ABSTRACT
Student participation in governance of education is of growing interest. However, it remains unclear what factors render this participation in institutional governance a success or a failure. Another question is: what are the perceived benefits for schools and students? We empirically explored experiences and perspectives of student representatives and program directors of all (8) medical and (1) veterinary schools in the Netherlands on factors that influence student participation in institutional governance and its values and challenges for schools and student representatives. A constructivist grounded theory study was performed. A theoretical sample of student representatives was invited to fill out an explorative, qualitative questionnaire. Next, focus groups with student representatives and interviews with all program directors were conducted. Data was analyzed using open, axial and selective coding by all authors. Experiences and perspectives of students and program directors were remarkably similar in both perceived influences and values. Four main categories of influences could be distinguished in student participation: (1) individual student characteristics, (2) individual staff characteristics, (3) the organization of student representatives and (4) the school's organization, including its culture and policy regarding student participation. A cohesive, well-organized and independent student organization has crucial impact on student participation in educational governance processes. For representatives, major benefits of participation are personal and career development. Challenges are low effectiveness and efficiency of their actions. A clear school policy on student participation and better introduction, feedback and coaching of representatives should be provided to improve student participation in governance processes.
Subject(s)
Cooperative Behavior , Education, Veterinary/organization & administration , Faculty, Medical , Students , Female , Focus Groups , Humans , Interviews as Topic , Male , Netherlands , Qualitative Research , Surveys and QuestionnairesABSTRACT
Ever since Darwin's early descriptions of coral reefs, scientists have debated how one of the world's most productive and diverse ecosystems can thrive in the marine equivalent of a desert. It is an enigma how the flux of dissolved organic matter (DOM), the largest resource produced on reefs, is transferred to higher trophic levels. Here we show that sponges make DOM available to fauna by rapidly expelling filter cells as detritus that is subsequently consumed by reef fauna. This "sponge loop" was confirmed in aquarium and in situ food web experiments, using (13)C- and (15)N-enriched DOM. The DOM-sponge-fauna pathway explains why biological hot spots such as coral reefs persist in oligotrophic seas--the reef's paradox--and has implications for reef ecosystem functioning and conservation strategies.
Subject(s)
Anthozoa/metabolism , Coral Reefs , AnimalsABSTRACT
Red meat intake has been linked to increased colorectal cancer (CRC) risk. Although the underlying mechanisms remain unclear, experimental studies suggest a role for dietary heme iron. Because heme iron was shown to promote specific mutations, it would be insightful to link heme iron data to CRC with mutations in key genes in an observational, population-based study. We investigated the association between dietary heme iron intake and risk of CRC with mutations in APC (adenomatous polyposis coli) and KRAS (Kirsten ras) and P53 overexpression in the Netherlands Cohort Study. After 7.3 years of follow-up, excluding the first 2.3 years due to incomplete coverage of the pathology registry and to avoid preclinical disease, adjusted hazard ratios (including adjustment for total meat) and 95% confidence intervals were calculated, using 4026 subcohort members (aged 55-69 years at baseline), 435 colon and 140 rectal cancer patients. When comparing the highest with the lowest tertile of intake, heme iron intake was associated with an increased risk of CRC harboring activating mutations in KRAS (hazard ratio = 1.71, 95% confidence interval: 1.15-2.57; P for trend = 0.03) and CRC without truncating mutations in APC (hazard ratio = 1.79, 95% confidence interval: 1.23-2.60; P for trend = 0.003). We observed a positive association between heme iron intake and the risk of CRC with activating G>A mutations in KRAS (P for trend = 0.01) and overall G>A mutations in APC (P for trend = 0.005). No associations were found with CRC harboring G>T mutations in KRAS/APC. Heme iron intake was positively associated with the risk of P53 overexpressed tumors but not with tumors without P53 overexpression (Pheterogeneity = 0.12). Heme iron intake was associated with an increased risk of colorectal tumors harboring G>A transitions in KRAS and APC and overexpression of P53. These novel findings suggest that alkylating rather than oxidative DNA-damaging mechanisms are involved in heme-induced colorectal carcinogenesis.
