Insulin resistance, central obesity, and risk of colorectal adenomas

BACKGROUND:

Increasing evidence supports insulin resistance (IR) as the underpinning of the obesity‐colorectal neoplasia link. The homeostasis model assessment‐IR (HOMA‐IR) is a widely accepted index of evolving hyperinsulinemia and early IR. Studies of the relation between HOMA‐IR and colorectal adenomas are limited. Therefore, the authors sought to determine the associations of HOMA‐IR and central obesity (waist to hip ratio [WHR]) with risk of colorectal adenomas in a screening colonoscopy‐based study.

METHODS:

The authors collected lifestyle information and fasting blood samples from 1222 participants (320 incident adenoma cases and 902 without adenomas) before their screening colonoscopies. Unconditional logistic regression models were used to assess risk associations.

RESULTS:

In multivariate analysis of participants (n = 1093) reporting no antidiabetic medication use, those in the top quartile of WHR were twice as likely (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.33‐3.57; P‐trend = .003) and those in the top quartile of HOMA‐IR were 63% more likely (OR, 1.63; 95% CI, 1.09‐2.44; P‐trend = .01) to have adenomas compared with those in the bottom quartiles. Stratified analysis revealed a statistically significant interaction between HOMA‐IR and sex (P‐interaction = .04), with the association largely limited to men; compared with those in the bottom tertile, men in the top tertile of HOMA‐IR were twice more likely to have adenomas (OR, 2.11; 95% CI, 1.18‐3.78; P‐trend = .01).

CONCLUSIONS:

The results support central obesity and insulin resistance, particularly in men, as important risk factors for the development of early colorectal neoplasia. Cancer 2012;. © 2011 American Cancer Society.     

Insulin resistance-related genes and advanced left-sided colorectal adenoma.

BACKGROUND: Insulin resistance has been linked with colorectal neoplasia through a number of mechanistic and observational studies. Allelic variants of genes encoding components of the insulin pathway, including insulin (INS), insulin receptor (INSR), and insulin receptor substrate-1 and insulin receptor substrate-2 (IRS1 and IRS2) have been associated with hyperinsulinemia and insulin resistance and may, therefore, predict susceptibility to colorectal neoplasia. METHODS: We investigated whether single nucleotide polymorphisms (SNP) in the INS, INSR, IRS1, and IRS2 genes are associated with risk of advanced left-sided colorectal adenoma, a cancer precursor. We analyzed 20 SNPs in a largely Caucasian study population comprising 766 cases with advanced adenomas of the distal colon and 771 controls, all of whom had undergone flexible sigmoidoscopy as part of the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. RESULTS: Overall, we found limited evidence for a role of gene variants of the insulin signaling pathway and prevalence of advanced colorectal adenoma. We observed a statistically significant interaction between INSR genotypes and body mass index (BMI) with colorectal adenoma prevalence (P value for global test = 0.003) and suggestion of an interaction between INSR genotypes and glycemic load (P value for global test = 0.06); however, exploration of the interaction of BMI and glycemic load with the individual SNPs in INSR did not suggest a single SNP that may explain the significance of these global tests of interaction and did not yield any consistent patterns. CONCLUSION: These findings do not provide strong evidence for associations between polymorphic variation in genes of the insulin signaling pathway and advanced left-sided colorectal adenoma. Evidence for interaction between INSR variants and BMI and glycemic load for risk of advanced left-sided colorectal adenoma requires independent confirmation, and genotyping of INSR across a broader region and at greater density may be necessary to fully elucidate the nature of these interactions.     

Insulin resistance and breast-cancer risk.

Life-style has a major influence on the incidence of breast cancer. To evaluate the effects of life-style related metabolic-endocrine factors on breast cancer risk we conducted a case-control study comparing 223 women aged 38 to 75 years presenting with operable (stage I or II) breast cancer and 441 women of the same age having no breast cancer, who participated in a population-based breast cancer screening program. Women reporting diabetes mellitus were excluded. Sera from 110 women of the same age group presenting with early stage melanoma, lymphoma or cervical cancer were used as a second 'other-cancer control group'. Serum levels of C-peptide were significantly higher in early breast cancer cases compared to controls. The same was found for the ratios C-peptide to glucose or C-peptide to fructosamine, indicating insulin resistance. Sex hormone binding globulin was inversely, triglycerides and available estradiol were positively related to C-peptide. Serum C-peptide levels were related to body mass index (BMI), and to waist/hip ratio (WHR), in particular in controls. However, the relative increase of C-peptide, C-peptide to glucose or C-peptide to fructosamine in cases was independent of BMI or WHR. The log relative risk was linearly related to the log C-peptide levels. Relative risk according to quintiles, and adjusted for age, family history, BMI and WHR, for women at the 80% level was 2.9 as compared with those at the 20% level for C-peptide. Elevated C-peptide or C-peptide to fructosamine values were not observed in the sera from women belonging to the 'other-cancer control group'. This study suggests that hyperinsulinemia with insulin resistance is a significant risk factor for breast cancer independent of general adiposity or body fat distribution.     

