Dietary marine n-3 fatty acids in relation to risk of distal colorectal adenoma in women.

Epidemiologic studies of dietary marine n-3 fatty acids and risk of colorectal cancer have been inconsistent, and their relation to risk of colorectal adenoma has not been evaluated in detail. We examined dietary marine n-3 fatty acids and the ratio of marine n-3 to total n-6 fatty acids (n-3/n-6 ratio) in relation to risk of adenoma of the distal colon or rectum among 34,451 U.S. women who were initially free of colorectal cancer or polyps, who completed a semiquantitative food frequency questionnaire in 1980, and who underwent endoscopy from 1980 to 1998. We documented 1,719 distal colorectal adenoma cases (705 large adenomas, 897 small adenomas, 1,280 distal colon adenomas, and 505 rectal adenomas) during 18 years of follow-up. Neither dietary marine n-3 fatty acids nor n-3/n-6 ratio were associated with risk of total distal colorectal adenoma after adjustment for age and established risk factors [multivariable relative risk (RR) for extreme quintiles of dietary marine n-3 fatty acids = 1.04; 95% confidence interval (95% CI), 0.84-1.27, P(trend) = 0.66; RR for extreme quintiles of n-3/n-6 ratio = 1.02; 95% CI, 0.83-1.25; P(trend) = 0.86]. Similarly, no significant associations were observed separately for distal colon or rectal adenoma. However, higher intake of dietary marine n-3 fatty acids was nonsignificantly but suggestively inversely associated with large adenoma (RR, 0.74; 95% CI, 0.54-1.01; P(trend) = 0.16) but directly associated with small adenoma (RR, 1.36; 95% CI, 1.02-1.81; P(trend) = 0.09). Our findings do not support the hypothesis that a higher intake of marine n-3 fatty acids or a higher n-3/n-6 ratio reduces the risk of distal colorectal adenoma but are suggestive that higher intake may reduce the progression of small adenomas to large adenomas.     

Leptin concentrations, leptin receptor polymorphisms, and colorectal adenoma risk.

Obesity has been shown to be associated with an increased risk of both colorectal cancer and adenomatous polyps. One mechanism underlying this relationship may involve the growth-promoting effects of the circulating hormones associated with obesity, such as leptin. We conducted a gastroenterology clinic-based, case-control study to evaluate the relationship between circulating leptin concentrations and colorectal adenoma risk; in addition, we evaluated the relationship between leptin receptor polymorphisms and adenoma risk. Individuals with adenomas (n = 157) and colonoscopy-negative controls (n = 191), who had a clinically indicated colonoscopy, were recruited from a large health maintenance organization in the Seattle metropolitan area from 1999 to 2003. Odds ratios and 95% confidence intervals were obtained using logistic regression, adjusting for age at diagnosis, body mass index, family history of colorectal cancer, smoking history, nonsteroidal anti-inflammatory drug use, physical activity, and, among women, menopausal status and postmenopausal hormone use. Among men, those in the highest tertile of leptin concentrations had a 3.3-fold (95% confidence interval, 1.2-8.7) increased adenoma risk compared with those in the lowest tertile (P trend = 0.01). There were no associations between leptin concentrations and adenoma risk in women. There were no associations of leptin receptor genotypes or haplotypes and adenoma risk. The results of this study suggest that, in men, leptin may be associated with risk of colorectal adenomas.     

Plasma carotenoid, alpha-tocopherol and retinol concentrations and risk of colorectal adenomas: A case-control study in Japan

To investigate associations between plasma carotenoids, alpha-tocopherol and retinol with colorectal adenomas risk, we measured concentrations in 224 asymptomatic colorectal adenoma cases and 230 population-based controls matched for age and sex. After adjustment for age, history of colorectal adenomas and cancers, BMI, smoking, drinking status, multivitamin consumption and plasma total cholesterol, the risk of colorectal adenomas in the highest quartile was approximately half of that of men in the lowest quartile for alpha-carotene (OR=0.38; 95% CI: 0.18-0.84; P(trend)=0.01), beta-carotene (OR=0.51; 95% CI: 0.24-1.07; P(trend)=0.03) and total carotenoids (OR=0.48; 95% CI: 0.22-1.03; P(trend)=0.04). In addition, a protective association for alpha-carotene in women was also indicated, but which did not reach statistical significance (OR=0.53; 95% CI: 0.19-1.52; P(trend)=0.35). Our findings suggest a protective effect of carotenoids against the development of colorectal adenomas.     

