Panagiota N. Mitrou

Index-based Dietary Patterns and Risk of Colorectal Cancer The NIH-AARP Diet and Health Study

The authors compared how four indexes-the Healthy Eating Index-2005, Alternate Healthy Eating Index, Mediterranean Diet Score, and Recommended Food Score-are associated with colorectal cancer in the National Institutes of Health-AARP Diet and Health Study (n = 492,382). To calculate each score, they merged data from a 124-item food frequency questionnaire completed at study entry (1995-1996) with the MyPyramid Equivalents Database (version 1.0). Other variables included energy, nutrients, multivitamins, and alcohol. Models were stratified by sex and adjusted for age, ethnicity, education, body mass index, smoking, physical activity, and menopausal hormone therapy (in women). During 5 years of follow-up, 3,110 incident colorectal cancer cases were ascertained. Although the indexes differ in design, a similarly decreased risk of colorectal cancer was observed across all indexes for men when comparing the highest scores with the lowest: Healthy Eating Index-2005 (relative risk (RR) = 0.72, 95% confidence interval (CI): 0.62, 0.83); Alternate Healthy Eating Index (RR = 0.70, 95% CI: 0.61, 0.81); Mediterranean Diet Score (RR = 0.72, 95% CI: 0.63, 0.83); and Recommended Food Score (RR = 0.75, 95% CI: 0.65, 0.87). For women, a significantly decreased risk was found with the Healthy Eating Index-2005, although Alternate Healthy Eating Index results were similar. Index-based dietary patterns that are consistent with given dietary guidelines are associated with reduced risk.

Comparing 3 Dietary Pattern Methods—Cluster Analysis, Factor Analysis, and Index Analysis—With Colorectal Cancer Risk The NIH–AARP Diet and Health Study

The authors compared dietary pattern methods-cluster analysis, factor analysis, and index analysis-with colorectal cancer risk in the National Institutes of Health (NIH)-AARP Diet and Health Study (n = 492,306). Data from a 124-item food frequency questionnaire (1995-1996) were used to identify 4 clusters for men (3 clusters for women), 3 factors, and 4 indexes. Comparisons were made with adjusted relative risks and 95% confidence intervals, distributions of individuals in clusters by quintile of factor and index scores, and health behavior characteristics. During 5 years of follow-up through 2000, 3,110 colorectal cancer cases were ascertained. In men, the vegetables and fruits cluster, the fruits and vegetables factor, the fat-reduced/diet foods factor, and all indexes were associated with reduced risk; the meat and potatoes factor was associated with increased risk. In women, reduced risk was found with the Healthy Eating Index-2005 and increased risk with the meat and potatoes factor. For men, beneficial health characteristics were seen with all fruit/vegetable patterns, diet foods patterns, and indexes, while poorer health characteristics were found with meat patterns. For women, findings were similar except that poorer health characteristics were seen with diet foods patterns. Similarities were found across methods, suggesting basic qualities of healthy diets. Nonetheless, findings vary because each method answers a different question.

N-nitroso compounds and cancer incidence: the European Prospective Investigation into Cancer and Nutrition (EPIC)–Norfolk study

BACKGROUND Humans are exposed to preformed N-nitroso compounds (NOCs) and endogenous NOCs. Several NOCs are potential human carcinogens, including N-nitrosodimethylamine (NDMA), but evidence from population studies is inconsistent. OBJECTIVE We examined the relation between dietary NOCs (NDMA), the endogenous NOC index, and dietary nitrite and cancer incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk, United Kingdom, study. DESIGN This was a prospective study of 23,363 men and women, aged 40-79 y, who were recruited in 1993-1997 and followed up to 2008. The baseline diet was assessed with food-frequency questionnaires. RESULTS There were 3268 incident cancers after a mean follow-up of 11.4 y. Dietary NDMA intake was significantly associated with increased cancer risk in men and women [hazard ratio (HR): 1.14; 95% CI: 1.03, 1.27; P for trend = 0.03] and in men (HR: 1.24; 95% CI: 1.07, 1.44; P for trend = 0.005) when the highest quartile was compared with the lowest quartile in age- and sex-adjusted analyses but not in multivariate analyses (HR: 1.10; 95% CI: 0.97, 1.24; HR for men: 1.18; 95% CI: 1.00, 1.40; P for trend ≥ 0.05). When continuously analyzed, NDMA was associated with increased risk of gastrointestinal cancers (HR: 1.13; 95% CI: 1.00, 1.28), specifically of rectal cancer (HR: 1.46; 95% CI: 1.16, 1.84) per 1-SD increase after adjustment for age, sex, body mass index, cigarette smoking status, alcohol intake, energy intake, physical activity, education, and menopausal status (in women). The endogenous NOC index and dietary nitrite were not significantly associated with cancer risk. There was a significant interaction between plasma vitamin C concentrations and dietary NDMA intake on cancer incidence (P for interaction < 0.00001). CONCLUSIONS Dietary NOC (NDMA) was associated with a higher gastrointestinal cancer incidence, specifically of rectal cancer. Plasma vitamin C may modify the relation between NDMA exposure and cancer risk.