Subject(s)
Colorectal Neoplasms/etiology , Genes, ras/genetics , Heme/metabolism , Iron, Dietary/adverse effects , Meat/adverse effects , Mutation/genetics , Case-Control Studies , Cohort Studies , Colorectal Neoplasms/genetics , Female , Genes, APC , Genes, p53/genetics , Humans , Male , Middle Aged , Risk , Risk FactorsABSTRACT
BACKGROUND: We investigated how body size and physical activity influence the risk of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC). METHODS: In the Netherlands Cohort Study (nâ=â120,852), risk factors were self-reported at baseline in 1986. After 7.3 years of follow-up, 603 cases and 4,631 sub-cohort members were available. CIMP status according to the Weisenberger markers was determined using methylation specific PCR on DNA from paraffin embedded tumor tissue. Hazard rate ratios (HR) and 95% confidence intervals for CIMP (27.7%) and non-CIMP (72.3%) tumors were calculated according to BMI, BMI at age 20, BMI change, trouser/skirt size, height, and physical activity. RESULTS: BMI modeled per 5 kg/m(2) increase was associated with both CIMP and non-CIMP tumors, however, HRs were attenuated when additionally adjusted for trouser/skirt size. Trouser/skirt size, per 2 size increase, was associated with both tumor subtypes, even after adjustment for BMI (CIMP HR: 1.20, 95%CI: 1.01-1.43; non-CIMP HR: 1.14, 95%CI: 1.04-1.28). Height per 5 cm was associated with both tumor sub-types, but HRs were attenuated when adjusted for body weight. BMI at age 20 was positively associated with increased risk of CIMP tumors and the association was significantly less pronounced for non-CIMP tumors (P-heterogeneityâ=â0.01). Physical activity was inversely associated with both subtypes, but a dose-response association was observed only for non-CIMP tumors (P-trendâ=â0.02). CONCLUSIONS: Body size, especially central adiposity, may increase the risk of both CIMP and non-CIMP tumors. Body fat at young age may differentially influence risk. Physical activity appears to decrease the risk of CRC regardless of these molecular subtypes.
Subject(s)
Body Size , Colorectal Neoplasms/genetics , Colorectal Neoplasms/physiopathology , CpG Islands/genetics , DNA Methylation , Motor Activity , Phenotype , Aged , Body Height , Body Mass Index , Cohort Studies , Female , Humans , Male , Middle Aged , Prospective Studies , Risk , Time Factors , Waist CircumferenceABSTRACT
Within the Netherlands Cohort Study (1986), we examined associations between alcohol consumption, the alcohol dehydrogenase 1C (ADH1C) genotype, and risk of colorectal cancer (CRC). After a follow-up period of 7.3 years, 594 CRC cases with information on genotype and baseline alcohol intake were available for analyses. Adjusted incidence rate ratios (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. In subjects who reported to have consumed equal amounts of total alcohol both 5 years before baseline and at baseline, drinkers of ≥30g of alcohol per day with the ADH1C*2/*2 genotype were associated-although not statistically significant-with an increased risk of CRC relative to abstainers with the ADH1C*1/*1 genotype (RR: 1.91, 95% CI: 0.68, 5.34). The risk estimate in this exposure group increased slightly when compared with light drinkers of ≥0.5-<5g/day with the ADH1C*1/*1 genotype (RR: 2.32, 95% CI: 0.80, 6.72). The interaction term however, was not statistically significant (P>.05). In subjects who reported to have consumed equal amounts of total alcohol both 5 years before baseline and at baseline, drinkers of ≥30g of alcohol per day were associated-although not statistically significant-with an increased risk of CRC relative to abstainers (RR: 1.38, 95% CI: 0.80, 2.38). This risk estimate for high-level drinkers became stronger when compared with light drinkers (RR: 1.74, 95% CI: 1.01, 2.99). As main effect of genotype, we observed that the ADH1C*2/*2 genotype was associated with a 42% increase in risk of CRC when compared with the ADH1C*1/*1 genotype. In conclusion, both genotype and alcohol consumption were associated with an increased risk of CRC. Owing to limited statistical power, we found no apparent evidence for the ADH1C genotype as effect modifier of the relationship between alcohol intake and CRC. Nevertheless, the interaction deserves further investigation in larger genetic epidemiologic studies.
Subject(s)
Alcohol Dehydrogenase/genetics , Alcohol Drinking/epidemiology , Alcohol Drinking/genetics , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Aged , Cohort Studies , Diet , Female , Genotype , Humans , Male , Middle Aged , Molecular Epidemiology , Netherlands/epidemiologyABSTRACT
Dietary methyl donors might influence DNA methylation during carcinogenesis of colorectal cancer (CRC). Among 609 CRC cases and 1,663 subcohort members of the Netherlands Cohort Study on diet and cancer (n = 120,852), we estimated CRC risk according to methyl donor intake across genotypes of folate metabolizing enzymes and methyltransferases.Although diet-gene interactions were not statistically significant, methionine intake was inversely associated with CRC among subjects having both common rs2424913 and rs406193 DNMT3B C > T genotypes (highest versus lowest tertile: RR = 0.44; p (trend) = 0.05). Likewise, vitamin B2 was modestly inversely associated among individuals with the MTHFR c.665CC (rs1801133) genotype (RR = 0.66; p (trend) = 0.08), but with a significant reduced risk when ≤ 1 rare allele occurred in the combination of folate metabolizing enzymes MTHFR, MTRR and MTR (RR = 0.30; p (trend) = 0.005). Folate or vitamin B6 were neither inversely associated with CRC nor was methyl donor intake associated with the CpG island methylator phenotype (CIMP).Despite the absence of heterogeneity across genotypes, might an effect of methyl donors on CRC be more pronounced among individuals carrying common variants of folate metabolizing enzymes or DNA methyltransferases. Combining genotypes may assist to reveal diet associations with CRC, possibly because rare variants of related genes may collectively affect specific metabolic pathways or enzymatic functions.