Vitamins B2, B6, and B12 and risk of new colorectal adenomas in a randomized trial of aspirin use and folic acid supplementation

BACKGROUND: Folate, other vitamin B cofactors, and genes involved in folate-mediated one-carbon metabolism all may play important roles in colorectal neoplasia. In this study, we examined the associations between dietary and circulating plasma levels of vitamins B(2), B(6), and B(12) and risk colorectal adenomas. METHODS: The Aspirin/Folate Polyp Prevention Study is a randomized clinical trial of folic acid supplementation and incidence of new colorectal adenomas in individuals with a history of adenomas (n = 1,084). Diet and supplement use were ascertained through a food frequency questionnaire administered at baseline. Blood collected at baseline was used to determine plasma B-vitamin levels. We used generalized linear regression to estimate risk ratios (RR) and 95% confidence intervals (95% CI) as measures of association. RESULTS: We found a borderline significant inverse association with plasma B(6) [pyridoxal 5'-phosphate (PLP)] and adenoma risk (adjusted RR Q4 versus Q1, 0.78; 95% CI, 0.61-1.00; P(trend) = 0.08). This association was not modified by folic acid supplementation or plasma folate. However, the protective association of PLP with adenoma risk was observed only among subjects who did not drink alcohol (P(interaction) = 0.03). Plasma B(2) (riboflavin) was inversely associated with risk of advanced lesions (adjusted RR Q4 versus Q1, 0.51; 95% CI, 0.26-0.99; P(trend) = 0.12). No significant associations were observed between adenoma risk and plasma vitamin B(12) or dietary intake of vitamin B(2) and B(6). When we examined specific gene-B-vitamin interactions, we observed a possible interaction between methylenetetrahydrofolate reductase -C677T and plasma B(2) on risk of all adenomas. CONCLUSION: Our results suggest that high levels of PLP and B(2) may protect against colorectal adenomas.     

Plasma phyto-oestrogens and prostate cancer in the European Prospective Investigation into Cancer and Nutrition

We examined plasma concentrations of phyto-oestrogens in relation to risk for subsequent prostate cancer in a case–control study nested in the European Prospective Investigation into Cancer and Nutrition. Concentrations of isoflavones genistein, daidzein and equol, and that of lignans enterolactone and enterodiol, were measured in plasma samples for 950 prostate cancer cases and 1042 matched control participants. Relative risks (RRs) for prostate cancer in relation to plasma concentrations of these phyto-oestrogens were estimated by conditional logistic regression. Higher plasma concentrations of genistein were associated with lower risk of prostate cancer: RR among men in the highest vs the lowest fifth, 0.71 (95% confidence interval (CI) 0.53–0.96, P trend=0.03). After adjustment for potential confounders this RR was 0.74 (95% CI 0.54–1.00, P trend=0.05). No statistically significant associations were observed for circulating concentrations of daidzein, equol, enterolactone or enterodiol in relation to overall risk for prostate cancer. There was no evidence of heterogeneity in these results by age at blood collection or country of recruitment, nor by cancer stage or grade. These results suggest that higher concentrations of circulating genistein may reduce the risk of prostate cancer but do not support an association with plasma lignans.     