APOE genotype, lipids, and coronary heart disease risk: a prospective population study.

BACKGROUND The risk of coronary heart disease (CHD) may be related to genetic mutations in the production of apolipoprotein E via alterations to the metabolism of CHD-related blood lipids such as low-density lipoprotein cholesterol and triglycerides. METHODS The relationship between APOE genotype (*E3/*E3, *E3/*E4, *E2/*E3, *E4/*E4, *E2/*E4, and *E2/*E2) and fatal and nonfatal CHD was examined among 10 035 men and 12 134 women, aged 440 to 79 years, from the Norfolk, England, arm of the European Prospective Into Nutrition and Cancer Study (1993-2007). During an average of 11 years of follow-up, 2712 CHD events were documented. RESULTS The hazard ratio for CHD was 0.88 (95% confidence interval, 0.77-0.99) for *E2 carriers (*E2/*E2 and *E2/*E3) and 1.09 (1.00-1.19) for *E4 carriers (*E3/*E4 and *E4/*E4) compared with homozygous *E3/*E3 individuals after age and sex adjustment. Similar values were obtained when systolic blood pressure, body mass index, diabetes mellitus, alcohol intake, physical activity, and smoking were added to the model. After additional adjustment for baseline levels of the ratio of low- to high-density lipoprotein cholesterol, the hazard ratios (and 95% confidence intervals) for *E2 and *E4 carriers were 0.97 (0.85-1.10) and 1.06 (0.97-1.15), respectively, when compared with *E3 homozygotes. No interactions by sex, smoking status, or age groups were observed. CONCLUSION In the largest prospective cohort study to date, CHD risk was not associated with APOE genotype after controlling for a variety of cardiovascular risk factors, particularly the ratio of low- to high-density lipoprotein cholesterol.

Associations between food patterns defined by cluster analysis and colorectal cancer incidence in the NIH-AARP diet and health study.

Background/Objectives:To examine associations between food patterns, constructed with cluster analysis, and colorectal cancer incidence within the National Institutes of Health–AARP Diet and Health Study.Subjects/Methods:A prospective cohort, aged 50–71 years at baseline in 1995–1996, followed until the end of 2000. Food patterns were constructed, separately in men (n=293 576) and women (n=198 730), with 181 food variables (daily intake frequency per 1000 kcal) from a food frequency questionnaire. Four large clusters were identified in men and three in women. Cox proportional hazards regression examined associations between patterns and cancer incidence.Results:In men, a vegetable and fruit pattern was associated with reduced colorectal cancer incidence (multivariate hazard ratio, HR: 0.85; 95% confidence interval, CI: 0.76, 0.94), when compared to less salutary food choices. Both the vegetable and fruit pattern and a fat-reduced foods pattern were associated with reduced rectal cancer incidence in men. In women, a similar vegetable and fruit pattern was associated with colorectal cancer protection (age-adjusted HR: 0.82; 95% CI: 0.70, 0.95), but the association was not statistically significant in multivariate analysis.Conclusions:These results, together with findings from previous studies support the hypothesis that micronutrient dense, low-fat, high-fiber food patterns protect against colorectal cancer.