Subject(s)
Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , CpG Islands/genetics , DNA Methylation , Diet , Genetic Predisposition to Disease , Aged , Epigenesis, Genetic , Female , Folic Acid/metabolism , Genotype , Humans , Male , Methionine/metabolism , Methyltransferases/genetics , Middle Aged , Polymerase Chain Reaction , Promoter Regions, Genetic , Vitamin B 6/metabolismABSTRACT
Olfactomedin-4 (OLFM-4) is an extracellular matrix protein that is highly expressed in human endometrium. We have examined the regulation and function of OLFM-4 in normal endometrium and in cases of endometriosis and endometrial cancer. OLFM-4 expression levels are highest in proliferative-phase endometrium, and 17ß-estradiol up-regulates OLFM-4 mRNA in endometrial explant cultures. Using the luciferase reporter under control of the OLFM-4 promoter, it was shown that both 17ß-estradiol and OH-tamoxifen induce luciferase activity, and epidermal growth factor receptor-1 is required for this estrogenic response. In turn, EGF activates the OLFM-4 promoter, and estrogen receptor-α is needed for the complete EGF response. The cellular functions of OLFM-4 were examined by its expression in OLFM-4-negative HEK-293 cells, which resulted in decreased vimentin expression and cell adherence as well as increased apoptosis resistance. In cases of endometriosis and endometrial cancer, OLFM-4 expression correlated with the presence of epidermal growth factor receptor-1 and estrogen receptor-α (or estrogen signaling). An increase of OLFM-4 mRNA was observed in the endometrium of endometriosis patients. No change in OLFM-4 expression levels were observed in patients with endometrial cancer relative with controls. In conclusion, cross-talk between estrogen and EGF signaling regulates OLFM-4 expression. The role of OLFM-4 in endometrial tissue remodeling before the secretory phase and during the predisposition and early events in endometriosis can be postulated but requires additional investigation.
Subject(s)
Endometrium/physiology , Epidermal Growth Factor/metabolism , Estrogens/metabolism , Granulocyte Colony-Stimulating Factor/metabolism , Signal Transduction/physiology , Adult , Aged , Aged, 80 and over , Apoptosis , Cell Adhesion , Cells, Cultured , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Endometriosis/metabolism , Endometrium/cytology , Endometrium/pathology , ErbB Receptors/genetics , ErbB Receptors/metabolism , Female , Granulocyte Colony-Stimulating Factor/genetics , Humans , Menstrual Cycle/physiology , Middle Aged , Promoter Regions, Genetic , Trefoil Factor-1 , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Vimentin/metabolismABSTRACT
BACKGROUND: Energy restriction during childhood and adolescence is suggested to lower colorectal cancer (CRC) risk. We investigated this in the Netherlands Cohort Study. METHODS: Information on diet and other risk factors was collected by a baseline questionnaire in 1986 when cohort members were 55-69 years of age (n = 120 852). Three indicators of early life exposure to energy restriction were assessed: father's employment status during the Economic Depression (1932-40), place of residence during Second World War years (1940-44) and the 'Hunger Winter' (1944-45), a severe famine. Using the case-cohort approach, incidence rate ratios (RRs) and 95% confidence intervals (CIs) were calculated for total colorectal, proximal colon, distal colon, rectosigmoid and rectal cancers, according to the three time periods of energy restriction. After 16.3 years of follow-up, 2573 cases were available for multivariate analyses. RESULTS: Men who lived in a western city during the Hunger Winter and therefore exposed to the highest degree of energy restriction, had a lower risk of developing CRC (RR: 0.81, 95% CI: 0.68-0.98), and tumours of the proximal colon (RR: 0.72, 95% CI: 0.54-0.96) and rectum (RR: 0.71, 95% CI: 0.53-0.96). In women, non-statistically significant inverse associations were observed for tumours of the distal colon, rectosigmoid and rectum. Inverse associations were also observed between the other two exposure times and studied endpoints, though not statistically significant. CONCLUSIONS: This unique observational evidence suggests that severe energy restriction during childhood and adolescence may lower CRC risk, especially in men, thus providing insight regarding the role of energy intake during early life in CRC development.