Lignan transformation by gut bacteria lowers tumor burden in a gnotobiotic rat model of breast cancer

High dietary lignan exposure is implicated in a reduced breast cancer risk in women. The bacterial transformation of plant lignans to enterolignans is thought to be essential for this effect. To provide evidence for this assumption, gnotobiotic rats were colonized with the lignan-converting bacteria Clostridium saccharogumia, Eggerthella lenta, Blautia producta and Lactonifactor longoviformis (LCC rats). Germ-free rats were used as the control. All animals were fed a lignan-rich flaxseed diet and breast cancer was induced with 7,12-dimethylbenz(a)anthracene. The lignan secoisolariciresinol diglucoside was converted into the enterolignans enterodiol and enterolactone in the LCC but not in the germ-free rats. This transformation did not influence cancer incidence at the end of the 13 weeks experimental period but significantly decreased tumor numbers per tumor-bearing rat, tumor size, tumor cell proliferation and increased tumor cell apoptosis in LCC rats. No differences between LCC and control rats were observed in the expression of the genes encoding the estrogen receptors (ERs) α, ERβ and G-coupled protein 30. The same was true for IGF-1 and EGFR involved in tumor growth. The activity of selected enzymes involved in the degradation of oxidants in plasma and liver was significantly increased in the LCC rats. However, plasma and liver concentrations of reduced glutathione and malondialdehyde, considered as oxidative stress markers, did not differ between the groups. In conclusion, our results show that the bacterial conversion of plant lignans to enterolignans beneficially influences their anticancer effects.     

Calcium, phosphorus, vitamin D, dairy products and colorectal carcinogenesis: a French case--control study.

A protective effect of calcium against colorectal cancer has been described in Anglo-Saxon but not in Latin communities, and no such effect has been observed regarding adenomas. We investigated the relationship between calcium, dairy products and the adenoma-carcinoma sequence in a French region by comparing small adenoma ( < 10 mm, n = 154), large adenoma (n = 208) and polyp-free (n = 426) subjects, and cancer cases (n = 171) with population controls (n = 309). There was no protective effect of calcium against colorectal tumours except for low fat calcium and large adenomas in men (OR for highest quintile = 0.3, P for trend = 0.06). There was even a trend towards an increased risk of cancer with dairy calcium in men and non-dairy calcium in women. Vitamin D was inversely related to the risk of small adenomas in women (OR for highest quintile = 0.4, P for trend = 0.04). Regarding dairy products, only consumption of yoghurt displayed an inverse relationship with risk of large adenomas, in both men and women. These data failed to demonstrate a protective effect of calcium against colorectal carcinogenesis. They suggest that the type of dairy product might be the important factor with regard to prevention of colorectal tumours.     

Glycemic index, glycemic load, and carbohydrate intake in relation to risk of distal colorectal adenoma in women.

Case-control studies and a cohort study have shown inconsistent associations between a high glycemic index or a high glycemic load and risk of colorectal cancer. These dietary variables have not been examined in relation to risk of colorectal adenoma. We thus examined the associations between dietary glycemic index, glycemic load, and carbohydrate intake with risk of adenoma of the distal colon or rectum among 34,428 US women who were initially free of cancer or polyps, who completed a semi-quantitative food-frequency questionnaire in 1980, and who underwent endoscopy from 1980 through 1998. 1,715 adenoma cases (704 large adenomas, 894 small adenomas, 1,277 distal colon adenomas, and 504 rectal adenomas) were documented during 18 years of follow-up. Dietary glycemic index, glycemic load, and carbohydrate intake were not related to risk of total colorectal adenoma after adjustment for age and established risk factors [relative risk (RR) for extreme quintiles of glycemic index = 1.11, 95% confidence interval (CI) 0.94-1.32, P for trend = 0.66; RR for glycemic load = 0.92, 95% CI 0.76-1.11, P for trend = 0.63; RR for carbohydrate intake = 0.90, 95% CI 0.73-1.11, P for trend = 0.64]. In addition, no significant associations were found for large or small adenoma, distal colon or rectal adenoma, or across strata of body mass index. Our findings do not support the hypothesis that a high glycemic index diet, a high glycemic load diet, or high carbohydrate intake overall are associated with risk of colorectal adenoma.     

