Heme and chlorophyll intake and risk of colorectal cancer in the Netherlands cohort study.

BACKGROUND: The evidence for red meat as a determinant of colorectal cancer remains equivocal, which might be explained by differences in heme content. Heme is the pro-oxidant, iron-containing porphyrin pigment of meat and its content depends on the type of meat. Chlorophyll from green vegetables might modify this association. METHODS: The Netherlands Cohort Study was initiated in 1986 when a self-administered questionnaire on risk factors for cancer was completed by 120,852 subjects ages 55 to 69 years. After 9.3 years of follow-up through the Cancer Registry, 1,535 incident colorectal cancer cases (869 men and 666 women) were available. Nineteen of the 150 items in the validated dietary questionnaire related to consumption of specific types of fresh and processed meat. Heme iron content was calculated as a type-specific percentage of the total iron content and chlorophyll content of vegetables was derived from the literature. RESULTS: Multivariate rate ratios for quintiles of heme iron intake and colon cancer were 1.00, 0.98, 1.04, 1.13, and 1.29 (P(trend) = 0.10) among men and 1.00, 1.31, 1.44, 1.18, and 1.20 (P(trend) = 0.56) among women, respectively. No consistent associations were observed for rectal cancer. Rate ratios for colon cancer increased across successive quintiles of the ratio of heme/chlorophyll among men only (1.00, 1.08, 1.01, 1.32, and 1.43; P(trend) = 0.01). No associations were observed between fresh meat and colorectal cancer. CONCLUSION: Our data suggest an elevated risk of colon cancer in men with increasing intake of heme iron and decreasing intake of chlorophyll. Further research is needed to confirm these results.     

Associations of dietary methyl donor intake with MLH1 promoter hypermethylation and related molecular phenotypes in sporadic colorectal cancer

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.     

A prospective study of dietary folate intake and risk of colorectal cancer: modification by caffeine intake and cigarette smoking.

Epidemiologic evidence indicates an inverse association of folate intake with risk of colorectal cancer, but whether this association is modified by intake of caffeine (in coffee and tea) or cigarette smoking--factors that possibly interfere with folate--has not been studied. Thus, we examined whether the association between dietary folate intake and incidence of colorectal cancer is modified by caffeine intake and smoking. Cox proportional hazards modeling was used to estimate rate ratios relating dietary folate intake to colorectal cancer incidence among 61,433 women ages 40 to 75 years at recruitment into the Swedish Mammography Cohort in 1987 to 1990. From March 1987 through June 2004, a total of 805 incident cases of colorectal cancer were diagnosed. After controlling for age and other potential confounders, we observed an inverse association between dietary folate intake and risk of colon cancer (rate ratio for the highest versus the lowest quintile, 0.61; 95% confidence interval, 0.41-0.91; P(trend) = 0.02), but not of rectal cancer (rate ratio, 0.93; 95% confidence interval, 0.55-1.56; P(trend) = 0.97). The inverse association between dietary folate intake and colon cancer risk was most pronounced among smokers (P(interaction) = 0.03). We found no apparent modification of risk by caffeine intake. Findings from this population-based cohort study support an inverse association between dietary folate intake and risk of colon cancer and suggest that smokers might benefit most from a high dietary folate intake.     

Dietary folate intake and k-ras mutations in sporadic colon and rectal cancer in The Netherlands Cohort Study

