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Purpose of Review In this review, we describe molecular pathological epidemiology (MPE) studies from around the world that have studied diet and/or lifestyle factors in relation to molecular markers of (epi) genetic pathways in colorectal cancer (CRC), and explore future perspectives in this realm of research. The main focus of this review is diet and lifestyle factors for which there is evidence for an association with CRC as identified by the World Cancer Research Fund reports. In addition, we review promising hypotheses, that warrant consideration in future studies.Recent Findings Associations between molecular characteristics of CRC have been published in relation to smoking, alcohol consumption; body mass index (BMI); waist: hip ratio; adult attained height; physical activity; early life energy restriction; dietary acrylamide, fiber, fat, methyl donors, omega 3 fatty acids; meat, including total protein, processed meat, and heme iron; and fruit and vegetable intake.Summary MPE studies help identify where associations between diet, lifestyle, and CRC risk may otherwise be masked and also shed light on how timing of exposure can influence etiology. Sample size is often an issue, but this may be addressed in the future by pooling data.

The Mediterranean Diet (MD) has been associated with reduced mortality and risk of cardiovascular diseases, but there is only limited evidence on cancer. We investigated the relationship between adherence to MD and risk of postmenopausal breast cancer (and estrogen/progesterone receptor subtypes, ER/PR). In the Netherlands Cohort Study, 62,573 women aged 55-69 years provided information on dietary and lifestyle habits in 1986. Follow-up for cancer incidence until 2007 (20.3 years) consisted of record linkages with the Netherlands Cancer Registry and the Dutch Pathology Registry PALGA. Adherence to MD was estimated through the alternate Mediterranean Diet Score excluding alcohol. Multivariate case-cohort analyses were based on 2,321 incident breast cancer cases and 1,665 subcohort members with complete data on diet and potential confounders. We also conducted meta-analyses of our results with those of other published cohort studies. We found a statistically significant inverse association between MD adherence and risk of ER negative (ER-) breast cancer, with a hazard ratio of 0.60 (95% Confidence Interval, 0.39-0.93) for high versus low MD adherence (p(trend)=0.032). MD adherence showed only nonsignificant weak inverse associations with ER positive (ER+) or total breast cancer risk. In meta-analyses, summary HRs for high versus low MD adherence were 0.94 for total postmenopausal breast cancer, 0.98 for ER+, 0.73 for ER- and 0.77 for ER-PR- breast cancer. Our findings support an inverse association between MD adherence and, particularly, receptor negative breast cancer. This may have important implications for prevention because of the poorer prognosis of these breast cancer subtypes. What's new? When it comes to diet and breast cancer risk, dietary patterns may be of greater importance than individual foods or nutrients. It remains uncertain, however, whether specific dietary patterns impact breast cancer risk. The Mediterranean Diet (MD), which is linked to reduced cardiovascular disease risk, is of particular interest. Here, MD adherence was investigated for potential associations with risk of postmenopausal breast cancer. Analyses of data on 62,573 women ages 55-69 enrolled in the Netherlands Cohort Study show that increased MD adherence is associated with reduced risk of estrogen receptor-negative breast cancer. A meta-analysis of cohort studies confirmed the finding.

Background: Sodium intake, but not potassium or fluid intake, has been associated with higher renal cell cancer (RCC) risk. However, risk factors may differ by molecular sub-types of the tumour. In renal physiology, electrolyte and water homeostasis is facilitated by ion transport mechanisms (ITM). Aberrant regulation of ITM genes, for example by promoter CpG island methylation, may modify associations between sodium, potassium and fluid intake and RCC risk.Methods: We identified ARHGDIG, ATP1A1, SCNN1B and SLC8A3 as ITM genes exhibiting RCC-specific promoter methylation and down-regulation. Methylation-specific polymerase chain reaction (PCR) was used to analyse promoter CpG island methylation in tumour DNA of 453 RCC cases from the Netherlands Cohort Study (n = 120 852) after 20.3 years of follow-up. Diet was measured at baseline using food-frequency questionnaires. Cox regression analyses were restricted to clear-cell (cc) RCC (n = 306) and stratified by tumours with no, low (1 gene) and high (>= 2 genes) methylation.Results: Sodium intake (high vs low) increased ccRCC risk particularly in tumours with a high methylation index: hazard ratio (HR) [95% confidence interval (CI)]: 2.04 (1.16-3.58), whereas heterogeneity across the methylation index was not significant (P-heterogeneity = 0.26). Potassium intake was differentially associated with ccRCC risk (P-heterogeneity = 0.008); the risk for high (vs low) potassium intake was low for unmethylated tumours [HR (95% CI): 0.60 (0.36-1.01)], but high for tumours with a high methylation index [HR (95% CI): 1.60 (0.96-2.65)]. Risks similarly differed for fluid intake, though not significantly (P-heterogeneity = 0.54).Conclusions: Our findings suggest for the first time that dietary intakes are differentially associated with ccRCC risk according to molecular subtypes defined by ITM gene-specific promoter methylation.

