Risk Factor For Colon Cancer Research Articles

Curcumin suppresses intestinal polyps in APC Min mice fed a high fat diet

Colorectal cancer (CRC) is a leading cause of cancer deaths in the United States. Various risk factors have been associated with CRC including increasing age and diet. Epidemiological and experimental studies have implicated a diet high in fat as an important risk factor for colon cancer. High fat diets can promote obesity resulting in insulin resistance and inflammation and the development of oxidative stress, increased cell proliferation, and suppression of apoptosis. Because of the high consumption of dietary fats, especially saturated fats, by Western countries, it is of interest to see if non-nutrient food factors might be effective in preventing or delaying CRC in the presence of high saturated fat intake. Curcumin (Curcuma longa), the main yellow pigment in turmeric, was selected to test because of its reported anti-tumor activity. APC Min mice, which develop intestinal polyps and have many molecular features of CRC, were fed a diet containing 35% pork fat, 33% sucrose, and a protein and vitamin mineral mixture (HFD) with or without 0.5% curcumin. These cohorts were compared to APC Min mice receiving standard rodent chow (RC) with 8% fat. APC Min mice fed the HFD for 3 months had a 23% increase in total number of polyps compared to APC Min mice on RC. Curcumin was able to significantly reverse the accelerated polyp development associated with the HFD suggesting it may be effective clinically in helping prevent colon cancer even when ingesting high amounts of fatty foods. The anti-tumor effect of curcumin was shown to be associated with enhanced apoptosis and increased efficiency of DNA repair. Since curcumin prevented the gain in body weight seen in APC Min mice ingesting the HFD, modulation of energy metabolism may also be a factor.

Relationship of resistin levels with endometrial cancer risk

Cancer of endometrium (CAE) is the most common gynecologic malignancy in industrialized nations. Increased resistin levels, an adipocytokine produced by adipose tissue and macrophages, have been considered as a risk factor in gastric, colon and breast cancer, recently. No studies associating resistin levels with endometrial cancer have been done so far. The purpose of this case-control study was to determine the relationship between serum circulating resistin levels and resistin gene -420C>G (rs3219175) variant in endometrial cancer patients. 37 Caucasian female patients and 39 healthy controls were enrolled in this study. Difference in resistin levels between age and BMI matched patients group (mean 24.2 ng/ml) and control subjects (mean 10.1 ng/ml) were statistically significant (p <001). We also determined single nucleotide polymorphism -420C>G (rs3219175) within resistin gene and no significant association between resistin levels and investigated polymorphism was found. Furthermore, no significant association between higher resistin levels and diabetes mellitus 2, body mass index, smoking or age have been observed within studied groups. To our knowledge, this is the first study examining the relationship between serum resistin levels and endometrial cancer and our results show, that patients with endometrial cancer have significantly increased circulating levels of resistin compared to control subjects.

Ameliorative effects of konjac glucomannan on human faecal β-glucuronidase activity, secondary bile acid levels and faecal water toxicity towards Caco-2 cells

Konjac glucomannan (KGM) has been shown to increase human colon microbial ecology and reduce faecal toxicity in mice. The main goal of the present study was to assess the effects of a KGM supplement into a low-fibre diet on precancerous markers of colon cancer in a double-blind, placebo- and diet-controlled study. Adult volunteers consumed defined diets supplemented with konjac (4·5g/d) or placebo (maize starch) for 4 weeks. Stools collected before and at the end of the supplementation were analysed for β-glucosidase, β-galactosidase and β-glucuronidase activities, microflora and bile acids. Faecal water was co-incubated with Caco-2 cells, a model of human colonocytes, to determine the cytotoxicity and DNA-damaging effect as assessed by the comet assay. The results indicated that the KGM supplement significantly decreased faecal β-glucuronidase activity by 25·6 (se 7·8)% and faecal secondary bile acid level by 42·4 (se 11·8)%. In contrast, consuming the defined diet supplemented with placebo for 4 weeks did not improve these determinants. The KGM-supplemented diet, but not the placebo diet, significantly increased the survival rate (%) of Caco-2 cells co-incubated with faecal water for 1 and 3h, respectively. In addition, KGM significantly reduced the DNA damage induced by the faecal water alone or in combination with H2O2. The faecal bifidobacteria and lactobacilli levels increased only with the KGM-supplemented diet. Therefore, we conclude that supplementation of KGM into a low-fibre diet improved the faecal microbial ecology and metabolites, which may contribute to the reduced toxicity of faecal water and precancerous risk factors of human colon cancer.