We studied the association between dietary folate and specific K-ras mutations in colon and rectal cancer in The Netherlands Cohort Study on diet and cancer. After 7.3 years of follow-up, 448 colon and 160 rectal cancer patients and 3,048 sub-cohort members (55-69 years at baseline) were available for data analyses. Mutation analysis of the K-ras gene was carried out on all archival adenocarcinoma specimens. Case-cohort analyses were used to compute adjusted incidence rate ratios (RR) and 95% confidence intervals (CI) for colon and rectal cancer overall and for K-ras mutation status subgroups according to 100 mug/day increased intake in dietary folate. Dietary folate intake was not significantly associated with colon cancer risk for men or women, neither overall nor with K-ras mutation status. For rectal cancer, folate intake was associated with a decreased disease risk in men and was most pronounced for K-ras mutated tumors, whereas an increased association was observed for women. Regarding the K-ras mutation status in women, an increased association was observed for both wild-type and mutated K-ras tumors. Specifically, folate intake was associated with an increased risk of G>T and G>C transversions in rectal tumors (RR = 2.69, 95% CI = 1.43-5.09), but inversely associated with G>A transitions (RR = 0.08, 95% CI = 0.01-0.53). Our data suggest that the effect of folate on rectal cancer risk is different for men and women and depends on the K-ras mutation status of the tumor.     

Cholecystectomy and colorectal cancer: Evidence from a cohort study on diet and cancer

The association between cholecystectomy and subsequent risk for colorectal carcinoma was investigated in a prospective cohort study on diet and cancer (n = 120,852), which is being conducted in the Netherlands from 1986 onwards among 120,852 men and women, aged 55 to 69. After a follow-up period of 3.3 years, 478 incident cases of colorectal cancer (258 men and 220 women) were identified in the cohort, 64 of whom reported at baseline to have undergone previous gall-bladder surgery (21 men and 43 women). After adjustment for age and familial history of large-bowel cancer, the relative rate (RR) for colorectal cancer in subjects who had undergone cholecystectomy compared with those who had not was 1.81 in men (p=0.02) and 1.47 in women (p=0.05). Additional adjustment for parity, Quetelet index, alcohol intake and other dietary variables resulted in a RR of 1.78 in men and 1.51 in women. In women, the highest RR was detected in the right colon (RR = 1.89), whereas in men, no site within the large bowel accounted specifically for the increased relative rate. In both men and women, the rate appeared to increase from approximately 6 years after cholecystectomy onward. According to the TNM stage of the disease, cholecystectomized patients were not detected at an earlier stage than the other patients. It is concluded that in this study the positive association between colorectal cancer and cholecystectomy cannot be explained by detection bias or ascertainment bias and is not confounded by risk factors for gallstone disease or dietary factors.     

A cohort study of dietary iron and heme iron intake and risk of colorectal cancer in women

In a cohort study of 49,654 Canadian women, we assessed the association of colorectal cancer with total iron and heme iron intake, excluding iron supplements. Among women aged 40-59 years, followed for an average of 16.4 years, we identified 617 incident colorectal cancer cases. Data from a food frequency questionnaire administered at baseline were used to calculate red meat intake and intake of total dietary iron, iron from meat, and heme iron. Analyses were carried out for all cases and for the proximal colon, distal colon, and rectum, using Cox proportional hazards models. We found no association of intake of iron, heme iron, or iron from meat with risk of colorectal cancer overall or with any of the subsites, nor was there effect modification by alcohol consumption or hormonal replacement therapy.     

Sugar intake and colorectal cancer risk: A prospective Japanese cohort study

The influence of sugar consumption on the risk of colorectal cancer (CRC) remains controversial. Prospective cohort studies focusing on total and specific types of sugar intake among the Asian population who have different patterns of sugar intake sources than American and European populations are scarce. We intended to examine the association of sugar intake with CRC risk among middle-aged adults in a Japanese large-scale population-based cohort study. The participants (42,405 men and 48,600 women) who were 45–74 years old and answered the questionnaire in 1995–1999 in the Japan Public Health Center-based Prospective Study were followed up until December 2013. Total sugars, total fructose, and specific types of sugar intake were estimated using a validated 147-item food frequency questionnaire and divided into quintiles (Q1–Q5). We used Cox proportional hazard regression models adjusted for potential confounders to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During the follow-up, 2118 CRC cases (1226 men and 892 women) were identified. We did not observe any clear association between all types of sugar intake and an increased risk of CRC. Analyses by tumor sites yielded a positive association of total sugar consumption with rectal cancer in women (1.75 [1.07–2.87] for Q1 vs. Q5; p _{linear trend} = 0.03), but no statistically significant trend was detected among men. Sugar intake was not associated with CRC risk in middle-aged Japanese adults. However, for rectal cancer, the probability of an increased risk among women with a higher total sugar intake cannot be excluded.     