Subject(s)
Colorectal Neoplasms/epidemiology , Diet , Energy Intake , Hunger , Adolescent , Adult , Aged , Body Weights and Measures , Child , Exercise , Female , Humans , Male , Middle Aged , Netherlands/epidemiology , Prospective Studies , Residence Characteristics/statistics & numerical data , Risk Factors , Smoking/epidemiology , Socioeconomic Factors , Young AdultABSTRACT
BACKGROUND: Exposure to energy restriction during childhood and adolescence is associated with a lower risk of developing colorectal cancer (CRC). Epigenetic dysregulation during this critical period of growth and development may be a mechanism to explain such observations. Within the Netherlands Cohort Study on diet and cancer, we investigated the association between early life energy restriction and risk of subsequent CRC characterized by the (promoter) CpG island methylation phenotype (CIMP). METHODOLOGY/PRINCIPAL FINDINGS: Information on diet and risk factors was collected by baseline questionnaire (n = 120,856). Three indicators of exposure were assessed: place of residence during the Hunger Winter (1944-45) and World War II years (1940-44), and father's employment status during the Economic Depression (1932-40). Methylation specific PCR (MSP) on DNA from paraffin embedded tumor tissue was performed to determine CIMP status according to the Weisenberger markers. After 7.3 years of follow-up, 603 cases and 4631 sub-cohort members were available for analysis. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals for CIMP+ (27.7%) and CIMP- (72.3%) tumors according to the three time periods of energy restriction, adjusted for age and gender. Individuals exposed to severe famine during the Hunger Winter had a decreased risk of developing a tumor characterized by CIMP compared to those not exposed (HR 0.65, 95%CI: 0.45-0.92). Further categorizing individuals by an index of '0-1' '2-3' or '4-7' genes methylated in the promoter region suggested that exposure to the Hunger Winter was associated with the degree of promoter hypermethylation ('0-1 genes methylated' HR = 1.01, 95%CI:0.74-1.37; '2-3 genes methylated' HR = 0.83, 95% CI:0.61-1.15; '4-7 genes methylated' HR = 0.72, 95% CI:0.49-1.04). No associations were observed with respect to the Economic Depression and WWII years. CONCLUSIONS: This is the first study indicating that exposure to a severe, transient environmental condition during adolescence and young adulthood may result in persistent epigenetic changes that later influence CRC development.
Subject(s)
Colorectal Neoplasms/etiology , Colorectal Neoplasms/genetics , Epigenesis, Genetic , Gene Expression Regulation , Starvation/genetics , Adolescent , Aged , Child , Cohort Studies , CpG Islands , Diet , Female , Humans , Male , Middle Aged , Netherlands , Promoter Regions, Genetic , Risk FactorsABSTRACT
Aberrant DNA methylation affects carcinogenesis of colorectal cancer. Folate metabolizing enzymes may influence the bioavailability of methyl groups, whereas DNA and histone methyltransferases are involved in epigenetic regulation of gene expression. We studied associations of genetic variants of folate metabolizing enzymes (MTHFR, MTR, and MTRR), DNA methyltransferase DNMT3b, and histone methyltransferases (EHMT1, EHMT2, and PRDM2), with colorectal cancers, with or without the CpG island methylator phenotype (CIMP), MLH1 hypermethylation, or microsatellite instability. Incidence rate ratios were calculated in case-cohort analyses, with common homozygotes as reference, among 659 cases and 1,736 subcohort members of the Netherlands Cohort Study on diet and cancer (n = 120,852). Men with the MTHFR 677TT genotype were at decreased colorectal cancer risk (incidence rate ratio, 0.49; P = 0.01), but the T allele was associated with increased risk in women (incidence rate ratio, 1.39; P = 0.02). The MTR 2756GG genotype was associated with increased colorectal cancer risk (incidence rate ratio, 1.58; P = 0.04), and inverse associations were observed among women carrying DNMT3b C-->T (rs406193; incidence rate ratio, 0.72; P = 0.04) or EHMT2 G-->A (rs535586; incidence rate ratio, 0.76; P = 0.05) polymorphisms. Although significantly correlated (P < 0.001), only 41.5% and 33.3% of CIMP tumors harbored MLH1 hypermethylation or microsatellite instability, respectively. We observed inverse associations between MTR A2756G and CIMP among men (incidence rate ratio, 0.58; P = 0.04), and between MTRR A66G and MLH1 hypermethylation among women (incidence rate ratio, 0.55; P = 0.02). In conclusion, MTHFR, MTR, DNMT3b, and EHMT2 polymorphisms are associated with colorectal cancer, and rare variants of MTR and MTRR may reduce promoter hypermethylation. The incomplete overlap between CIMP, MLH1 hypermethylation, and microsatellite instability indicates that these related "methylation phenotypes" may not be similar and should be investigated separately.