Characterization of the association between 8q24 and colon cancer: gene-environment exploration and meta-analysis

BackgroundGenome-wide association studies and subsequent replication studies have shown that single nucleotide polymorphisms (SNPs) in the chromosomal region 8q24 are associated with colorectal cancer susceptibility.MethodsWe examined 11 SNP markers in the 8q24 region between 128.47 and 128.54 Mb, using a total of 1,987 colon cases and 2,339 controls who self-reported as white from two independent, well-characterized study populations. Analysis was performed separately within each study, and combined using random effects meta-analysis. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) and to test for effect modification by known colon cancer risk factors. We also performed a meta-analysis combining our results with previous studies.ResultsWe observed evidence of association for four SNPs in low to high linkage disequilibrium (r2 ranging from 0.18 to 0.93) localized in a 16.2 kb region defined by rs10505477 and rs1056368. The combined results for our two studies of colon cancer showed an OR of 1.10 (95% CI: 1.01-1.20, Ptrend = 0.023), and a meta-analysis of our results with previously reported studies of colon and colorectal cancer strongly support the association for this SNP (combined OR for rs6983267 = 1.21, 95% CI: 1.18-1.24, p = 5.5 × 10-44). We did not observe any notable evidence of effect modification by known colon cancer risk factors, and risk did not differ significantly by tumor site or stage.ConclusionsOur study confirms the association between polymorphisms on chromosome 8q24 and colon cancer risk and suggests that the susceptibility locus in region 8q24 is not strongly modified by various lifestyle, environmental, and demographic risk factors for colon cancer.

Abstract A84: Red and processed meat-derived mutagen exposure and colorectal cancer risk in a population-based case-control study

Abstract A recent report issued jointly by the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) concluded that the evidence to support a positive association between greater intakes of red and processed meat and colorectal cancer was convincing, but the evidence for specific meat components explaining these associations remained inconclusive. To explore potential underlying mechanisms for these observations, we examined associations of mutagens generated through meat cooking and meat processing methods with colorectal cancer in a large multisite population-based case-control study in a contiguous 19-county area in central and northeast Pennsylvania. Participants (863 healthy controls, 483 incident colon and 196 incident rectal cancer cases) completed a detailed lifestyle questionnaire and the 137-item National Cancer Institute's Diet History Questionnaire (DHQ). The DHQ included a detailed cooked and processed meat module to estimate intakes of heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs), nitrites, and nitrates. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between meat exposures and colorectal cancer stratified by sub-site of the large intestine were estimated from unconditional logistic regression models. After multivariate adjustment for age, total energy intake, sex, body mass index, energy-adjusted total fruit and vegetable intake, and past regular NSAID use, positive associations with HCAs and PAHs, as measured by total mutagenic activity, were stronger for rectal cancer (OR = 1.55, 95% CI: 0.97, 2.47; P for trend = 0.049) than colon cancer, whereas positive associations with nitrites plus nitrates were stronger for colon cancer (OR = 1.31, 95% CI: 0.91-1.87; P for trend = 0.031). Our findings support the hypothesis that greater exposure to HCAs, PAHs, nitrites, and nitrates is a plausible mechanism by which red and processed meat may increase colorectal cancer risk. Our sub-site analyses indicate that associations between meat-derived exposures and colon and rectal cancer may differ, which underscores the need for additional studies that examine dietary risk factors for colon and rectal cancer as separate endpoints. The investigation of interactions between genetic polymorphisms and meat exposures in relation to colorectal cancer risk is underway in our study population. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A84.