Phytoestrogen concentrations in serum and spot urine as biomarkers for dietary phytoestrogen intake and their relation to breast cancer risk in European prospective investigation of cancer and nutrition-norfolk.

Subjects of this study consisted of 333 women (aged 45-75 years) drawn from a large United Kingdom prospective study of diet and cancer, the European Prospective Investigation of Cancer and Nutrition-Norfolk study. Using newly developed gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry methods incorporating triply (13)C-labeled standards, seven phytoestrogens (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) were measured in 114 spot urines and 97 available serum samples from women who later developed breast cancer. Results were compared with those from 219 urines and 187 serum samples from healthy controls matched by age and date of recruitment. Dietary levels were low, but even so, mean serum levels of phytoestrogens were up to 600 times greater than postmenopausal estradiol levels. Phytoestrogen concentrations in spot urine (adjusted for urinary creatinine) correlated strongly with that in serum, with Pearson correlation coefficients > 0.8. There were significant relationships (P < 0.02) between both urinary and serum concentrations of isoflavones across increasing tertiles of dietary intakes. Urinary enterodiol and enterolactone and serum enterolactone were significantly correlated with dietary fiber intake (r = 0.13-0.29). Exposure to all isoflavones was associated with increased breast cancer risk, significantly so for equol and daidzein. For a doubling of levels, odds ratios increased by 20-45% [log(2) odds ratio = 1.34 (1.06-1.70; P = 0.013) for urine equol, 1.46 (1.05-2.02; P = 0.024) for serum equol, and 1.22 (1.01-1.48; P = 0.044) for serum daidzein]. These estimates of risk are similar to those established for estrogens and androgens in postmenopausal breast cancer but need confirmation in larger studies.     

Insulin-like Growth Factor (IGF)-I, IGF-binding Protein-3 and Colorectal Adenomas in Japanese Men

Several epidemiological studies have found that high levels of plasma insulin-like growth factor (IGF)-I and low levels of IGF-binding protein (IGFBP)-3 are related to an increased risk of colorectal cancer or late-stage adenomas. We examined the relation of body mass index, fasting and 2-h postload plasma glucose levels and plasma concentrations of IGF-I and IGFBP-3 to colorectal adenomas in middle-aged Japanese men. The study subjects comprised 157 cases of histologically diagnosed colorectal adenomas and 311 controls with normal colonoscopy or non-polyp benign lesions in a consecutive series of 803 men receiving a preretirement health examination at two hospitals of the Self Defense Forces (SDF). After adjustment for rank in the SDF, hospital, smoking and IGFBP-3, a statistically nonsignificant modest increase in the prevalence odds of colorectal adenomas was observed for the highest versus the lowest quartile level of IGF-I. The increase was slightly greater with further adjustment for 2-h glucose concentrations (adjusted odds ratio 1.8, 95% confidence interval 1.0–4.5, trend P =0.06). Men with high levels of IGFBP-3 showed only a minimal decrease in risk after adjustment for IGF-I. The association with IGF-I was less evident for advanced adenomas (≥5 mm in size or tubulovillous/villous). Fasting and 2-h glucose and body mass index were more strongly positively associated with colorectal adenomas than IGF-I, especially with advanced adenomas, independently of IGF-I and IGFBP-3. The findings suggest that plasma IGF-I and IGFBP-3 may be involved in colorectal tumorigenesis regardless of the stage in growth of adenoma, but not as a mediator for the effects of being overweight or of hyperglycemia.     

Insulin-like growth factor (IGF)-I, IGF-binding protein-3 and colorectal adenomas in Japanese men.