FANCF基因启动子甲基化在散发性肿瘤的发生和耐药性形成中的作用

FANCF是范可尼贫血 (Fanconi anemia,FA) 蛋白互补基团的重要成员之一,FANCF作为关键因子参与FA复合体的稳定及FANCD2泛素化激活过程,因此是维持FA/BRCA通路功能所必需的重要蛋白.FANCF通过FA/BRCA通路,参与细胞周期的调控、细胞凋亡、DNA的修复、基因转录与基因稳定性等多种生命信号的转导与调控.FANCF蛋白低表达及功能缺失与FANCF基因启动子超甲基化相关.本文主要综述了FANCF基因启动子甲基化与某些散发性肿瘤的发生和耐药性形成的相关研究,为进一步研究散发性肿瘤的发生和耐药性产生机制奠定一定的理论基础.     

High-resolution methylation analysis of the hMLH1 promoter in sporadic endometrial and colorectal carcinomas

BACKGROUND: Microsatellite instability (MSI) has been reported in endometrial carcinoma (EC) and in colorectal carcinoma (CRC), primarily as a result of defective DNA mismatch repair (MMR). The MMR gene hMLH1 commonly is inactivated in both EC and CRC. In the current study, epigenetic mechanisms involved in hMLH1 inactivation have been investigated to further elucidate the role of these mechanisms in the pathogenesis of EC and CRC. METHODS: Polymerase chain reaction (PCR)-based microsatellite analysis performed on paraffin-embedded tissues was used to select 42 sporadic carcinomas (21 ECs and 21 CRCs) with MSI. Immunohistochemistry (IHC), using the anti-hMLH1 antibody, and mutation analysis, using denaturing high-performance liquid chromatography and automated sequencing, were performed on unstable carcinoma samples. Methylation analysis, using modified protocols for bisulfite treatment and methylation-specific PCR (MSP), was performed on DNA from archival tissue samples. RESULTS: No MSI-positive tumor samples with normal hMLH1 immunostaining (n = 7) exhibited hMLH1 promoter methylation, whereas 8 of 35 unstable cases with loss of hMLH1 expression (23%) exhibited MSP amplification. Among analyzed cases, germ-line mutations of hMLH1 were found in 4 of 20 unmethylated samples (20%) and in 0 of 8 methylated samples. Bisulfite sequencing of amplification products from methylated samples demonstrated that almost all CpG dinucleotides within the hMLH1 promoter elements underwent methylation. CONCLUSIONS: Although an MMR gene other than hMLH1 may be responsible for genetic instability in MSI-positive/IHC-positive tumors, the presence of MSP amplification and allelic deletions within the hMLH1 locus in subsets of MSI-positive/IHC-negative cases strongly suggests that hMLH1 promoter methylation may contribute to the inactivation of both hMLH1 alleles. Bisulfite analysis suggests that the mechanisms of hMLH1 silencing may depend on CpG density rather than site-specific methylation. Cancer 2003;98:1540-6.     