Plasma levels of resistin-like molecule beta in humans

Background: Resistin-like molecules (RELM) are expressed in many tissues and among those, RELMβ is most abundantly expressed in the colon. Based on animal studies, RELMβ is induced by high fat diets, obesity, and intestinal microflora and may play a role in insulin resistance and intestinal inflammation. In the present study, we evaluated whether RELMβ could be measured in human plasma and the influence of selected host and behavioral factors on RELMβ levels, including known risk factors for colorectal cancer. Methods: The subjects for this pilot study were derived from healthy controls who participated in a population-based case–control study of colorectal cancer in Metropolitan Detroit. The subjects were 45–80 years of age without history of cancer or colorectal resection. Results: RELMβ was present in human plasma, with levels in the range of 0.08–0.26ng/mL. Lower RELMβ levels were found in subjects with non-Caucasian race, lower pack-years of smoking, and higher physical activity index scores. Other variables such as dietary intakes, gender, obesity, use of non-steroidal anti-inflammatory agents and history of polyps were not associated with RELMβ levels. Conclusions: The direct association of RELMβ with smoking and inverse association with physical activity, both of which are risk factors for colon cancer, indicates that RELMβ may be involved in mediating the effects of these two lifestyle factors on risk of colon cancer.

Adenoma Rates in HIV-infected Patients: Ccorrelation with CD4 Count

Purpose: HIV-associated malignancies are common, but whether colon cancer is increased in patients with HIV remains unclear. Colon cancer screening guidelines have not recognized HIV-infected patients as a high-risk group and little research has been done to clarify the yield of colonoscopy in this group. There also is controversy about adenoma frequency in HIV, and no previous study has evaluated the relationship between CD4 count and presence of adenomas. We sought to determine if polyp yield is altered in patients with and without HIV who undergo screening colonoscopy and if CD4 count is an adenoma-predicting factor. Methods: A retrospective review was performed using records of asymptomatic patients referred for colonoscopy screening from January 2006 to October 2009. A control group of 121 HIV-uninfected patients was randomly chosen from similarly referred patients during that same period. 136 HIV-infected patients were identified, 39 of whom were excluded because of gastrointestinal symptoms that prompted referral. Colonoscopy reports, CD4 count at the time of study and pathology results were reviewed. Advanced adenomas were defined as those larger than 1 cm or with histology showing villous or serrated features or high grade dysplasia. Results: 29% of the patients with HIV had adenomas compared with 22% of the control group (p=0.43). Advanced adenomas were seen in 8.2% and 3.3% of HIV-patients and controls (p=0.14) respectively. When stratified by CD4 count, 62% of HIV-patients with a CD4 < 200 had polyps (p=0.005) and 14% had advanced adenomas (p=0.10). In those with a CD4 < 300, 46% had adenomas (p=0.023). In patients with a CD4 > 500, the adenoma and advanced adenoma prevalence were 32% (0.281) and 11% (p=0.281) respectively. There was no association between polyp location and either HIV status or CD4 count. Conclusion: In our series of 97 patients with HIV who underwent colon cancer screening, HIV per se was not a risk factor for colon cancer or adenoma occurrence. However, low CD4 count was a significant risk factor for adenomatous polyps, and there was an increasing prevalence of both adenomas and advanced adenomas as the CD4 count decreased. This study suggests that patients with HIV and a low CD4 count, especially those with CD4 counts <300 should receive earlier screening for polyps and more frequent surveillance colonoscopy. Further studies should be performed to determine the cost-benefit analysis of this recommendation.

Neighborhood socioeconomic status and behavioral pathways to risks of colon and rectal cancer in women

Neighborhood amenities and resources plausibly determine individual modifiable risk factors for colon and rectal cancer. Evidence on the associations between neighborhood socioeconomic status (SES) and incident colon and rectal cancer is limited. The authors analyzed a prospective cohort of 111,129 women in the Nurses' Health Study with no history of cancer in 1986 followed to 2006. Neighborhood SES was based on Census-derived characteristics of block groups of residence. Cox models were used to estimate the multivariate-adjusted associations between neighborhood SES and incident colon and rectal cancer, and to examine for effect modification. For significant associations, path models were estimated with behavioral risk factors included as potential mediators. Neighborhood SES was unassociated with colon cancer among all women. However, among women with college or greater education, higher neighborhood SES was inversely related to colon cancer (P for trend = .01; P for interaction between neighborhood SES and education = .03). Path analysis suggested mediation by red meat intakes and body mass index (BMI). Higher neighborhood SES was inversely related to rectal cancer among all women (relative risk in highest quintile, 0.64; 95% confidence interval, 0.44-0.93; P for trend = .08). Path analysis was consistent with mediation by multivitamin use and BMI. These findings suggest that living in a higher-SES neighborhood may protect against rectal cancer in women and colon cancer in higher-educated women, mediated by selected behavioral risk factors. Risk factor differences between colon and rectal cancer may account for discrepancies in estimated neighborhood effects by cancer site.