Several epidemiological studies have found that high levels of plasma insulin-like growth factor (IGF)-I and low levels of IGF-binding protein (IGFBP)-3 are related to an increased risk of colorectal cancer or late-stage adenomas. We examined the relation of body mass index, fasting and 2-h postload plasma glucose levels and plasma concentrations of IGF-I and IGFBP-3 to colorectal adenomas in middle-aged Japanese men. The study subjects comprised 157 cases of histologically diagnosed colorectal adenomas and 311 controls with normal colonoscopy or non-polyp benign lesions in a consecutive series of 803 men receiving a preretirement health examination at two hospitals of the Self Defense Forces (SDF). After adjustment for rank in the SDF, hospital, smoking and IGFBP-3, a statistically nonsignificant modest increase in the prevalence odds of colorectal adenomas was observed for the highest versus the lowest quartile level of IGF-I. The increase was slightly greater with further adjustment for 2-h glucose concentrations (adjusted odds ratio 1.8, 95% confidence interval 1.0-4.5, trend P=0.06). Men with high levels of IGFBP-3 showed only a minimal decrease in risk after adjustment for IGF-I. The association with IGF-I was less evident for advanced adenomas (>5 mm in size or tubulovillous/villous). Fasting and 2-h glucose and body mass index were more strongly positively associated with colorectal adenomas than IGF-I, especially with advanced adenomas, independently of IGF-I and IGFBP-3. The findings suggest that plasma IGF-I and IGFBP-3 may be involved in colorectal tumorigenesis regardless of the stage in growth of adenoma, but not as a mediator for the effects of being overweight or of hyperglycemia.     

Risk factors for advanced colorectal adenomas: a pooled analysis.

Although most colorectal cancers arise from adenomatous polyps, most adenomas do not progress to invasive cancer. Understanding the epidemiology of advanced adenomas, specifically those with severe dysplasia, carcinoma in situ, or intramucosal carcinoma, is crucial to uncovering why some adenomas progress and some do not. Using data from four colonoscopy-based adenoma case-control studies, we compared two case groups: subjects with advanced adenomas (those with severe dysplasia, carcinoma in situ, or intramucosal carcinoma; n = 119) and subjects with nonadvanced adenomas (those with none, mild, or moderate dysplasia; n = 441) to a polyp-free control group (n = 1866) in regard to frequently studied risk factors for colorectal neoplasia. All of the cases were newly diagnosed and had no prior history of adenomas. We used an unordered polytomous logistic model to calculate multivariate odds ratios for advanced and nonadvanced adenoma cases relative to polyp-free controls. Among women, ever use of hormone replacement therapy was more strongly associated with reduced risk of advanced adenomas relative to polyp-free controls [odds ratio (OR), 0.4; 95% confidence interval (CI), 0.2-0.9] than with reduced risk of nonadvanced adenomas (OR, 0.7; 95% CI, 0.4-1.0). Among men, increased physical activity (>or=2 h/week) was more strongly associated with reduced risk for advanced adenomas (OR, 0.4; 95% CI, 0.2-1.0) than with reduced risk for nonadvanced adenomas (OR, 0.8; 95% CI, 0.5-1.2). Apart from these differences, most other risk factors, including body size and cigarette smoking were similar in their association with advanced and nonadvanced adenomas, suggesting that many risk factors for colorectal neoplasia may be important to adenoma formation but not to dysplasia per se.     

Polymorphisms in PTGS1 (=COX-1) and risk of colorectal polyps.

Two isoforms of prostaglandin H synthase (PTGS = COX) are key enzymes in prostaglandin synthesis and primary targets for aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). Use of aspirin or other NSAIDs is associated with a lower risk and reduced recurrence of colorectal adenomas, established precursors of adenocarcinoma. This study investigated risk of colorectal adenomatous and hyperplastic polyps associated with several polymorphisms in the coding region of PTGS1. Within the Minnesota polyp case-control study, patients with colorectal adenomatous (n = 521) or hyperplastic (n = 194) polyps and n = 621 polyp-free controls were genotyped for four PTGS1 polymorphisms (R8W, L15-L16del, P17L, L237M); these had been predicted to affect protein function based on sequence-homology software. Age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed. Whereas there was no appreciable difference in adenoma or hyperplastic polyp risk associated with R8W, P17L, and L237M, an increased risk was observed for individuals heterozygous for the L15-L16del polymorphism (OR = 3.6, 95% CI 1.2-11.2). The variant L15-L16del allele appeared to be associated with a stronger increase in adenoma risk among nonusers of aspirin/other NSAIDs. The reduced risk observed with aspirin/other NSAID use was limited to those wild type for P17L [PP users: OR = 0.6 (0.5-0.8) versus PP nonusers: 1.0 (referent) (P interaction = 0.03)]. To our knowledge, this study represents the first investigation of polymorphisms in PTGS1 and risk of colorectal polyps. The L15-L16del variant allele may result in an increased risk of colorectal adenomas, whereas P17L may be relevant to the pharmacogenetics of aspirin. These preliminary findings require confirmation in larger studies of colorectal neoplasia.     