Subject(s)
Colorectal Neoplasms/genetics , CpG Islands/genetics , DNA Methylation , Epigenesis, Genetic , Neoplasm Proteins/genetics , Polymorphism, Single Nucleotide/genetics , Promoter Regions, Genetic/genetics , Adaptor Proteins, Signal Transducing/genetics , Aged , Biomarkers, Tumor/genetics , Cohort Studies , Colorectal Neoplasms/diagnosis , DNA (Cytosine-5-)-Methyltransferases/genetics , Female , Genotype , Histocompatibility Antigens/genetics , Histone-Lysine N-Methyltransferase/genetics , Humans , Male , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Microsatellite Instability , Middle Aged , MutL Protein Homolog 1 , Neoplasm Staging , Netherlands , Nuclear Proteins/genetics , Prognosis , Prospective Studies , Risk Factors , TRPM Cation Channels/genetics , DNA Methyltransferase 3BABSTRACT
Within the Netherlands Cohort Study on diet and cancer, we investigated associations between total alcohol consumption, specific alcoholic beverage consumption and risk of colorectal cancer (CRC) according to anatomical subsite. Hazard Ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Analyses were performed on 2,323 CRC cases, available after 13.3 years of follow-up. Compared to abstaining, alcohol consumption of >/=30.0 g/day ( approximately 3 alcoholic drinks) was positively associated with the risk of CRC (HR: 1.32, 95% CI: 1.06-1.65). Analyses restricted to subjects who reported to have consumed equal amounts of alcohol 5 years before baseline compared to baseline, showed elevated risk estimates for consumers of >/=30.0 g of total alcohol per day as well (HR: 1.53, 95% CI: 1.16-2.01). Suggestive of a subsite-specific effect, cancer risk seemed to increase from proximal colon through rectum; HR: 1.29, 95% CI: 0.85-1.96 for proximal colon cancer, HR: 1.41, 95% CI: 0.94-2.11 for distal colon cancer, HR: 2.07, 95% CI: 1.03-4.18 for rectosigmoid cancer and HR: 1.69, 95% CI: 1.08-2.64 for rectal cancer. No associations were observed between consumption of alcoholic beverages and CRC risk when compared with the nondrinkers of the specific beverage and after adjustment for total alcohol intake. No evidence was found for sex-specific effects of alcohol and alcoholic beverages. In conclusion, our data showed a positive association between alcohol consumption and risk of CRC, which seemed to be mainly explained by the alcoholic content of alcoholic beverages, rather than other constituents. Also, cancer risk may vary according to anatomical subsite.
Subject(s)
Alcohol Drinking , Alcoholic Beverages/adverse effects , Colorectal Neoplasms/epidemiology , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Netherlands/epidemiology , Proportional Hazards Models , Risk Factors , Surveys and QuestionnairesABSTRACT
Intake of dietary factors that serve as methyl group donors may influence promoter hypermethylation in colorectal carcinogenesis. We investigated whether dietary folate, vitamin B2 and vitamin B6, methionine and alcohol were associated with mutL homologue 1 (MLH1) hypermethylation and the related molecular phenotypes of MLH1 protein expression, microsatellite instability (MSI) and BRAF mutations in patients with colorectal carcinomas. Within the Netherlands Cohort Study on diet and cancer (n = 120 852), 648 cases (367 men and 281 women) and 4059 subcohort members were available for data analyses from a follow-up period between 2.3 and 7.3 years after baseline. Gender-specific adjusted incidence rate ratios (RRs) were calculated over categories of dietary intake in case-cohort analyses. The intakes of folate, vitamin B2, methionine and alcohol were not associated with risk of tumors showing MLH1 hypermethylation, those lacking MLH1 protein expression or with MSI. Among men, we observed strong positive associations between folate and BRAF-mutated tumors (RR = 3.04 for the highest versus lowest tertile of intake, P(trend) = 0.03) and between vitamin B6 and tumors showing MLH1 hypermethylation (highest versus lowest tertile: RR = 3.23, P(trend) = 0.03). Among women, the relative risks of tumors with BRAF mutations or MLH1 hypermethylation were also increased in the highest tertiles of folate and vitamin B6 intake, respectively, but these did not reach statistical significance. The positive associations between folate intake and tumors harboring BRAF mutations and between vitamin B6 intake and those showing MLH1 hypermethylation were most pronounced among men and may suggest that these vitamins enhance colorectal cancer risk through genetic as well as epigenetic aberrations.