The epidemiologic evidence on the role of dietary consumption on the risk of bladder cancer in the Chinese population is limited. We investigated the role of dietary consumption and diet diversity on the risk of developing bladder cancer within a Chinese population. A case–control study of 487 cases and 469 controls was conducted in four hospitals in China. A food frequency questionnaire was used to gather information on the consumption of 35 food items. Unconditional logistic regression models were used to derive odds ratios (ORs) and corresponding 95 % confidence intervals (95 % CI) for the relationship between dietary factors, dietary diversity scores, and bladder cancer. The ORs of bladder cancer for red meat (OR = 1.8, 95 % CI:1.1–3.0;p trend = 0.01), organ meat (OR = 1.6, 95 % CI:0.9–2.9;p trend = 0.04), leafy vegetables (OR = 2.9, 95 % CI:1.6–5.4;p trend = 0.003), bulb vegetables (OR = 2.3, 95 % CI:1.3–4.0;p trend = 0.003), and preserved vegetables (OR = 2.3, 95 % CI:1.2–4.2;p trend = 0.02) were significantly increased when comparing the highest to lowest level of consumption. The ORs for white fresh fish (OR = 0.5, 95 % CI:0.3–0.9;p trend = 0.004), citrus fruits (OR = 0.4, 95 % CI:0.3–0.8;p trend = 0.007), stone fruits (OR = 0.4, 95 % CI:0.2–0.6;p trend

Background Observational studies examining associations between adult height and risk of colorectal, prostate, and lung cancers have generated mixed results. We conducted meta-analyses using data from prospective cohort studies and further carried out Mendelian randomization analyses, using height-associated genetic variants identified in a genome-wide association study (GWAS), to evaluate the association of adult height with these cancers. Methods and Findings A systematic review of prospective studies was conducted using the PubMed, Embase, and Web of Science databases. Using meta-analyses, results obtained from 62 studies were summarized for the association of a 10-cm increase in height with cancer risk. Mendelian randomization analyses were conducted using summary statistics obtained for 423 genetic variants identified from a recent GWAS of adult height and from a cancer genetics consortium study of multiple cancers that included 47,800 cases and 81,353 controls. For a 10-cm increase in height, the summary relative risks derived from the meta-analyses of prospective studies were 1.12 (95% CI 1.10, 1.15), 1.07 (95% CI 1.05, 1.10), and 1.06 (95% CI 1.02, 1.11) for colorectal, prostate, and lung cancers, respectively. Mendelian randomization analyses showed increased risks of colorectal (odds ratio [OR] = 1.58, 95% CI 1.14, 2.18) and lung cancer (OR = 1.10, 95% CI 1.00, 1.22) associated with each 10-cm increase in genetically predicted height. No association was observed for prostate cancer (OR = 1.03, 95% CI 0.92, 1.15). Our meta-analysis was limited to published studies. The sample size for the Mendelian randomization analysis of colorectal cancer was relatively small, thus affecting the precision of the point estimate. Conclusions Our study provides evidence for a potential causal association of adult height with the risk of colorectal and lung cancers and suggests that certain genetic factors and biological pathways affecting adult height may also affect the risk of these cancers., In a Mendelian randomisation study Pierce and colleagues show a genetic association between adult height and increased risk of colorectal and lung cancer., Author Summary Why Was This Study Done? Several previous observational studies have examined the association between adult height and risk of cancers of the lung, colon/rectum, and prostate; however, it remains unclear whether adult height is indeed related to the risk of these cancers. What Did the Researchers Do and Find? We conducted a systematic review and meta-analysis of prospective cohort studies that examined the association between adult height and the risk of colorectal, lung, and prostate cancers. To overcome inherent limitations of observational study designs, we conducted Mendelian randomization analyses using genetic data generated from a large multi-center consortium study including 47,800 cases and 81,353 controls. In the meta-analysis of the prospective observational studies, we found a 12% increased risk of colorectal cancer, a 7% increased risk of prostate cancer, and a 6% increased risk of lung cancer for every ten-centimeter increase in height, and this increased risk was corroborated in the Mendelian randomization analyses for colorectal (58%) and lung cancer (10%). What Do These Findings Mean? Our study provides strong evidence for an association between adult height and risk of colorectal and lung cancer, and suggests that certain genetic and biological factors that affect height may also affect the risk of these cancers. However, our meta-analysis was limited to published studies, and the sample size for the Mendelian randomization analysis for colorectal cancer was relatively small, affecting the precision of the risk estimate.