Genetic polymorphisms of CYP2E1 and risk of colorectal adenomas in the Self Defense Forces Health Study

CYP2E1 is an enzyme involved in the metabolism of N-nitrosamines and other carcinogenic substances. Functional RsaI and 96-bp insertion polymorphisms in 5'-flanking region have drawn interest in relation to the risk of colorectal cancer. We investigated the relation of these genetic polymorphisms and colorectal adenoma, a well-established precursor lesion of colorectal cancer. Subjects were 455 cases of colorectal adenomas and 1,052 controls of normal colonoscopy among men receiving a preretirement health examination in the Self Defense Forces. Genotypes were determined by either PCR-RFLP or PCR method. Statistical adjustment was made for smoking, alcohol use, body mass index, physical activity, and others. Individuals with RsaI c2 allele showed a decreased risk of proximal colon adenomas; adjusted odds ratios (95% confidence interval) of proximal and distal adenomas for the c1/c2 or c2/c2 genotype versus c1/c1 was 0.61 (0.41-0.88) and 0.95 (0.71-1.27), respectively. CYP2E1 96-bp insertion allele was associated with an increased risk of large (> or = 5 mm) adenomas; adjusted odds ratios (95% confidence interval) of large and small adenomas for having at least one insertion allele were 1.41 (1.03-1.94) and 0.94 (0.71-1.25), respectively. A suggestive effect modification was noted for alcohol consumption on the association between RsaI polymorphism and proximal adenomas (P(interaction) = 0.09) as well as on the association between 96-bp insertion and large adenomas (P(interaction) = 0.05). These findings indicate that variation in activity and inducibility of CYP2E1 contribute to the development of colorectal carcinogenesis.     

Plasma insulin-like growth factor I is inversely associated with colorectal adenoma recurrence: a novel hypothesis.

The insulin-like growth factor I (IGF-I) axis has been proposed to be a significant factor in the development of certain cancers, including colorectal. However, results from epidemiologic studies suggest modest effects on colorectal cancer risk. Using cross-sectional and prospective study designs within the same cohort of men who had at least one adenoma at baseline, we investigated whether plasma IGF-I, IGF-I binding protein 1, and IGF-I binding protein 3 were associated with colorectal adenoma characteristics at baseline and whether their levels were related to odds for adenoma recurrence. Plasma levels of each marker were measured at baseline in 299 male participants in the Wheat Bran Fiber Trial, who were followed prospectively for recurrence of their adenomatous lesions. In cross-sectional analyses, plasma IGF-I was significantly positively associated with the presence of adenomas with any villous features (P = 0.04). In contrast, IGF-I levels were inversely associated with odds of colorectal adenoma recurrence, with adjusted odds ratios (95% confidence interval) of 0.55 (0.29-1.01) and 0.49 (0.26-0.91) for the second and third tertiles of IGF-I, respectively, compared with the first tertile (P(trend) = 0.02). The inverse association was stronger for advanced adenoma recurrence (P(trend) = 0.02) than for nonadvanced recurrence (P(trend) = 0.10). These results suggest that, once an adenoma is removed, higher IGF-I levels reduce the odds of the formation of new lesions in the colorectum.     