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Colorectal Neoplasms/genetics , DNA Methylation , Diet , Methionine/administration & dosage , Nuclear Proteins/genetics , Promoter Regions, Genetic/genetics , Proto-Oncogene Proteins B-raf/genetics , Adaptor Proteins, Signal Transducing/metabolism , Aged , Cohort Studies , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/metabolism , DNA, Neoplasm/genetics , DNA, Neoplasm/metabolism , Female , Folic Acid/administration & dosage , Humans , Male , Microsatellite Repeats , Middle Aged , MutL Protein Homolog 1 , Mutation/genetics , Netherlands/epidemiology , Nuclear Proteins/metabolism , Phenotype , Proto-Oncogene Proteins B-raf/metabolism , Riboflavin/administration & dosage , Surveys and Questionnaires , Vitamin B 12/administration & dosage , Vitamin B 6/administration & dosageABSTRACT
OBJECTIVE: To investigate baseline fat intake and the risk of colon and rectal tumors lacking MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) repair gene expression and harboring mutations in the APC (adenomatous polyposis coli) tumor suppressor gene and in the KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) oncogene. METHODS: After 7.3 years of follow-up of the Netherlands Cohort Study (n = 120,852), adjusted incidence rate ratios (RR) and 95% confidence intervals (CI) were computed, based on 401 colon and 130 rectal cancer patients. RESULTS: Total, saturated and monounsaturated fat were not associated with the risk of colon or rectal cancer, or different molecular subgroups. There was also no association between polyunsaturated fat and the risk of overall or subgroups of rectal cancer. Linoleic acid, the most abundant polyunsaturated fatty acid in the diet, was associated with increased risk of colon tumors with only a KRAS mutation and no additional truncating APC mutation or lack of MLH1 expression (RR = 1.41, 95% CI 1.18-1.69 for one standard deviation (i.e., 7.5 g/day) increase in intake, p-trend over the quartiles of intake <0.001). Linoleic acid intake was not associated with risk of colon tumors without any of the gene defects, or with tumors harboring aberrations in either MLH1 or APC. CONCLUSION: Linoleic acid intake is associated with colon tumors with an aberrant KRAS gene, but an intact APC gene and MLH1 expression, suggesting a unique etiology of tumors with specific genetic aberrations.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Adenomatous Polyposis Coli Protein/genetics , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Dietary Fats/administration & dosage , Genes, ras/genetics , Mutation/genetics , Nuclear Proteins/genetics , Aged , Cohort Studies , Diet , Female , Follow-Up Studies , Humans , Immunoenzyme Techniques , Male , Middle Aged , MutL Protein Homolog 1 , Netherlands/epidemiology , Prospective StudiesABSTRACT
High alcohol consumption is related to colorectal cancer (CRC). Our objective was to study associations between alcohol consumption and risk of CRC according to characteristics of aetiological pathways: the chromosomal instability (CIN) and the microsatellite instability (MIN) pathway. We classified CIN+ tumours (tumours with either a truncating APC mutation, an activating K-ras mutation or overexpression of p53), MIN+ tumours (tumours lacking hMLH1 expression) and CIN- /MIN- tumours (tumours without these defects). In the Netherlands Cohort Study on diet and cancer, 120852 men and women, aged 55-69 years, completed a questionnaire on risk factors for cancer at baseline (1986). Case-cohort analyses were conducted using 573 CRC cases with complete data after 7 x 3 years of follow-up, excluding the first 2 x 3 years. Adjusted incidence rate ratios (RR) and 95 % confidence intervals (CI) were estimated. Compared with abstaining, alcohol consumption of >or=30 g/d was positively associated with the risk of CRC irrespective of genetic or molecular aberrations present, although statistical significance was not reached (RR 1 x 35 (95 % CI 0 x 9-2 x 0) for the CIN+ tumours, RR 1 x 59 (95 % CI 0 x 4-5 x 8) for the MIN+ tumours and RR 1.15 (95 % CI 0 x 5-2 x 7) for the CIN- /MIN- tumours). Beer, wine and liquor consumption were, independent of their alcoholic content, not consistently associated with the risk of CRC within the defined subgroups. In conclusion, our results indicate that a daily alcohol consumption of >or=30 g is associated with an increase in risk of CRC, independent of the presence or absence of the studied characteristics of different aetiological pathways.