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.     

Television watching and risk of colorectal adenoma

Background:

Prolonged TV watching, a major sedentary behaviour, is associated with increased risk of obesity and diabetes and may involve in colorectal carcinogenesis.

Methods:

We conducted a cross-sectional analysis among 31 065 men with ⩾1 endoscopy in the Health Professionals Follow-up Study (1988–2008) to evaluate sitting while watching TV and its joint influence with leisure-time physical activity on risk of colorectal adenoma. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).

Results:

Prolonged sitting while watching TV was significantly associated with increased risk of colorectal adenoma (n=4280), and adjusting for physical activity or a potential mediator body mass index did not change the estimates. The ORs (95% CIs) across categories of TV watching (0–6, 7–13, 14–20, and 21+ h per week) were 1.00 (referent), 1.09 (1.01–1.17), 1.16 (1.06–1.27), and 1.10 (0.97–1.25) (OR per 14-h per week increment=1.11; 95% CI: 1.04–1.18; P_trend=0.001). Compared with the least sedentary (0–6 h per week of TV) and most physically active (highest quintile) men, the most sedentary (14+ h per week) and least active (lowest quintile) men had a significant increased risk of adenoma (OR=1.25; 95% CI: 1.05–1.49), particularly for high-risk adenoma.

Conclusions:

Prolonged TV viewing is associated with modest increased risk of colorectal adenoma independent of leisure-time physical activity and minimally mediated by obesity.     

Methionine synthase D919G polymorphism, folate metabolism, and colorectal adenoma risk.

Methionine synthase [5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR)] is involved in folate-mediated one-carbon metabolism, a pathway known to play a role in colorectal carcinogenesis. We investigated whether the MTR D919G polymorphism was associated with risk of colorectal adenoma in a colonoscopy-based study of 513 cases and 609 controls from Minneapolis, MN. Adenoma risk appeared nonsignificantly increased among women with DG or GG genotype [adjusted odds ratio (OR) versus DD, 1.4; 95% confidence interval (CI), 0.9-2.1] but not men (OR, 1.0; 95% CI, 0.7-1.5). An interaction with methionine intake was observed among women, such that low versus high intake was associated with a 2.3-fold increased risk only among those with DG or GG genotype (95% CI, 1.1-4.9; P for interaction = 0.05). Similarly, risk associated with alcohol intake was not elevated among women with the DD genotype; however, consumption of >7 g of alcohol/day versus none was associated with an increased risk among women with DG or GG genotype (adjusted OR, 2.5; 95% CI, 1.4-4.4; P for interaction = 0.03). An interaction between MTR D919G and the thymidylate synthase (TS or TYMS) 3'-untranslated region polymorphism 1494del6 was also observed among women (P for interaction = 0.007). No evidence of interaction with intake of folate, vitamin B(12), or vitamin B(6) or with genotype at MTHFR C677T or the TS enhancer region 28-bp repeat polymorphism was seen. These findings add to what is known about the complexities of genetic variations in one-carbon-metabolizing enzymes in relation to colorectal carcinogenesis.     

Coffee intake and the risk of colorectal adenoma: The colorectal adenoma study in Tokyo