Selenium supplementation and colorectal adenomas: an analysis of the nutritional prevention of cancer trial

Selenium status has been inversely associated with colorectal cancers (CRC) and adenomas. This investigation evaluates the association between selenium supplementation and prevalent and incident colorectal adenomas and CRC detected during the Nutritional Prevention of Cancer trial follow-up. Of the 1,312 randomized to 200 mcg of selenized yeast of matching placebo, 598 participants underwent endoscopic screening (flexible sigmoidoscopy or colonoscopy) for CRC sometime during the follow-up period, which ended in February 1, 1996. There was no colorectal screening performed at baseline. Of those screened, 77% were male (with a mean age of 62.8 years), 42% were former and 25% were current smokers. Adenomas were classified as prevalent (identified at the first endoscopic examination post-randomization during the follow-up period) or incident (identified at the second or subsequent examination). Ninety-nine prevalent and 61 incident adenomas were ascertained. Logistic regression odds ratios (OR) and 95% confidence intervals (CI) were calculated, adjusting for age, gender and smoking status. For prevalent adenomas, there was a suggestive but nonsignificant decrease in risk associated with selenium treatment (OR = 0.67, 95% CI = 0.43-1.05). Subjects in the lowest tertile of baseline selenium (OR = 0.27, 95% CI = 0.09-0.77) and current smokers (OR = 0.27, 95% CI = 0.11-0.66) had significant reductions in risk. The OR for incident adenomas was 0.98 (95% CI = 0.57-1.68). In addition to being associated with a reduced risk of incident CRC, selenium supplementation was associated with a significantly reduced risk of prevalent adenomas, but only among subjects with either a low baseline selenium level or among current smokers.     

Prediagnostic serum selenium concentration and the risk of recurrent colorectal adenoma: a nested case-control study

Several studies have suggested that selenium may help to prevent colorectal neoplasia. To investigate the relation between prediagnostic serum selenium concentrations and colorectal adenomas, we conducted a nested case-control study using data from a large, multicenter, adenoma prevention trial. Cases comprised a total of 276 patients who developed a colorectal adenoma between the year 1 and year 4 follow-up exam. Controls were 276 patients who did not develop an adenoma during this time interval, matched to case subjects on age, sex, and clinical center. Total and bound selenium concentrations were measured from baseline or year 1 serum samples using instrumental neutron activation analysis. We estimated the odds ratios of colorectal adenoma in relation to serum selenium concentrations adjusting for age, clinical center, and sex. Compared with the lowest quintile, the odds ratio for the highest quintile was 0.76 (95% confidence interval, 0.44-1.30) for total selenium and 0.60 (95% confidence interval, 0.34-1.05) for bound selenium, and there was no apparent trend in risk (P for trend = 0.50 for total selenium and P for trend = 0.20 for bound selenium). Thus, our findings do not indicate a clear association between serum selenium concentrations and adenoma recurrence.     

Relationship of diet to risk of colorectal adenoma in men.

BACKGROUND: Rates of colorectal cancer in various countries are strongly correlated with per-capita consumption of red meat and animal fat and inversely associated with fiber consumption. There have been few studies, however, of dietary risk factors for colorectal adenomas, which are precursors of cancer. PURPOSE: Our purpose was to determine prospectively the relationship between dietary factors and risk of colorectal adenomas. METHODS: Using data from the Health Professionals Follow-up Study, we documented 170 cases of adenomas of the left colon or rectum in 7284 male health professionals who completed a food-frequency questionnaire in 1986 and who had a colonoscopy or sigmoidoscopy between 1986 and 1988. Relative risk (RR) of adenoma was determined according to quintiles of nutrient intakes. RESULTS: After adjustment for total energy intake, saturated fat was positively associated with risk of colorectal adenoma (P for trend = .006); RR for the highest versus the lowest quintile of intake was 2.0 (95% confidence interval [CI] = 1.2-3.2). Dietary fiber was inversely associated with risk of adenoma (P for trend less than .0001); RR for men in the highest versus the lowest quintile was 0.36 (95% CI = 0.22-0.60). All sources of fiber (vegetables, fruits, and grains) were associated with decreased risk of adenoma. For subjects on a high-saturated fat, low-fiber diet, the RR was 3.7 (95% CI = 1.5-8.8) compared with those on a low-saturated fat, high-fiber diet. The ratio of the intake of red meat to the intake of chicken and fish was positively associated with risk of adenoma (P for trend = .02). CONCLUSIONS: These prospective data provide evidence for the hypothesis that a diet high in saturated fat and low in fiber increases the risk of colorectal adenoma. They also support existing recommendations to substitute chicken and fish for red meat in the diet and to increase intake of vegetables, fruits, and grains to reduce risk of colorectal cancer.     