Subject(s)
Alcohol Drinking/adverse effects , Colorectal Neoplasms/etiology , Aged , Alcohol Drinking/epidemiology , Chromosomal Instability , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Epidemiologic Methods , Female , Genes, APC , Genetic Predisposition to Disease , Humans , Male , Microsatellite Instability , Middle Aged , Mutation , Netherlands/epidemiologyABSTRACT
Folate deficiency has been associated with colorectal cancer risk and may be involved in colorectal carcinogenesis through increased chromosome instability, gene mutations, and aberrant DNA methylation. Within the Netherlands Cohort Study on diet and cancer, we investigated the associations between dietary folate intake and colorectal cancer risk with (APC(+)) and without (APC(-)) truncating APC mutations, accounting for hMLH1 expression and K-ras mutations. In total, 528 cases and 4200 subcohort members were available for data analyses of the study cohort (n = 120,852) from a follow-up period between 2.3 and 7.3 y after baseline. Adjusted gender-specific incidence rate ratios (RR) over tertiles of folate intake were calculated in case-cohort analyses for colon and rectal cancer. Although relatively high folate intake was not associated with overall colorectal cancer risk, it reduced the risk of APC(-)colon tumors in men (RR 0.58, 95% CI 0.32-1.05, P(trend) = 0.06 for the highest vs. lowest tertile of folate intake). In contrast, it was positively associated with APC(+) colon tumors in men (highest vs. lowest tertile: RR 2.77, 95% CI 1.29-5.95, P(trend) = 0.008) and was even stronger when the lack of hMLH1 expression and K-ras mutations were excluded (RR 3.99, 95% CI 1.43-11.14, P(trend) = 0.007). Such positive associations were not observed among women; nor was folate intake associated with rectal cancer when APC mutation status was taken into account. Relatively high folate consumption reduced the risk of APC(-) colon tumors, but folate intake was positively associated with APC(+) colon tumors among men. These opposite results may indicate that folate enhances colorectal carcinogenesis through a distinct APC mutated pathway.
Subject(s)
Colorectal Neoplasms/genetics , Folic Acid/administration & dosage , Genes, APC , Mutation , Adaptor Proteins, Signal Transducing , Aged , Carrier Proteins/genetics , Cohort Studies , Colonic Neoplasms/genetics , DNA, Neoplasm/genetics , DNA, Neoplasm/isolation & purification , Diet , Female , Humans , Male , Middle Aged , MutL Protein Homolog 1 , Nuclear Proteins/genetics , Patient Selection , Proportional Hazards Models , Rectal Neoplasms/genetics , Surveys and QuestionnairesABSTRACT
The first metabolite of alcohol, acetaldehyde, may trigger replication errors and mutations in DNA, which may predispose to developing colorectal cancer (CRC). In a prospective study on colon and rectal cancer, we investigated the following hypotheses: alcohol consumption is associated with an increased risk of mutations in the K-ras oncogene, and beer consumption is associated with an increased risk of G-->A mutations in this gene. Therefore, we studied the associations between consumption of alcohol and alcoholic beverages and the risk of CRC without and with specific K-ras gene mutations. In 1986, 120,852 men and women, aged 55-69 years, completed a questionnaire on risk factors for cancer. The case-cohort approach was used for data processing and analyses. After 7.3 years of follow-up, excluding the first 2.3 years, complete data from 4,076 subcohort members, 428 colon and 150 rectal cancer patients, were available for data analyses. Incidence rate ratios (RRs) and corresponding 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards models. Compared to abstaining, a total alcohol consumption of 30.0 g/day and more was associated with the risk of colon and rectal cancer with and without a K-ras mutation in both men and women. Independent from alcohol intake, liquor consumption when compared to nonliquor consumption was associated with an increased risk of rectal cancer with a wild type K-ras in men (RR: 2.25, 95% CI: 1.0-5.0). Beer consumption was not clearly associated with the risk of colon and rectal tumors harboring G-->A mutations in the K-ras gene in men. This association could not be assessed in women because of sparse beer consumption. In conclusion, alcohol does not seem to be involved in predisposing to CRC through mutations in the K-ras gene, and specifically beer consumption is not associated with colon and rectal tumors harboring a G-->A mutation.
Subject(s)
Alcohol Drinking/adverse effects , Alcohol Drinking/epidemiology , Colonic Neoplasms/epidemiology , Colonic Neoplasms/genetics , Genes, ras/genetics , Rectal Neoplasms/epidemiology , Rectal Neoplasms/genetics , Aged , Alcoholic Beverages/adverse effects , Beer/adverse effects , Cohort Studies , Data Interpretation, Statistical , Diet , Exons/genetics , Female , Humans , Male , Middle Aged , Models, Statistical , Netherlands/epidemiology , Proportional Hazards Models , Smoking/epidemiologyABSTRACT
BACKGROUND: The early to intermediate stages of the majority of colorectal tumours are thought to be driven by aberrations in the Wnt (APC, CTNNB1) and Ras (K-ras) pathways. A smaller proportion of cancers shows mismatch repair deficiency. The aim of this study was to analyse the co-occurrence of these genetic alterations in relation to tumour and patient characteristics. METHODS: In a group of 656 unselected sporadic colorectal cancer patients, aberrations in the APC, K-ras, CTNNB1 genes, and expression of hMLH1 were investigated. Additionally, tumours were divided in groups based on molecular features and compared with respect to patient's age at diagnosis, sex, family history of colorectal cancer, tumour sub-localisation, Dukes' stage and differentiation. RESULTS: Mutations at the phosphorylation sites (codons 31, 33, 37, and 45) in the CTNNB1 gene were observed in tumours from only 5/464 patients. Tumours with truncating APC mutations and activating K-ras mutations in codons 12 and 13 occurred at similar frequencies (37% (245/656) and 36% (235/656), respectively). Seventeen percent of tumours harboured both an APC and a K-ras mutation (109/656). Nine percent of all tumours (58/656) lacked hMLH1 expression. Patients harbouring a tumour with absent hMLH1 expression were older, more often women, more often had proximal colon tumours that showed poorer differentiation when compared to patients harbouring tumours with an APC and/or K-ras mutation. CONCLUSION: CTNNB1 mutations seem to be of minor importance in sporadic colorectal cancer. The main differences in tumour and patient characteristics are found between groups of patients based on mismatch repair deficiency.