ObjectiveNitrate and nitrite are probable human carcinogens when ingested under conditions that increase the formation of N-nitroso compounds. There have been limited efforts to develop US databases of dietary nitrate and nitrite for standard FFQ. Here we describe the development of a dietary nitrate and nitrite database and its calibration.DesignWe analysed data from a calibration study of 1942 members of the NIH–AARP (NIH–AARP, National Institutes of Health–AARP) Diet and Health Study who reported all foods and beverages consumed on the preceding day in two non-consecutive 24 h dietary recalls (24HR) and completed an FFQ. Based on a literature review, we developed a database of nitrate and nitrite contents for foods reported on these 24HR and for food category line items on the FFQ. We calculated daily nitrate and nitrite intakes for both instruments, and used a measurement error model to compute correlation coefficients and attenuation factors for the FFQ-based intake estimates using 24HR-based values as reference data.ResultsFFQ-based median nitrate intake was 68·9 and 74·1 mg/d, and nitrite intake was 1·3 and 1·0 mg/d, in men and women, respectively. These values were similar to 24HR-based intake estimates. Energy-adjusted correlation coefficients between FFQ- and 24HR-based values for men and women respectively were 0·59 and 0·57 for nitrate and 0·59 and 0·58 for nitrite; energy-adjusted attenuation factors were 0·59 and 0·57 for nitrate and 0·47 and 0·38 for nitrite.ConclusionsThe performance of the FFQ in assessing dietary nitrate and nitrite intakes is comparable to that for many other macro- and micronutrients.

To study how a vegetarian or low meat diet influences the risk of colorectal cancer compared to a high meat diet and to assess the explanatory role of factors associated with these diets. In the Netherlands Cohort Study – Meat Investigation Cohort (NLCS-MIC) (cohort of 10,210 individuals including 1040 self-defined vegetarians), subjects completed a baseline questionnaire in 1986, based on which they were classified into vegetarians (n = 635), pescetarians (n = 360), 1 day/week- (n = 1259), 2–5 day/week- (n = 2703) and 6-7 day/week meat consumers (n = 5253). After 20.3 years of follow-up, 437 colorectal cancer cases (307 colon, 92 rectal) were available. A non-significantly decreased risk of CRC for vegetarians, pescetarians and 1 day/week compared to 6-7 day/week meat consumers was observed (age/sex adjusted Hazard Ratios (HR): 0.73(0.47–1.13), 0.80(0.47–1.39) and 0.72(0.52–1.00), respectively). Most of the differences in HR between these groups could be explained by intake of dietary fiber and soy products. Other (non-)dietary factors characteristic for a vegetarian or low meat diet had negligible individual effects, but attenuated the HRs towards the null when combined. Vegetarians, pescetarians and 1 day/week meat eaters showed a non-significantly decreased risk of colorectal cancer compared to 6-7 day/week meat consumers, mainly due to differences in dietary pattern other than meat intake.