Colon cancer in rapidly developing countries: review of the lifestyle, dietary, consanguinity and hereditary risk factors

Colon cancer rates are rising dramatically in once low incidence nations. These nations are undergoing rapid economic development and are known as “nations in transition” (NIT). This review identifies some of the most common etiological risk factors of colon cancer in these nations and evaluates the existing epidemiological evidence. The main risk factors which were found to be prevalent in NIT include: lifestyle factors such as physical inactivity, obesity and abdominal adiposity, alcohol consumption and cigarette smoking; dietary factors such as fatty food and red meat consumption. Protective factors included white meat and fiber consumption. Several studies found to have significantly higher rates of colon cancer among the young population (<40 years old). There appears to be a quantitative and qualitative increase in risk to relatives of patients diagnosed at a young age compared with those diagnosed later in life, at least part of which is likely to be the result of a hereditary susceptibility. Close relatives of patients with colon cancer are at an increased risk of developing a colon cancer. Close relatives of early onset cases warrant more intensive endoscopic screening and at an earlier age than relatives of patients diagnosed at older ages. Furthermore, these suggest the existence of genetic predispositions in these nations which need to be investigated further and have implications for screening programs. In conclusion, public health awareness campaigns promoting prevention of modifiable risk factors and screening initiatives with guidelines suited to the age-specific incidence rates of NIT are needed very urgently.

Prognostic impact of ERβ and MMP7 expression on overall survival in colon cancer

Estrogen receptor beta (ERβ) is the most highly expressed protein in patients with colon cancer. Matrix metalloproteinase 7 (MMP7) is consistently expressed throughout cancer progression. We have previously shown that endocrine therapy can inhibit MMP7 expression in colon cancer cells. In this study, we aim to identify the prognostic effects and correlation of ERβ and MMP7 in the context of colon cancer. ERβ and MMP7 levels were assessed by immunohistochemistry in normal mucosa and tumoral tissues from 423 patients with stage I-III colon cancer. The Cox proportional hazards regression model was applied to analyze the lifetime data, including overall survival (OS) and cause-specific survival (CSS). The 5-year survival rate was significantly higher in patients with high expression of nuclear ERβ than in patients with low expression (84.3% vs. 63.9%, respectively, p < 0.05). High expression of MMP7 was related to decreased OS (72% vs. 90%, respectively, p = 0.008) and 5-year survival (86.6% vs. 88.8%, respectively, p = 0.005) compared to patients with low expression of MMP7. In the subset of patients with high expression levels of tumoral nuclear ERβ, high expression of MMP7 was related to OS and CSS among colon cancer patients with high expression of ERβ. In conclusion, our results suggest that low expression of ERβ was a risk factor in colon cancer, and high expression of MMP7 was an independent prognostic factor of ERβ-positive patients with colon cancer.

Distribution of trace elements like calcium, copper, iron and zinc in serum samples of colon cancer – A case control study

The pathogenesis of a number of diseases like cardiovascular diseases, diabetes and cancer has been associated with changes in the balance of certain trace elements. In the present study we aimed to investigate the levels of trace elements like calcium, copper, iron and zinc in colon cancer patients in comparison with healthy controls. Serum samples were collected from 256 colon cancer patients and 180 healthy age and sex matched controls. Trace element levels were detected using commercially available kits and an Auto-Analyzer (ChemWell 2910, Awareness Technology, and USA). The concentrations of calcium, copper and iron were not significantly different in patients in comparison with healthy controls. The concentration of zinc was significantly lower in colon cancer patients (p=0.001) as compared to normal subjects. Deficiency of zinc may play a role in the development of colon cancer or may contribute to damage already underway. Zn may represent an independent risk factor for colon cancer and therefore a possible target for prevention.