Coffee is a commonly consumed beverage which contains several potential anticarcinogenic and chemopreventive compounds, and has been hypothesized to have protective effects in colorectal neoplasia. However, the limited available data on coffee consumption in relation to colorectal adenoma (CRA), a precursor lesion to most colorectal cancers, remain largely inconsistent. In this study, we evaluated the association of coffee intake with the risk of CRA in a middle‐aged Japanese population. Study subjects were selected from examinees who underwent total colonoscopy as part of a cancer screening program and responded to self‐administered dietary and lifestyle questionnaires. A total of 738 patients with adenoma and 697 controls were included in the study. Coffee intake was assessed with a food frequency questionnaire, and divided into quartiles based on the distribution among controls. Unconditional logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (CI) of CRA, with adjustment for potential confounding factors. High coffee consumption was associated with a reduced risk of CRA, with a multivariate‐adjusted OR for the highest versus lowest quartile of coffee intake of 0.67 (95% CI = 0.48–0.93; p_trend = 0.02). The inverse association of coffee intake was limited to proximal (OR = 0.64; 95%CI = 0.44–0.95; p_trend = 0.04) and distal colon adenoma (OR = 0.62; 95%CI = 0.39–0.99; p_trend = 0.06), and appeared to be more evident with small (OR = 0.68; 95%CI = 0.49–0.96; p_trend = 0.04) and single adenomas (OR = 0.65; 95%CI = 0.44–0.95; p_trend = 0.02). Green tea intake was not found to be associated with CRA risk. This study provides support for the protective effect of coffee drinking on colon adenomas, a precursor of colon cancer.     

Microsomal epoxide hydrolase polymorphisms and risk for advanced colorectal adenoma.

Cigarette smoking is a risk factor for colorectal adenoma, a precursor of colorectal cancer. Microsomal epoxide hydrolase (EPHX1) metabolizes polycyclic aromatic hydrocarbons, carcinogens found in cigarette smoke. Nonsynonymous variants of EPHX1 at Tyr(113)His (exon 3) and His(139)Arg (exon 4) are associated, respectively, with low ((113)His) and high ((139)Arg) predicted activity. Among participants randomized to the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we evaluated risks for advanced adenoma in relation to cigarette use and these two EPHX1 variants. We compared 772 cases with advanced adenoma (adenoma >/=1 cm or containing high-grade dysplasia or villous, including tubulovillous, elements) of the distal colon (left-sided, descending colon and sigmoid or rectum) to 777 gender- and age-matched controls who were screen-negative for left-sided adenoma. Compared to those with homozygous genotypes predicting low EPHX1 activity, advanced adenoma risks tended to be elevated for carriers of (113)TyrTyr [odds ratios (OR), 1.5; 95% confidence intervals (CI), 1.0-2.2] and (139)ArgArg (OR, 1.4; 95% CI, 0.8-2.5) and for subjects who carried a greater number of the alleles ((113)Tyr or (139)Arg) associated with high predicted enzymatic activity (P(trend) = 0.03). The increased risk associated with the increasing number of putative high-activity alleles was most apparent among current and recent (quit <10 years) cigarette smokers (P(trend) = 0.02). In conclusion, EPHX1 variants at codon 113 and 139 associated with high predicted enzymatic activity appear to increase risk for colorectal adenoma, particularly among recent and current smokers.     

Folate metabolism polymorphisms influence risk of colorectal adenoma recurrence.

Folate intake is inversely related to risk of developing colorectal neoplasia. Associations between risk of colorectal neoplasia and polymorphisms in genes coding for enzymes involved in folate metabolism have also been reported, suggesting a relationship between genotype and development of colorectal neoplasia. To further investigate the effects of folate metabolism genotypes on colorectal neoplasia, we genotyped 546 patients participating in a randomized controlled trial of folate supplementation for the prevention of colorectal adenoma recurrence. A significantly reduced risk of recurrence was observed in patients heterozygous for the MTRR A66G polymorphism [relative risk (RR), 0.64; 95% confidence interval (95% CI), 0.46-0.90] or heterozygous for the MTHFR A1298C polymorphism (RR, 0.71; 95% CI, 0.52-0.97). Furthermore, a significant reduction in recurrence risk was seen in MTRR A66G heterozygotes who received folate supplements but not in those who did not receive folate. Patients heterozygous for the MTHFR C677T polymorphism had a nonsignificant risk reduction (RR, 0.92; 95% CI, 0.69-1.23), as did patients with one or two variant alleles for the MTR A2756G polymorphism (RR, 0.82; 95% CI, 0.60-1.12). No influence on recurrence risk was observed for the TSER, TSER 3R G>C, and TS 1494del6 variants. These findings provide additional support for the hypothesis that germ line variants in folate metabolism genes influence the development of colorectal adenomas.     

Plasma enterolignans are associated with lower colorectal adenoma risk.