Hypertension is an established risk factor for renal cell cancer (RCC). The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure and is closely linked to hypertension. RAAS additionally influences homeostasis of electrolytes (e.g. sodium and potassium) and fluid. We investigated single nucleotide polymorphisms (SNPs) in RAAS and their interactions with hypertension and intakes of sodium, potassium and fluid regarding RCC risk in the Netherlands Cohort Study (NLCS), which was initiated in 1986 and included 120,852 participants aged 55-69 years. Diet and lifestyle were assessed by questionnaires and toenail clippings were collected. Genotyping of toenail DNA was performed using the SEQUENOM(R) MassARRAY(R) platform for a literature-based selection of 13 candidate SNPs in seven key RAAS genes. After 20.3 years of follow-up, Cox regression analyses were conducted using a case-cohort approach including 3583 subcohort members and 503 RCC cases. Two SNPs in AGTR1 were associated with RCC risk. AGTR1_rs1492078 (AA vs GG) decreased RCC risk [hazard ratio (HR) (95% confidence interval (CI)): 0.70(0.49-1.00)], whereas AGTR1_rs5186 (CC vs AA) increased RCC risk [HR(95%CI): 1.49(1.08-2.05)]. Associations were stronger in participants with hypertension. The RCC risk for AGT_rs3889728 (AG+AA vs GG) was modified by hypertension (P-interaction=0.039). SNP-diet interactions were not significant, although HRs suggested interaction between SNPs in ACE and sodium intake. SNPs in AGTR1 and AGT influenced RCC susceptibility, and their effects were modified by hypertension. Sodium intake was differentially associated with RCC risk across genotypes of several SNPs, yet some analyses had probably inadequate power to show significant interaction. Results suggest that RAAS may be a candidate pathway in RCC etiology. (c) 2014 Wiley Periodicals, Inc.

The contribution of cigarette smoking to sporadic colorectal cancer may differ according to molecular aspects of the tumor or according to glutathione S-transferase M1 (GSTM1) or glutathione S-transferase T1 (GSTT1) genotype. In the prospective Netherlands Cohort Study on Diet and Cancer, adjusted incidence rate ratios for 1986-1993 were computed for overall colorectal cancer, tumors with and without adenomatous polyposis coli (APC) mutations, and tumors with and without human mut-L homologue 1 (hMLH1) expression, according to cigarette smoking characteristics (661 cases, 2,948 subcohort members). Case-only analyses were performed to estimate odds ratios for interaction between cigarette smoking and GSTM1 and GSTT1 genotypes. In comparison with never smokers, a high smoking frequency increased the risk of colorectal cancer (for a five-cigarette/day increment, incidence rate ratio (IRR) = 1.07, 95% confidence interval (CI): 1.03, 1.12), and this association was stronger in 371 tumors without a truncating APC mutation (IRR = 1.11, 95% CI: 1.05, 1.17). Long-term smoking was associated with lack of hMLH1 expression in 56 tumors (for a 10-year increment, IRR = 1.17, 95% CI: 1.00, 1.37). No statistically significant interactions between smoking and GSTM1 or GSTT1 genotype were observed. These results indicate that cigarette smoking is associated with risk of colorectal cancer, and this association may depend on molecular characteristics of the tumor as defined by APC mutation and hMLH1 expression status. Copyright © 2005 by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. Chemicals / CAS: glutathione transferase, 50812-37-8; protein MLH1, 155577-96-1; Carrier Proteins; Glutathione Transferase, EC 2.5.1.18; MLH1 protein, human; Neoplasm Proteins; Nuclear Proteins

Contains fulltext : 98290.pdf (Publisher’s version ) (Open Access) BACKGROUND: The evidence that red and processed meat influences colorectal carcinogenesis was judged convincing in the 2007 World Cancer Research Fund/American Institute of Cancer Research report. Since then, ten prospective studies have published new results. Here we update the evidence from prospective studies and explore whether there is a non-linear association of red and processed meats with colorectal cancer risk. METHODS AND FINDINGS: Relevant prospective studies were identified in PubMed until March 2011. For each study, relative risks and 95% confidence intervals (CI) were extracted and pooled with a random-effects model, weighting for the inverse of the variance, in highest versus lowest intake comparison, and dose-response meta-analyses. Red and processed meats intake was associated with increased colorectal cancer risk. The summary relative risk (RR) of colorectal cancer for the highest versus the lowest intake was 1.22 (95% CI = 1.11-1.34) and the RR for every 100 g/day increase was 1.14 (95% CI = 1.04-1.24). Non-linear dose-response meta-analyses revealed that colorectal cancer risk increases approximately linearly with increasing intake of red and processed meats up to approximately 140 g/day, where the curve approaches its plateau. The associations were similar for colon and rectal cancer risk. When analyzed separately, colorectal cancer risk was related to intake of fresh red meat (RR(for 100 g/day increase) = 1.17, 95% CI = 1.05-1.31) and processed meat (RR (for 50 g/day increase) = 1.18, 95% CI = 1.10-1.28). Similar results were observed for colon cancer, but for rectal cancer, no significant associations were observed. CONCLUSIONS: High intake of red and processed meat is associated with significant increased risk of colorectal, colon and rectal cancers. The overall evidence of prospective studies supports limiting red and processed meat consumption as one of the dietary recommendations for the prevention of colorectal cancer.