Risk factors and incidence of de novo malignancy in liver transplant recipients: a systematic review

Orthotopic liver transplant (OLT) is an established life saving procedure for both acute and chronic liver failure, but incidences and risk factors for development of these malignancies are yet to be established. To determine the incidences and risk factors associated with de novo malignancy after OLT. We performed a systematic review of relevant epidemiological studies available on MEDLINE, which provided information on the incidences and risk factors for the development malignancies in adult OLT recipients published from 1983 to 2009. All data was compiled from retrospective studies. Independent risk factors for the development of de novo malignancy in adult OLT recipients were identified to be statistically significant including immunosuppression, hepatitis C virus infection, smoking, alcoholic cirrhosis and sun exposure. OLT recipients with smoking and alcohol history are of particular risk for head and neck and lung cancers. Primary sclerosing cholangitis and inflammatory bowel disease were found to be independent risk factors for colon cancer. Adult OLT recipients are at increased risk for the development of post-transplant malignancies and obviates the need for surveillance protocols that are safe and cost-effective. OLT recipients should be advised on taking proper precautions in the sun, smoking cessation, and eliminating alcohol consumption. Given the emergence of alcoholic cirrhosis as a leading indication for liver transplantation, the early detection of lung and head and neck cancers is of particular importance.

A Prospective Study of Body Mass Index, Weight Change, and Risk of Cancer in the Proximal and Distal Colon

Body mass index (BMI) is an established risk factor for colon cancer, but risks may differ between genders and colon subsites. Moreover, whether weight change influences risk is not yet clarified. We investigated these issues in a large, Norwegian, population-based cohort study. Participants' weight was measured at examinations up to three times between 1974 and 1988. Hazard ratios (HR) and confidence intervals (CI) were estimated using Cox regression. During follow-up of 38,822 men and 37,357 women, we identified 228 proximal and 174 distal colon cancer cases in men and 237 and 159 cases, respectively, in women. The association between BMI and colon cancer risk differed between subsites in men (P = 0.02) but not in women (P = 0.95). In men, HRs (95% CIs) per 5 kg/m(2) were 1.07 (0.86-1.33) and 1.49 (1.19-1.87) for proximal and distal colon, respectively. In women, corresponding HRs (95% CIs) were 1.15 (0.99-1.34) and 1.25 (1.05-1.49). Among overweight men (BMI > or = 25 kg/m(2)), weight gain > or = 10 kg gave higher colon cancer risk than weight maintenance (HR, 2.09; 95% CI, 1.21-3.63), whereas risks were similar among men with stable weight, weight loss, or gains <10 kg. Weight change was not associated with risk in women. The influence of BMI on colon cancer risk differed between subsites in men. Weight gains <10 kg did not influence risk. Our results support gender differences and the hypothesis of different etiologies for colon subsites. Whether weight loss in the overweight decreases risk of colon cancer warrants further study.

Abstract 5702: Soluble epoxide hydrolase: unique biomarker and chemopreventive target of chronic colitis-induced carcinogenesis

Abstract Chronic ulcerative colitis (UC) is a well-recognized risk factor of colon cancer; aberrant arachidonic acid (AA) metabolism in UC is a key event leading to cancer development. Epoxyeicosatrienoic acids (EETs) are AA metabolites with anti-inflammatory activity; under physiological conditions, EETs are quickly inactivated as they are converted to their corresponding dihydroxyeicosatrienoic acids (DHETs) by the enzyme soluble epoxide hydrolase (sEH). The inhibition of sEH retards hydrolysis of the epoxide, reducing the conversion of EETs to DHETs. Thus, sEH would be a unique target for colitis. However, the role of sEH in chronic colitis and its associated carcinogenesis is not known. In the present study, we have determined if the sEH over-expresses in human ulcerative colitis and its associated dysplasia and carcinoma. Tissue microarrays contained 180 patients (4 tissue samples/patient) with UC (72 patients), UC-dysplasia (54 patients), and UC-carcinoma (54 patients) were established. Using specific anti-sEH antibody and immunohistochemistry approach, distinct expression of sEH was found in the microarray samples. Normal colon displayed weak positivity in 39.1% (n=79), mainly in the focally reactive epithelia. In UC, 74.6% (n=72) displayed positivity, extensively expressed in the hyperplastic epithelia. 88.2% (n=54) of colitis-induced dysplasia and 93.9% (n=54) of colitis-induced carcinoma displayed positivity. Markedly increased sEH staining intensity was observed in UC-induced dysplasia and carcinoma. Secondly, the effect of highly selective and potent sEH inhibitor, trans/−4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), on chronic colitis-induced carcinoma development was determined in IL-10 knockout mice. t-AUCB was administered to IL-10 KO mice in the drinking fluid for three months with the doses of 1.25mg/kg and 2.5 mg/kg body weight (n=10 mice per group). Both low and high doses of t-AUCB significantly suppressed body weight reduction caused by colitis. Histopathologic analysis revealed that there were 80% tumor incidence (8/10 mice) in IL-10 colitis control mice; low and high doses of t-AUCB significantly inhibited the colitis-induced carcinoma development with tumor incidence 10% (1/10 mice) and 40% (4/10 mice), respectively. The tumor volume was markedly reduced (0.062 ± 0.019 cm3 in IL-10 KO colitis mice versus 0.026 ± 0.008 and 0.014 ± 0.012 cm3 in IL-10 KO colitis mice treated with low and high doses of t-AUCB, respectively). The results indicate that sEH is a crucial enzyme over-expressed in human colitis-induced carcinogenesis, and sEH inhibitor is an efficient approach for chemoprevention. (Supported by NIH CA137467 grant). Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5702.