Modest promoter methylation of E-cadherin gene in sporadic colorectal cancers: a quantitative analysis

Although E-cadherin expression is frequently reduced in colorectal cancers (CRCs), this does not appear to be due to gene mutation or allele loss. We investigated the hypothesis that promoter methylation could be responsible for suppression of E-cadherin expression in 142 pairs of sporadic CRCs and respective normal mucosae. E-cadherin expression was examined by Western blot. E-cadherin methylation at two promoter regions was quantitatively measured by methylation specific real time PCR (MethyLight). We found that E-cadherin protein levels were significantly lower in CRCs, even in Dukes' A tumors, compared to normal mucosae. Decreased E-cadherin protein expression in CRCs was an independent poor prognostic factor in multivariate disease-free survival analysis. However, the extent of DNA methylation was extremely modest at both regions of the E-cadherin promoter. There was no correlation between DNA methylation and E-cadherin protein levels in either tumors or matched normal tissues. These findings suggested that suppression of E-cadherin expression in CRCs is a significant event and is possibly involved in both carcinoma development and progression. However, our data did not support a crucial role of promoter methylation of the E-cadherin gene in the remarkable downregulation of E-cadherin expression in CRCs. Methylated E-cadherin gene as a CRC biomarker therefore needs further validation.     

A prospective cohort study on antioxidant and folate intake and male lung cancer risk.

Many studies have reported inverse associations between vegetable and fruit consumption and lung cancer risk. The aim of the present study was to elucidate the role of several antioxidants and folate in this relationship. In the Netherlands Cohort Study on Diet and Cancer, 58,279 men of ages 55-69 years at baseline in 1986 returned a questionnaire including a 150-item food frequency questionnaire. After 6.3 years of follow-up, 939 male lung cancer cases were registered. A new Dutch carotenoid database was used to estimate intake of alpha-carotene, beta-carotene, lutein + zeaxanthin, beta-cryptoxanthin, and lycopene, completed with the antioxidant vitamins C and E and folate. Using case-cohort analysis, rate ratios were calculated, adjusted for age, smoking, educational level, and family history of lung cancer. Protective effects on lung cancer incidence were found for lutein + zeaxanthin, beta-cryptoxanthin, folate, and vitamin C. Other carotenoids (alpha-carotene, beta-carotene, and lycopene) and vitamin E did not show significant associations. After adjustment for vitamin C, only folate remained inversely associated, and after adjustment for folate, only beta-cryptoxanthin and vitamin C remained significantly associated. Inverse associations were strongest among current smokers and weaker for former smokers at baseline. Inverse associations with carotenes, lutein + zeaxanthin, and beta-cryptoxanthin seemed to be limited to small cell and squamous cell carcinomas. Only folate and vitamin C intake appeared to be inversely related to small cell and squamous cell carcinomas and adenocarcinomas. Folate, vitamin C, and beta-cryptoxanthin might be better protective agents against lung cancer in smokers than alpha-carotene, beta-carotene, lutein + zeaxanthin, and lycopene.     

Coffee intake and breast cancer risk in the NIH-AARP diet and health study cohort

There are several biologic mechanisms whereby coffee might reduce breast cancer risk. Caffeine and caffeic acid, major coffee constituents, have been shown to suppress mammary tumor formation in animal models and to inhibit DNA methylation in human breast cancer cells, respectively. Coffee may also reduce risk through decreasing inflammation and influencing estrogen metabolism. However, epidemiologic studies have been inconsistent and few studies have examined the association by estrogen and progesterone receptor (ER/PR) status. We evaluated coffee intake for its effect on incident breast cancer in the National Institutes of Health-AARP Diet and Health Study cohort, which included 198,404 women aged 50-71 with no history of cancer, who in 1995-1996 completed a questionnaire capturing usual coffee intake over the past year. State cancer registry and mortality index linkage identified 9,915 primary incident breast carcinomas through December 2006; available information on hormone receptor (HR) status identified 2,051 ER+/PR+ and 453 ER-/PR- cancers. In multivariable proportional hazards models, coffee intake was not associated with breast cancer risk (p-value for trend = 0.38; relative risk = 0.98, 95% confidence interval: 0.91-1.07, for four or more cups per day as compared to women who never drank coffee), and results did not vary by body mass index or history of benign breast biopsy (p-value for interaction > 0.10). We found no evidence of a relationship with either caffeinated or decaffeinated coffee. Null findings persisted for risk of both HR-positive and -negative breast cancers. These findings from a large prospective cohort do not support a role of coffee intake in breast carcinogenesis.     