Lignans are biphenolic compounds that occur in foods of plant origin such as whole grains, seeds, fruits and vegetables, and beverages, such as coffee and tea. Plant lignans are converted by intestinal bacteria into the enterolignans, enterodiol and enterolactone. Enterolignans possess several biological activities, whereby they may influence carcinogenesis. We studied the associations between plasma enterolignans and the risk of colorectal adenomas in a Dutch case-control study. Colorectal adenomas are considered to be precursors of colorectal cancer. Cases (n = 532) with at least one histologically confirmed colorectal adenoma and controls (n = 503) with no history of any type of adenoma were included. Plasma enterodiol and enterolactone concentrations were measured by liquid chromatography with tandem mass spectrometry. Associations were stronger for incident than for prevalent cases. When only incident cases (n = 262) were included, high compared to low plasma concentrations of enterodiol were associated with a reduction in colorectal adenoma risk after adjustment for confounding variables. Enterodiol odds ratios (95% confidence intervals) were 1.00, 0.69 (0.42-1.13), 0.60 (0.37-0.99), and 0.53 (0.32-0.88) with a significant trend (P = 0.01) through the quartiles. Although enterolactone plasma concentrations were 10-fold higher, enterolactone's reduction in risk was not statistically significant (P for trend = 0.09). Use of oral antibiotic therapy could decrease the plasma concentrations of enterolactone. Exclusion of antibiotic users resulted in similar odds ratios for both enterolignans, but the association for enterolactone became somewhat stronger (P = 0.05 versus P = 0.09). We observed a substantial reduction in colorectal adenoma risk among subjects with high plasma concentrations of enterolignans, in particular, enterodiol. These findings could be important in the prevention of colorectal adenomas.     

Insulin resistance and prostate cancer risk

Because high waist-to-hip ratio (WHR) and high serum insulin levels have been reported to be associated with an increased risk of prostate cancer, we assessed the relationship between insulin resistance and prostate cancer risk in Chinese men. We measured fasting serum glucose and insulin levels in 128 case and 306 control subjects and used the homeostasis model assessment to derive indices of insulin sensitivity and resistance. Relative to men in the lowest tertiles, men in the highest tertile of insulin sensitivity had a reduced risk of prostate cancer (odds ratio [OR] = 0.35, 95% confidence interval [CI] = 0.21 to 0.60), but men in the highest tertile of insulin resistance had an increased risk of prostate cancer (OR = 2.78, 95% CI = 1.63 to 4.72). Considering insulin resistance and WHR together, the effect of insulin resistance was apparent in all tertiles of WHR, with men in the highest tertile of insulin resistance and WHR having the highest risk (OR = 8.21, 95% CI = 2.84 to 23.70). The associations between prostate cancer risk and insulin sensitivity or resistance were independent of total caloric intake and serum levels of insulin-like growth factors, sex hormones, and sex hormone-binding globulin. Because of the retrospective design of this study, the role of insulin resistance in prostate cancer needs to be confirmed in prospective studies.     

Meat, meat cooking methods and preservation, and risk for colorectal adenoma

Cooking meat at high temperatures produces heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). Processed meats contain N-nitroso compounds. Meat intake may increase cancer risk as HCAs, PAHs, and N-nitroso compounds are carcinogenic in animal models. We investigated meat, processed meat, HCAs, and the PAH benzo(a)pyrene and the risk of colorectal adenoma in 3,696 left-sided (descending and sigmoid colon and rectum) adenoma cases and 34,817 endoscopy-negative controls. Dietary intake was assessed using a 137-item food frequency questionnaire, with additional questions on meats and meat cooking practices. The questionnaire was linked to a previously developed database to determine exposure to HCAs and PAHs. Intake of red meat, with known doneness/cooking methods, was associated with an increased risk of adenoma in the descending and sigmoid colon [odds ratio (OR), 1.26; 95% confidence interval (95% CI), 1.05-1.50 comparing extreme quintiles of intake] but not rectal adenoma. Well-done red meat was associated with increased risk of colorectal adenoma (OR, 1.21; 95% CI, 1.06-1.37). Increased risks for adenoma of the descending colon and sigmoid colon were observed for the two HCAs: 2-amino-3,8-dimethylimidazo[4,5]quinoxaline and 2-amino-1-methyl-6-phenylimidazo[4,5]pyridine (OR, 1.18; 95% CI, 1.01-1.38 and OR, 1.17, 95% CI, 1.01-1.35, respectively) as well as benzo(a)pyrene (OR, 1.18; 95% CI, 1.02-1.35). Greater intake of bacon and sausage was associated with increased colorectal adenoma risk (OR, 1.14; 95% CI, 1.00-1.30); however, total intake of processed meat was not (OR, 1.04; 95% CI, 0.90-1.19). Our study of screening-detected colorectal adenomas shows that red meat and meat cooked at high temperatures are associated with an increased risk of colorectal adenoma.     