Dietary, lifestyle and clinicopathological factors associated with APC mutations and promoter methylation in colorectal cancers from the EPIC-Norfolk study†

The tumour suppressor APC is the most commonly altered gene in colorectal cancer (CRC). Genetic and epigenetic alterations of APC may therefore be associated with dietary and lifestyle risk factors for CRC. Analysis of APC mutations in the extended mutation cluster region (codons 1276‐1556) and APC promoter 1A methylation was performed on 185 archival CRC samples collected from participants of the European Prospective Investigation into Cancer (EPIC)‐Norfolk study, with the aim of relating these to high‐quality seven‐day dietary and lifestyle data collected prospectively. Truncating APC mutations (APC+) and promoter 1A methylation (PM+) were identified in 43% and 23% of CRCs analysed, respectively. Distal CRCs were more likely than proximal CRCs to be APC+ or PM+ (p = 0.04). APC+ CRCs were more likely to be moderately/well differentiated and microsatellite stable than APC− CRCs (p = 0.05 and 0.03). APC+ CRC cases consumed more alcohol than their counterparts (p = 0.01) and PM+ CRC cases consumed lower levels of folate and fibre (p = 0.01 and 0.004). APC+ or PM+ CRC cases consumed higher levels of processed meat and iron from red meat and red meat products (p = 0.007 and 0.006). Specifically, CRC cases harbouring GC‐to‐AT transition mutations consumed higher levels of processed meat (35 versus 24 g/day, p = 0.04) and iron from red meat and red meat products (0.8 versus 0.6 mg/day, p = 0.05). In a logistic regression model adjusted for age, sex and cigarette‐smoking status, each 19 g/day (1SD) increment increase in processed meat consumption was associated with cases with GC‐to‐AT mutations (OR 1.68, 95% CI 1.03–2.75). In conclusion, APC+ and PM+ CRCs may be influenced by diet and GC‐to‐AT mutations in APC are associated with processed meat consumption, suggesting a mechanistic link with dietary alkylating agents, such as N‐nitroso compounds. Copyright

Effects of body size and sociodemographic characteristics on differences between self-reported and measured anthropometric data in middle-aged men and women: the EPIC-Norfolk study

Background/Objectives:To investigate the effects of body size and sociodemographic characteristics on differences between self-reported (SR) and measured anthropometric data in men and women.Subjects/Methods:This study comprises 9933 men and 11 856 women aged 39–79 years at baseline survey (1993–1997) in the EPIC-Norfolk study (Norfolk arm of the European Investigation into Cancer and Nutrition Study). The effects of sex, measured height, weight, age group, educational level and social class on differences between SR and measured weight, height, body mass index (BMI), waist, hip and waist-to-hip ratio (WHR) were examined.Results:There were systematic differences between SR and measured anthropometric measurements by sex, measured height, weight and sociodemographic characteristics. Height was overestimated in both sexes while weight, waist, hip, and consequently, BMI and WHR were underestimated. Being male, shorter, heavier, older, and having no educational qualifications and manual occupation were independently associated with overreporting of height, and underreporting of weight was associated independently with being female, shorter, heavier, younger age, and higher education level and social class. Underreporting of waist circumference was strongly associated with being female and higher measured waist circumference, while underreporting of hip circumference was associated with being male and higher measured hip circumference. Furthermore, there was substantial degree of misclassification of BMI and waist circumference categories for both general and central obesity associated with SR data.Conclusions:These findings suggest that errors in SR anthropometric data, especially waist and hip circumference are influenced by actual body size as well as sociodemographic characteristics. These systematic differences may influence associations between SR anthropometric measures and health outcomes in epidemiological studies.

Baseline alcohol consumption, type of alcoholic beverage and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition-Norfolk study.