Microsatellite instability caused by hMLH1 promoter methylation increases with tumor progression in right-sided sporadic colorectal cancer

OBJECTIVE: A subset of sporadic colorectal cancers (SCRCs) exhibits microsatellite instability (MSI). Most MSI in SCRCs is caused by hMLH1 inactivation due to promoter methylation. However, the role of MSI in the progression of SCRCs remains unclear. METHODS: Thirty-two intramucosal cancers and 63 cancers with submucosal invasion were assigned to group 1 (early-stage cancer), and 30 Dukes' B and 26 Dukes' C cancers to group 2 (advanced-stage cancer). hMLH1 promoter methylation status was determined by methylation-specific PCR. MSI was determined using five markers. hMLH1 expression was determined immunohistochemically. RESULTS: MSI was found in 1 of 95 (1.1%) tumors in group 1, compared with 4 of 56 (7.1%) tumors in group 2. In right-sided tumors, the overall frequency of hMLH1-methylation-positive tumors in group 1 was not significantly different from that in group 2 (17 of 43, 39.5%, vs. 9 of 23, 39.1%). In right-sided tumors with hMLH1 promoter methylation, the frequency of MSI-positive tumors in group 1 was significantly lower than that in group 2 (1 of 17, 5.9%, vs. 4 of 9, 44.4%, p=0.0081). CONCLUSION: The frequency of MSI caused by hMLH1 promoter methylation increases with tumor progression in right-sided SCRCs.     

Magnesium intake and colorectal cancer risk in the Netherlands Cohort Study

Energy-adjusted magnesium intake was nonsignificantly inversely related to risk of colorectal cancer (n=2328) in the Netherlands Cohort Study on Diet and Cancer that started in 1986 (n=58 279 men and 62 573 women). Statistically significant inverse trends in risk were observed in overweight subjects for colon and proximal colon cancer across increasing quintiles of magnesium uptake (P-trend, 0.05 and 0.02, respectively). Although an overall protective effect was not afforded, our results suggest an effect of magnesium in overweight subjects, possibly through decreasing insulin resistance.     

Aberrant hypermethylation of OGDHL gene promoter in sporadic colorectal cancer

BackgroundAberrant methylation patterns of certain genes including tumor suppressors, a major epigenetic event, contribute mainly to tumorigenesis. Promoter CpG island methylation in Oxoglutarate dehydrogenase like (OGDHL) gene has been reported to reduce gene expression and hence apoptosis induction. This gene has been shown to be involved in colorectal cancer progression. In the present study, we investigated methylation status of OGDHL gene promoter in patients with colorectal cancer and evaluated its potential as a diagnostic biomarker.Methods and materialAfter collecting clinicopathologic data of patients, tumor and matched tumor free margin samples were obtained from 40 individuals; total genomic DNA was extracted and subjected to bisulfite modification. Methylation status of the gene promoter was studied using quantitative methylation-specific PCR method. Finally, its potential as a diagnostic biomarker was evaluated by receiver operating characteristic curve analysis.ResultsThere was not any significant correlation for clinicopathologic features including tumor stage, grade, size, and location with methylation status of OGDHL promoter. However, a significant high methylation level was observed in tumoral tissues compared with nontumoral marginal samples (P < 0.0001). Moreover, receiver operating characteristic curve analysis revealed 97.5% sensitivity and 95%, specificity for OGDHL promoter methylation in a cut off of 27.37% methylation as a biomarker for colorectal cancer.ConclusionThe promoter of OGDHL gene is hypermethylated in colorectal cancer and might be considered as a biomarker for its development.     

Clinicopathological features of sporadic MSI colorectal cancer and Lynch syndrome: a single-center retrospective cohort study

International Journal of Clinical Oncology - The clinical and pathological features of sporadic microsatellite instability-high (MSI) colorectal cancer (CRC) are still unclear. The present study...