Consumption of high‐fat diet enhanced the malignant progression of human colon cancer in xenograft mouse model

Obesity and diet‐induced overweight have been demonstrated as risk factors of colon cancer. Several studies suggested that loss of E‐cadherin adherent molecule has been associated with epithelial– mesenchymal transition (EMT) and the malignant progression of human colon cancer cells. However, the effects of high fat (HF) diet intake on the expression of E‐cadherin and in vivo malignant progression of human colon cancer have not been demonstrated well yet. Our results indicated that consumption of HF diet (45% of total energy intake) for 4 weeks would induce the tumor growth in human colon cancer HT‐29 cell bearing mice. Bioluminescence imaging analysis also confirmed that consumption of HF diet would stimulate the proliferation of human colon cancer. HF diet modulated the expression of E‐cadherin and β‐catenin in xenograft mouse model. Furthermore, consumption of HF diet enhanced the cellular proliferation through the modulation of proliferating cellular nuclear antigen (PCNA) and p21cip proteins. The possible molecular mechanisms of actions were, in part, through the activation of the MAPK/ERK signaling pathway and the suppression of E‐cadherin adhesion molecule. Take together; these results suggested that consumption of HF diet could modulate the growth and the malignant progression of human colon cancer cells in vivo.

Widespread and tissue specific age-related DNA methylation changes in mice

Aberrant methylation of promoter CpG islands in cancer is associated with silencing of tumor-suppressor genes, and age-dependent hypermethylation in normal appearing mucosa may be a risk factor for human colon cancer. It is not known whether this age-related DNA methylation phenomenon is specific to human tissues. We performed comprehensive DNA methylation profiling of promoter regions in aging mouse intestine using methylated CpG island amplification in combination with microarray analysis. By comparing C57BL/6 mice at 3-mo-old versus 35-mo-old for 3627 detectable autosomal genes, we found 774 (21%) that showed increased methylation and 466 (13%) that showed decreased methylation. We used pyrosequencing to quantitatively validate the microarray data and confirmed linear age-related methylation changes for all 12 genomic regions examined. We then examined 11 changed genomic loci for age-related methylation in other tissues. Of these, three of 11 showed similar changes in lung, seven of 11 changed in liver, and six of 11 changed in spleen, though to a lower degree than the changes seen in colon. There was partial conservation between age-related hypermethylation in human and mouse intestines, and Polycomb targets in embryonic stem cells were enriched among the hypermethylated genes. Our findings demonstrate a surprisingly high rate of hyper- and hypomethylation as a function of age in normal mouse small intestine tissues and a strong tissue-specificity to the process. We conclude that epigenetic deregulation is a common feature of aging in mammals.