Subject(s)
Adenomatous Polyposis Coli Protein/genetics , Carrier Proteins/biosynthesis , Carrier Proteins/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Genes, APC , Genes, ras , Mutation , Neoplasms/genetics , Nuclear Proteins/biosynthesis , Nuclear Proteins/genetics , beta Catenin/genetics , Adaptor Proteins, Signal Transducing , Aged , Base Pair Mismatch , Chromosome Aberrations , Cohort Studies , DNA Mutational Analysis , DNA Repair , Exons , Female , Humans , Male , Microsatellite Repeats , Middle Aged , Models, Statistical , MutL Protein Homolog 1 , Netherlands , Phosphorylation , Sex Factors , Time FactorsABSTRACT
OBJECTIVE: The aim of this study was to investigate the associations between meat and fish consumption and APC mutation status and hMLH1 expression in colon and rectal cancer. METHODS: The associations were investigated in the Netherlands Cohort Study, and included 434 colon and 154 rectal cancer patients on whom case-cohort analyses (subcohort n = 2948) were performed. RESULTS: Total meat consumption was not associated with the endpoints studied. Meat product (i.e. processed meat) consumption showed a positive association with colon tumours harbouring a truncating APC mutation, whereas beef consumption was associated with an increased risk of colon tumours without a truncating APC mutation (incidence rate ratio (RR) highest versus lowest quartile of intake 1.61, 95% confidence interval (CI) 0.96-2.71, p-trend = 0.04 and 1.58, 95% CI 1.10-2.25, p-trend = 0.01, respectively). Consumption of other meat (horsemeat, lamb, mutton, frankfurters and deep-fried meat rolls) was associated with an increased risk of rectal cancer without a truncating APC mutation (RR intake versus no intake 1.79, 95% CI 1.10-2.90). No associations were observed for meat consumption and tumours lacking hMLH1 expression. CONCLUSIONS: Our data indicate that several types of meat may contribute differently to the aetiology of colon and rectal cancer, depending on APC mutation status but not hMLH1 expression of the tumour.
Subject(s)
Adenomatous Polyposis Coli Protein/genetics , Carrier Proteins/genetics , Colonic Neoplasms/genetics , DNA-Binding Proteins/genetics , Diet , Fishes , Gene Expression , Genes, APC , Meat/classification , Nuclear Proteins/genetics , Rectal Neoplasms/genetics , Adaptor Proteins, Signal Transducing , Adenomatous Polyposis Coli/epidemiology , Adenomatous Polyposis Coli/genetics , Aged , Animals , Colonic Neoplasms/epidemiology , DNA Repair , Female , Humans , Male , Meat/adverse effects , Middle Aged , MutL Protein Homolog 1 , Mutation , Netherlands/epidemiology , Prospective Studies , Rectal Neoplasms/epidemiology , Surveys and QuestionnairesABSTRACT
We have studied menstrual effluent in order to identify soluble menstrual factors that induce epithelial to mesenchymal transitions (EMT) in mesothelial cells. A variety of molecules, such as nitric oxide and its reaction products, proteases (i.e. matrix metalloproteinases, plasmin) and proteins and/or peptides (i.e. growth factors: b-fibroblast growth factor, epidermal growth factor, hepatocyte growth factor, transforming growth factor-beta; cytokines: interleukin 1 beta, tumour necrosis factor-alpha [TNF-alpha]) may be involved in this process. We have demonstrated that TNF-alpha is involved in EMT, whereas the other molecules are not. Biochemical analysis has shown that the inducing menstrual factors are heat-labile molecules, are uncharged at neutral pH, have a molecular weight between 50-70 kDa (or are bound in complexes of that size) and are eluted in the albumin fraction during gel filtration chromatography. Further analysis of this fraction by using proteomics and mass spectrometry has led to the identification of alpha-enolase and haemoglobin whose inhibition partially prevents EMT. When antibodies against TNF-alpha, alpha-enolase and haemoglobin are combined, EMT is almost completely inhibited. Thus, the candidates for soluble menstrual factors that induce mesothelial EMT are TNF-alpha, alpha-enolase and haemoglobin.