women was slightly attenuated to 0.78 (95% CI = 0.59-1.03). No heterogeneity of effect was observed with HRT use or BMI. Among premenopausal women, current smokers of more than 15 cigarettes per day or who smoked for 30 years or more at the time of recruitment had a more than 2-fold increased risk of endometrial cancer compared to never smokers (HR = 2.54; 95% CI = 1.47-4.38 and HR = 2.23; 95% CI = 1.04-4.77, respectively). Past smoking was not associated with endometrial cancer risk, either among pre- or postmenopausal women. In this prospective study, we observed an increased risk of endometrial cancer with cigarette smoking in premenopausal women. The reduction of endometrial cancer risk observed among postmenopausal women does not have direct public health relevance since cigarette smoking is the main known risk factor for cancer.     

Lifetime and baseline alcohol intake and risk of colon and rectal cancers in the European prospective investigation into cancer and nutrition (EPIC)

Alcohol consumption may be associated with risk of colorectal cancer (CRC), but the epidemiological evidence for an association with specific anatomical subsites, types of alcoholic beverages and current vs. lifetime alcohol intake is inconsistent. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 478,732 study subjects free of cancer at enrolment between 1992 and 2000 were followed up for an average of 6.2 years, during which 1,833 CRC cases were observed. Detailed information on consumption of alcoholic beverages at baseline (all cases) and during lifetime (1,447 CRC cases, 69% of the cohort) was collected from questionnaires. Cox proportional hazard models were used to examine the alcohol-CRC association. After adjustment for potential confounding factors, lifetime alcohol intake was significantly positively associated to CRC risk (hazard ratio, HR=1.08, 95%CI=1.04-1.12 for 15 g/day increase), with higher cancer risks observed in the rectum (HR=1.12, 95%CI=1.06-1.18) than distal colon (HR=1.08, 95%CI=1.01-1.16), and proximal colon (HR=1.02, 95%CI=0.92-1.12). Similar results were observed for baseline alcohol intake. When assessed by alcoholic beverages at baseline, the CRC risk for beer (HR=1.38, 95%CI=1.08-1.77 for 20-39.9 vs. 0.1-2.9 g/day) was higher than wine (HR=1.21, 95%CI=1.02-1.44), although the two risk estimates were not significantly different from each other. Higher HRs for baseline alcohol were observed for low levels of folate intake (1.13, 95%CI=1.06-1.20 for 15 g/day increase) compared to high folate intake (1.03, 95%CI=0.98-1.09). In this large European cohort, both lifetime and baseline alcohol consumption increase colon and rectum cancer risk, with more apparent risk increases for alcohol intakes greater than 30 g/day.     

Dietary folate intake and pancreatic cancer risk: Results from the European prospective investigation into cancer and nutrition

Pancreatic cancer (PC) has an exceptionally low survival rate and primary prevention strategies are limited. Folate plays an important role in one-carbon metabolism and has been associated with the risk of several cancers, but not consistently with PC risk. We aimed to investigate the association between dietary folate intake and PC risk, using the standardised folate database across 10 European countries. A total of 477,206 participants were followed up for 11 years, during which 865 incident primary PC cases were recorded. Folate intake was energy-adjusted using the residual method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. In multivariable analyses stratified by age, sex, study centre and adjusted for energy intake, smoking status, BMI, educational level, diabetes status, supplement use and dietary fibre intake, we found no significant association between folate intake and PC risk: the HR of PC risk for those in the highest quartile of folate intake (≥353 μg/day) compared to the lowest (<241 μg/day) was 0.81 (95% CI: 0.51, 1.31; p_trend = 0.38). In current smokers, a positive trend was observed in PC risk across folate quartiles [HR = 4.42 (95% CI: 1.05, 18.62) for ≥353 μg/day vs. <241 μg/day, p_trend = 0.01]. Nonetheless, there was no significant interaction between smoking and dietary folate intake (p_interaction = 0.99). We found no association between dietary folate intake and PC risk in this large European study.     

The modifying effect of C-reactive protein gene polymorphisms on the association between central obesity and endometrial cancer risk

BACKGROUND.

Obesity is a major risk factor for endometrial cancer. Obesity, particularly central obesity, is considered as a systemic inflammatory condition and is related strongly to insulin resistance. C‐reactive protein (CRP) is the most recognized biologic marker of chronic systematic inflammation, and it is conceivable that the CRP gene may work together with obesity in the development of endometrial cancer.

METHODS.

On the basis of a population‐based case–control study in a Chinese population, the authors obtained obesity measurements and data on 6 CRP single‐nucleotide polymorphisms (SNPs) from 1046 patients with newly diagnosed endometrial cancer (cases) and from 1035 age frequency‐matched controls. The association of the CRP SNPs with endometrial cancer risk and their modification on the association between obesity and endometrial cancer risk were evaluated.

RESULTS.

Although CRP SNPs alone were not associated with endometrial cancer, the associations of endometrial cancer with central obesity, measured as the waist‐to‐hip ratio (WHR) and the waist circumference, seemed to be stronger in women who were homozygous for the major allele of reference SNP (rs)1130864 (cytidine [C]/C) than in women who had the C/thymidine (T) and T/T genotypes (interaction test: P = .013 for WHR; P = .083 for waist circumference). When the women were stratified further by menopausal status, the observed interactions persisted mainly in premenopausal women (interaction test: P < .001 for WHR; P = .002 for waist circumference).

CONCLUSIONS.

The current results suggested that, in the Chinese population that was studied, obesity‐related insulin resistance and proinflammatory effects may play an important role in endometrial cancer risk, and these effects were modified significantly by the CRP SNP rs1130864. Cancer 2008. © 2008 American Cancer Society.