Excessive alcohol consumption has been associated with increased risk of colorectal cancer (CRC). However, the effect of modest alcohol consumption or of particular types of beverages on CRC risk remains unclear. We examined whether consumption of total alcohol or specific types of alcoholic beverages relate to overall or site-specific CRC risk in a prospective population study of 24,244 participants and 407 incident CRC cases after 11 years of follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. Consumption of specific alcoholic beverages at baseline was collected using a detailed health and lifestyle questionnaire. Total alcohol consumption was not associated with CRC risk before or after adjustment for age, sex, weight, height, and smoking status (HR: 0.80, 95% CI: 0.51-1.26 for alcohol consumption of > or =21 units/week compared with non-drinkers), and further adjustment for education level, exercise, family history of CRC, and dietary factors did not significantly alter the risk estimates (HR: 0.70, 95% CI: 0.44-1.13). No significant associations were observed between consumption of specific alcoholic beverages (beer, sherry, or spirits) and CRC risk when compared with non-drinkers after adjustment for lifestyle and dietary factors. Daily consumption of > or =1 unit of wine appeared inversely related to CRC risk (HR: 0.61, 95% CI: 0.40-0.94). No evidence was found for sex-specific relationships, and further exclusion of cases incident within 3 years of baseline did not change the associations observed. In this population-based UK cohort, we did not find any significant adverse effect of alcohol over the moderate range of intake on colorectal cancer risk.

Self-reported and measured anthropometric data and risk of colorectal cancer in the EPIC-Norfolk study.

Background:Epidemiological studies have shown inconsistent results for the association between body size and colorectal cancer (CRC) risk. Inconsistencies may be because of the reliance on self-reported measures of body size.Objective:We examined the association of self-reported and directly assessed anthropometric data (body height, weight, body mass index (BMI), waist, hip, waist-to-hip ratio (WHR) and chest circumference) with CRC risk in the EPIC–Norfolk study.Design:A total of 20 608 participants with complete self-reported and measured height and weight and without any history of cancer were followed up an average of 11 years, during which 357 incident CRC cases were recorded. Hazard Ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models.Results:After adjustment for confounders, HRs among women in the highest quintile of the body size measure relative to the lowest quintile showed that measured height (HR=1.98, 95% CI=1.19–3.28, P trend=0.009), measured waist circumference (HR=1.65, 95% CI=0.97–2.86, P trend=0.009) and measured WHR (HR=2.07, 95% CI=1.17–3.67, P trend=0.001) were associated with increased CRC risk. Associations using corresponding self-reported measures were attenuated and not statistically significant. Conversely, the association of BMI with CRC risk in women was weaker using measured BMI (HR=1.57, 95% CI=0.91–2.73, P trend=0.05) compared with self-reported BMI (HR=1.97, 95% CI=1.18–3.30, P trend=0.02). In men no significantly increased CRC risk was observed with any of the anthropometric measures.Conclusions:Measured height, waist circumference and WHR were associated with CRC risk in women, whereas any significant associations with those measures were attenuated when self-reported data were used.

MLH1 Promoter Methylation, Diet, and Lifestyle Factors in Mismatch Repair Deficient Colorectal Cancer Patients From EPIC-Norfolk

There is conflicting evidence for the role diet and lifestyle play in the development of mismatch repair (MMR)-deficient colorectal cancers (CRC). In this study, associations between MMR deficiency, clinicopathological characteristics, and dietary and lifestyle factors in sporadic CRC were investigated. Tumor samples from 185 individuals in the EPIC-Norfolk study were analyzed for MLH1 gene promoter methylation and microsatellite instability (MSI). Dietary and lifestyle data were collected prospectively using 7-day food diaries (7dd) and questionnaires. MMR-deficient tumor cases (MLH1 promoter methylation positive, MSI-H) were more likely to be female, older at diagnosis, early Dukes’ stage (A/B), and proximal in location (MSI-H P = 0.03, 0.03, 0.02, and 0.001, respectively). Tumors with positive MLH1 promoter methylation (>20%) were associated with poor differentiation (P = 0.03). Low physical activity was associated with cases without MSI (P = 0.05). MMR deficiency was not significantly associated with cigarette smoking or alcohol, folate, fruit, vegetable, or meat consumption. We conclude that MMR-deficient tumors represent a distinct subset of sporadic CRC that are proximal in location, early Dukes’ stage, and poorly differentiated, in cases that are female and older at diagnosis. There is no overall role for diet and lifestyle in MMR status in CRC, consistent with age-related susceptibility to MLH1 promoter methylation.