Circulating vitamin D metabolites, polymorphism in vitamin D receptor, and colorectal adenoma risk.

OBJECTIVE: Vitamin D is a potential agent for the prevention of colorectal cancer possibly through mechanisms mediated by the vitamin D receptor (VDR). We investigated the association of circulating vitamin D metabolites and a genetic variant of the VDR gene with advanced colorectal adenoma, a precursor lesion of colorectal cancer. METHODS: Cases with advanced adenoma of the distal large bowel and gender- and ethnicity-matched controls with a negative sigmoidoscopy were randomly selected from participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial. Genotype analysis of the VDR TaqI polymorphism was completed on 763 cases and 774 controls. Serum levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] were measured in a subset of 394 cases and 397 controls. RESULTS: Serum levels of 25(OH)D were inversely associated with advanced adenoma risk in women but not in men. Comparing those in the highest quintile with those in the lowest quintile, the risk for advanced adenoma decreased by 73% in women [odds ratio (OR) = 0.27, 95% confidence interval (95% CI) = 0.11-0.69; P for trend = 0.0002], while the risk did not decrease in men (OR = 1.10, 95% CI = 0.60-2.05; P for trend = 0.85). In women, 25(OH)D levels were significantly higher in current users of hormone replacement therapy (HRT) than in former or never HRT users. Neither serum 1,25(OH)(2)D nor VDR TaqI genotype was associated with advanced adenoma risk. CONCLUSION: Higher serum 25(OH)D levels were associated with decreased adenoma risk. Serum 1,25(OH)(2)D and VDR TaqI genotype were not associated with adenoma risk.     

GSTM1, GSTT1, and GSTP1 polymorphisms and risk of advanced colorectal adenoma.

Cigarette smoking is a risk factor for colon adenoma. The glutathione S-transferase enzymes are involved in the detoxification of carcinogenic compounds including those found in tobacco smoke, and thus, may be important modifiers of individual risk of developing this disease. We examined the prevalence of GSTM1 and GSTT1 gene deletions, and two GSTP1 polymorphisms in 772 cases with advanced colorectal adenomas (>1 cm, villous elements or high-grade dysplasia) of the distal colon (descending or sigmoid colon or rectum) and 777 sigmoidoscopy negative controls enrolled in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Epidemiologic data on smoking was collected by self-administered questionnaire and DNA was extracted from whole blood or buffy coat. For GSTM1 and GSTT1, we used a newly developed TaqMan-based assay capable of discriminating heterozygous (+/-) individuals from those with two active alleles (+/+) and homozygous deletions (-/-). For GSTP1, the I105V and the A114V substitutions were identified using end point 5' nuclease assays (TaqMan). Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were determined using unconditional logistic regression, controlling for age, race, and gender. Advanced adenoma risk was increased in current/former smokers (OR, 1.4; 95% CI, 1.2-1.8). Risks were decreased in subjects with > or =1 inactive GSTM1 alleles (OR, 0.6; 95% CI, 0.4-0.9); and the association was independent of smoking status (P interaction = 0.59). Having > or =1 inactive GSTT1 allele was associated with increased risk among smokers (OR, 1.4; 95% CI, 1.1-1.9; P trend = 0.02) but not among never smokers (OR, 0.9; 95% CI, 0.6-1.3) and a significant interaction between smoking and genotype was observed (P interaction = 0.05). In summary, this is the first study to report associations between colorectal adenomas and GSTM1 wild-type and GSTT1 null allele among smokers. These findings only became apparent using a newly developed assay able to distinguish heterozygous from wild-type individuals. Our data provide evidence that phenotypic differences between these two groups exist.     

The methylenetetrahydrofolate reductase 677C-->T polymorphism and distal colorectal adenoma risk.