Abstract PL02-05: Aberrant crypt foci as surrogate markers for chemoprevention

Abstract Aberrant crypt foci (ACF) are putative preneoplastic lesions that occur in the colons of rodent tumor models and are abundant in the colorectum of humans. Although their presence within the colonic mucosa is incontrovertible, their clinical significance remains a source of controversy. In the following presentation, we will review the history of ACF from their first identification in rodent carcinogen models to their identification and characterization in human colons. In order to better define ACF, one must consider their histopathology, and, here, the difference between rodent and human is striking. Whereas in the rodent a single crypt can acquire dysplastic features, such is not the case in human where ACF as large as 50–100 crypts across are rarely dysplastic. In over 1500 lesions we have examined from approximately 500 patients, we observe that if endoscopic criteria are strictly adhered to, ACF are almost always hyperplastic lesions, with either a “distended” or “serrated” appearance when studied en face. We and others have clearly identified a number of colon cancer risk factors that also associate with at least the density of ACF in the distal 20 cm of colorectum. These risk factors include central obesity, increased bioavailability of IGF-1, prior or synchronous colon neoplasia, family history of colonic neoplasia and cigarette smoking. In fact, a history of 20 pack-years or more of smoking is associated with an increased likelihood (adjusted OR=3.45; 95% CI 1.93–6.18) of having more than the median number of ACF (≥ 15) compared to non-smokers (Anderson et al., under review). Considering their prevalence in the colons of cancer patients, their corresponding association with a panel of key colon cancer risk factors and their cancer-related molecular aberrations, we argue that these lesions may provide an important signal of one or more risk factors, and are likely part of the ‘field effect’ within the colonic mucosa. If a clearer association can be established with high-grade adenomas, we believe ACF will ultimately be of great utility as surrogate markers for cancer prevention studies. Citation Information: Cancer Prev Res 2010;3(1 Suppl):PL02-05.

Risk Factors for Colon Cancer in Northeastern Thailand: Interaction of MTHFR Codon 677 and 1298 Genotypes with Environmental Factors

BackgroundPolymorphisms in methylenetetrahydrofolate reductase (MTHFR), such as MTHFR C677T and A1298C, are associated with several cancers. This study aimed to evaluate the effects of MTHFR polymorphisms on colon cancer risk and possible interactions with environmental factors in a population from northeastern Thailand.MethodsThis hospital-based case–control study was conducted during 2002–2006; 130 colon cancer cases and 130 age- and sex-matched controls were enrolled. Information was collected and blood samples were obtained for assay of MTHFR C677T and A1298C polymorphisms by polymerase chain reaction with restriction fragment length polymorphism techniques. Associations between variables of interest and colon cancer were assessed using conditional logistic regression.ResultsIncreased risk of colon cancer was associated with alcohol consumption and bowel habits. Alcohol drinkers who consumed ≤0.50 or >0.50 units of alcohol per day had elevated risks (ORadj = 3.5; 95% CI: 1.19–10.25 and ORadj = 1.71; 95% CI: 0.74–3.96, respectively). The risk was also higher in subjects with frequent constipation (11.69; 2.18–62.79) and occasional constipation (3.43; 1.72–6.82). An interaction was observed between the MTHFR C677T polymorphism and freshwater fish consumption on colon cancer risk (P value for interaction = 0.031). Interactions were observed between the MTHFR A1298C polymorphism and bowel habits, family history of cancer, alcohol consumption, and beef consumption on colon cancer risk (P-value for interaction = 0.0005, 0.007, 0.067, 0.003, respectively).ConclusionsIn a Thai population, colon cancer risk was associated with alcohol and beef consumption, bowel habits, and family history of cancer. Interactions between MTHFR polymorphisms and environmental factors were also observed.

Assessing Obesity as a Risk Factor in Colon Cancer

Assessing Obesity as a Risk Factor in Colon Cancer

Consumption of Some Polyphenols Reduces Fecal Deoxycholic Acid and Lithocholic Acid, the Secondary Bile Acids of Risk Factors of Colon Cancer

This study was performed to examine the effect of dietary polyphenols on fecal secondary bile acids, such as deoxycholic acid and lithocholic acid, the risk factors of colon cancer, in rats fed a high-fat diet. In experiment 1, rats were fed a 30% beef tallow diet containing 0.5% polyphenols for 3 weeks. Dietary curcumin and caffeic acid significantly reduced the fecal concentration of deoxycholic acid. Dietary caffeic acid, catechin, rutin, and ellagic acid significantly reduced fecal lithocholic acid. Fecal hyodeoxycholic acid, a metabolite of lithocholic acid, was markedly lowered by dietary curcumin, caffeic acid, catechin, and rutin. In experiment 2, rats were fed a 30 or 5% beef tallow diet with or without the addition of 0.5% curcumin. In the rats without receiving curcumin, the fecal level of deoxycholic acid was significantly higher in the high-fat diet group than in the low-fat diet group. Fecal deoxycholic acid was significantly reduced by dietary curcumin in the high-fat diets but not in the low-fat diets. The results suggest novel effects of some polyphenols favorable for colon health by reducing secondary bile acids in animals fed a high-fat diet.