Apoptosis in normal rectal mucosa, baseline adenoma characteristics, and risk of future adenomas

Low apoptosis in the normal rectal mucosa has been associated with colorectal adenomas in cross-sectional studies. It is unknown whether apoptosis can predict the occurrence of new adenomas. We evaluated whether apoptosis at baseline colonoscopy, as well as patient and adenoma characteristics, could predict future occurrence of adenomas. Study subjects were participants in the Diet and Health Study III, a cross-sectional study of adenoma risk factors between August 1998 and March 2000. At baseline, subjects underwent colonoscopy and provided normal rectal mucosal biopsies to evaluate apoptosis as well as information about diet and lifestyle. The present study includes 257 subjects who returned for follow-up colonoscopy between 2000 and 2005. Apoptosis, number of adenomas, size, and atypia at baseline colonoscopy were evaluated as predictors of new adenomas. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). At baseline, low apoptosis was significantly associated with increased risk of adenomas (P = 0.0001). Compared with those in the lowest tertile, subjects with high apoptosis were less likely to have an adenoma at follow-up (crude OR, 0.25; 95% CI, 0.09-0.65; adjusted OR, 0.29; 95% CI, 0.08-1.06). Having three or more adenomas at baseline was associated with increased risk of new adenomas (crude OR, 2.46; 95% CI, 1.14-5.31; adjusted OR, 3.74; 95% CI, 1.01-13.83). This study suggests that lower apoptosis is associated with increased risk of future adenoma development. If confirmed in larger studies, apoptosis could potentially be used to identify patients at highest risk for developing new adenomas.     

Matrix Metalloproteinase-9 Expression in the Normal Mucosa–Adenoma–Dysplasia–Adenocarcinoma Sequence of the Colon

It has been proposed that matrix metalloproteinases (MMPs) play a role in tumor invasion. We determined protein expression of matrix metalloproteinase-9 (MMP-9) in colorectal cancer (CRC), corresponding normal mucosa and colorectal adenomas. For confirmation of immunohistochemical results MMP-9 TaqMan RT-PCR analysis was performed. Expression of MMP-9 was determined on paraffin embedded biopsy sections by immunohistochemistry in 31 CRC patients (from cancer tissue and corresponding normal mucosa) and in 30 patients with adenoma (nine adenomas with high grade of dysplasia). MMP-9 immunostaining was determined semi-quantitatively. For Taqman RT-PCR analyses normal mucosa (n = 5), adenoma without (n = 6) and with high grade dysplasia (n = 7) and CRC (n = 10) were investigated. Statistical analysis with ANOVA, LSD test and correlation analysis were performed. P value of <0.05 was considered significant. The MMP-9 expression in CRC was significantly higher compared to adenomas or the normal mucosa (P = 0.001). Significantly higher expression of MMP-9 has been observed in adenomas with high grade dysplasia compared to other adenomas or normal colon (P < 0.001). Diffuse strong MMP-9 expression was present in tumor as well as in stromal cells. In adenoma samples, dysplastic epithelial cells showed moderate intensive cytoplasmic MMP-9 expression, with a clear-cut differentiation between dysplastic and non-dysplastic areas. Staining intensity correlated with the grade of CRC. We demonstrate a significantly higher expression of MMP-9 in adenoma with high grade dysplasia-CRC sequence as compared to normal tissue. The over-expression of MMP-9 strongly suggests its association with colorectal carcinogenesis.