A common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, where a cytosine at nucleotide 677 is replaced by a thymine (677C-->T), is associated with enzyme thermolability and a reduction in the conversion of 5,10-methyltetrahydrofolate (5,10-MTHF) into 5-methyltetrahydrofolate. We assessed the association between homozygosity for the MTHFR 677CT genotype (TT) and colorectal adenoma risk in a large sigmoidoscopy-based case-control study of members of a prepaid health plan in Los Angeles. MTHFR genotype was determined for 471 cases and 510 age-, sex-, clinic-, and sigmoidoscopy-date-matched controls. Information on RBC and plasma folate levels were analyzed for 331 cases and 350 controls. When compared with the presence of at least one wild-type allele (CT/CC), the odds ratio (OR) for the TT genotype was 1.19 [95% confidence interval (CI), 0.77-1.76] after adjusting for race and the matching factors. Compared with those in the lowest quartiles of RBC and plasma folate and a wild-type allele, adenoma risk was increased for TT homozygotes in the lowest folate quartiles (genotype: OR, 2.04 and 95% CI, 0.6-7.0; OR, 1.84 and 95% CI, 0.6-7.0 for RBCs and plasma folate, respectively) and decreased in TT homozygotes in the highest quartiles (genotype: OR, 0.82 and 95% CI, 0.32-2.10; OR, 0.65 and 95% CI, 0.22-1.95, respectively). There was also a significant interaction between TT genotype and the increased adenoma risk associated with alcohol. These data are consistent with an interaction between MTHFR genotype and folate availability.     

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.     

Thymidylate synthase polymorphisms, folate and B-vitamin intake, and risk of colorectal adenoma

The effects of polymorphisms in genes coding for key folate metabolism enzymes such as thymidylate synthetase (TS) on colorectal neoplasia risk are likely to be influenced by gene-gene and gene-nutrient interactions. We investigated the combined effects of three polymorphisms in the TS gene region, TSER, TS 3R G>C, and TS 1494del6, dietary intakes of folate and other B vitamins, and genotype for other folate metabolism variants, in a colorectal adenoma (CRA) case-control study. Individuals homozygous for TS 1494del6 del/del were at significantly reduced CRA risk compared to those with either ins/del or ins/ins genotypes (odds ratio 0.52; 95% confidence interval: 0.31-0.85, P=0.009). We also observed evidence of interactions between TS 1494del6 genotype and intake of folate, and vitamins B6 and B12, and MTHFR C677T genotype, with the reduction in risk in del/del homozygotes being largely confined to individuals with high nutrient intakes and MTHFR 677CC genotype (P interaction=0.01, 0.006, 0.03, and 0.07, respectively). TSER genotype, when considered either alone or in combination with TS 3R G>C genotype, did not significantly influence CRA risk. These findings support a role for TS in colorectal carcinogenesis, and provide further evidence that functional polymorphisms in folate metabolism genes act as low-risk alleles for colorectal neoplasia and participate in complex gene-gene and gene-nutrient interactions.     

Associations between S-adenosylmethionine,S-adenosylhomocysteine,and colorectal adenoma risk are modified by sex

Methionine metabolism is an important component of one-carbon metabolism. S-adenosylmethionine (SAM), the methyl donor for nearly all methylation reactions, is irreversibly converted to S-adenosylhomocysteine (SAH), an inhibitor of methyltransferases, some of which are key enzymes for methylation. Changes in DNA methylation are common in colorectal cancers. We evaluated plasma SAM and SAH with colorectal adenoma risk in a matched case-control study conducted among individuals undergoing routine colonoscopy. 216 cases were individually matched to polyp-free controls in a 1:1 ratio on age (± 5 years), sex, race (white/non-white), study site (academic medical center/VA hospital) and date of sample collection (± 60 days). Sex-specific quantiles were evaluated based on the control distribution due to vastly different metabolite levels by sex. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Among males, both higher SAM (OR = 0.38, 95% CI: 0.18-0.77, p for trend = 0.007) and higher SAH (OR = 0.45, 95% CI: 0.22-0.91, p for trend = 0.02) were associated with statistically significantly decreased risks of colorectal adenoma in comparison to lowest plasma SAM or SAH tertile. Conversely, among females, both higher SAM and higher SAH were associated with increased risk of colorectal adenoma, which was statistically significant for SAH (OR = 5.18, 95% CI: 1.09-24.62, p for trend = 0.04). The difference in these associations between men and women was statistically significant (p < 0.05). The ratio of SAM/SAH was not associated with colorectal adenoma risk among males or females. These findings suggest SAM and SAH may be involved in the development of colorectal adenoma and the association may be modified by sex.