Item does not contain fulltext Surprisingly different frequencies and patterns of K-ras mutations are observed in human adenocarcinomas of the pancreas, colorectum and lung. Their respective relationships with smoking are apparently paradoxical. We evaluated all the available types of clinical and epidemiological studies on the relationship between tobacco smoking and the occurrence of K-ras mutations in human adenocarcinomas of the pancreas, colorectum and lung. We identified 8, 7 and 12 studies that analyzed the relationship between K-ras mutations and tobacco smoking in human neoplasms of the pancreas, colorectum and lung, respectively. A meta-analysis was undertaken for each site separately. In pancreatic adenocarcinomas lifetime history of tobacco consumption was not significantly associated with the frequency of K-ras mutations (OR=1.26; 95% CI=0.82-1.94). Similarly, no association was observed between smoking and K-ras mutations in colorectal adenocarcinomas (OR=0.94; CI=0.79-1.12), neither when colorectal adenomas and adenocarcinomas were jointly analyzed (OR=0.96; 95% CI=0.83-1.13). In lung adenocarcinoma, where only 15-25% of cases harbor a K-ras mutation, tumors from smokers were more likely to have K-ras mutations than tumors from non-smokers (OR=3.67; 95% CI=2.47-5.45). Furthermore, in lung adenocarcinomas K-ras mutations have a pattern different from that in pancreatic and colorectal adenocarcinomas. Results support the hypothesis that smoking influences the risk of pancreatic cancer - and possibly colorectal cancer - through events other than K-ras mutations. In adenocarcinoma of the lung, smoking may play a role in the occurrence of K-ras mutations. If the influence of tobacco products in the induction, acquisition and persistence of K-ras mutations had some tissue specificity, or was dependent on different factors in different organs, the corresponding mechanisms would deserve detailed research.

Contains fulltext : 50657.pdf (Publisher’s version ) (Closed access) K-ras mutation-positive (K-ras+) and -negative (K-ras-) colorectal adenomas may differ clinically and pathologically. As environmental compounds may cause mutations in the growth-related K-ras oncogene or affect clonal selection depending on mutational status, we evaluated whether the aetiology of K-ras+ and K-ras- adenomas differs. K-ras mutations in codons 12 and 13 were assessed in colorectal adenoma tissue (K-ras+: n = 81, K-ras-: n = 453). Dietary and lifestyle data were collected through questionnaires that were also administered to 709 polyp-free controls. Multiple logistic regression analyses showed that intake of vitamin B2 and monounsaturated fat were differently associated with risk of K-ras+ and K-ras- adenomas; vitamin B2 was inversely associated with K-ras- (highest vs. lowest tertile: odds ratio (OR) = 0.70, 95% confidence interval (CI) = 0.50-0.97, p trend = 0.020), but not with K-ras+ adenomas, and a positive association with monounsaturated fat was confined to K-ras- adenomas (OR = 1.57, 95% CI = 1.06-2.34, p trend = 0.029). Besides, potential, not statistically significant, differences in risk arose because red meat was distinctly positively associated with K-ras+ adenomas (OR = 1.70, 95% CI = 0.94-3.09, p trend = 0.061); total dietary and polyunsaturated fat tended to be inversely associated with risk of K-ras+ but not of K-ras- adenomas; inverse associations with dairy products, calcium, protein and tea were confined to K-ras- adenomas, and smoking was more markedly positively associated with K-ras- adenomas. No differences in risk of K-ras+ and K-ras- adenomas could be detected for other factors. In conclusion, dietary and lifestyle factors may influence risk of K-ras+ and K-ras- adenomas differently. However, epidemiological literature on diet, lifestyle and colorectal K-ras mutations is inconsistent.