Plasma lipoxin A4 and resolvin D1 are not associated with reduced adenoma risk in a randomized trial of aspirin to prevent colon adenomas

Inflammation plays a major role in colon carcinogenesis. Endogenously produced specialized proresolving lipid mediators (SPMs) play a central role in inflammation and tissue homeostasis, and have been implicated in carcinogenesis. We studied the associations of plasma levels of two SPMs [lipoxin A4 (LXA4) and resolvin D1(RvD1)] with risk for recurrent adenoma. In this pilot study, we used data and biosamples from an adenoma chemoprevention study investigating the effects of aspirin and/or folic acid on the occurrence of colorectal adenomas. In the parent study, 1121 participants with a recent adenoma were randomized to study agents to be taken until the next surveillance colonoscopy about 3 years later. In this pilot study, LXA4 and RvD1 from samples taken near the end of study treatment were measured in a randomly selected sub-set of 200 participants. Commercially available ELISA kits to assay the analytes were validated using a metabololipidomic LC-MS/MS assay. Poisson regression with a robust error variance was used to calculate risk ratios and 95% confidence intervals. Plasma LXA4 and RvD1 were not associated with the risk of adenoma occurrence. LXA4 at the end of study follow-up was 32% (P = 0.01) proportionately higher in women compared to men. A similar non-significant trend toward higher levels among women was observed for RvD1. Our preliminary findings provided no evidence that plasma LXA4 or RvD1 are associated with reduced risk of colorectal adenoma occurrence, but suggest LXA4 may differ among men and women. Future studies focusing on SPM's local effects and levels in the colon are needed

Folic Acid and Risk of Prostate Cancer: Results From a Randomized Clinical Trial

Data regarding the association between folate status and risk of prostate cancer are sparse and conflicting. We studied prostate cancer occurrence in the Aspirin/Folate Polyp Prevention Study, a placebo-controlled randomized trial of aspirin and folic acid supplementation for the chemoprevention of colorectal adenomas conducted between July 6, 1994, and December 31, 2006. Participants were followed for up to 10.8 (median = 7.0, interquartile range = 6.0–7.8) years and asked periodically to report all illnesses and hospitalizations. Aspirin alone had no statistically significant effect on prostate cancer incidence, but there were marked differences according to folic acid treatment. Among the 643 men who were randomly assigned to placebo or supplementation with folic acid, the estimated probability of being diagnosed with prostate cancer over a 10-year period was 9.7% (95% confidence interval [CI] = 6.5% to 14.5%) in the folic acid group and 3.3% (95% CI = 1.7% to 6.4%) in the placebo group (age-adjusted hazard ratio = 2.63, 95% CI = 1.23 to 5.65, Wald test P = .01). In contrast, baseline dietary folate intake and plasma folate in nonmultivitamin users were inversely associated with risk of prostate cancer, although these associations did not attain statistical significance in adjusted analyses. These findings highlight the potential complex role of folate in prostate cancer and the possibly different effects of folic acid–containing supplements vs natural sources of folate

Sample size requirements to detect the effect of a group of genetic variants in case-control studies

<p>Abstract</p> <p>Background</p> <p>Because common diseases are caused by complex interactions among many genetic variants along with environmental risk factors, very large sample sizes are usually needed to detect such effects in case-control studies. Nevertheless, many genetic variants act in well defined biologic systems or metabolic pathways. Therefore, a reasonable first step may be to detect the effect of a group of genetic variants before assessing specific variants.</p> <p>Methods</p> <p>We present a simple method for determining approximate sample sizes required to detect the average joint effect of a group of genetic variants in a case-control study for multiplicative models.</p> <p>Results</p> <p>For a range of reasonable numbers of genetic variants, the sample size requirements for the test statistic proposed here are generally not larger than those needed for assessing marginal effects of individual variants and actually decline with increasing number of genetic variants in many situations considered in the group.</p> <p>Conclusion</p> <p>When a significant effect of the group of genetic variants is detected, subsequent multiple tests could be conducted to detect which individual genetic variants and their combinations are associated with disease risk. When testing for an effect size in a group of genetic variants, one can use our global test described in this paper, because the sample size required to detect an effect size in the group is comparatively small. Our method could be viewed as a screening tool for assessing groups of genetic variants involved in pathogenesis and etiology of common complex human diseases.</p

Proliferation, apoptosis and their regulatory protein expression in colorectal adenomas and serrated lesions

Background Adenomas and serrated lesions represent heterogeneous sets of early precursors in the colorectum with varying malignant potential. They are often distinguished by their histopathologic differences, but little is known about potential differences in regulation of epithelial proliferation and apoptosis. Methods We conducted a protein expression analysis using tissue microarrays of 625 colorectal adenomas and 142 serrated lesions to determine potential differences in regulation of epithelial proliferation and apoptosis. We quantitated proliferation with Ki-67; apoptosis with activated caspase-3 (CASP3); up- and down-regulators of proliferation with cyclin D1, p16INK2, and p21Cip1; and apoptosis regulators with BAX, BCL2, and survivin. Linear mixed effects models and circos diagrams were used to determine relationships among expression and lesion characteristics. Results Adenomas had a significantly higher CASP-3 labeling index (LI) than serrated lesions, resulting in a lower net growth ratio (Ki-67 LI/activated CASP-3 LI, p-value&lt;0.0001). Cyclin D1 LI, p16 LI and p21 LI were lower in adenomas compared to serrated lesions, while expression of both BCL2 and BAX were higher (p &lt;0.001). Among adenomas, cyclin D1 LI and p16 LI levels increased with greater villous component, and the highest BAX expression was detected in adenomas larger than 2 cm (both p&lt;0.0001). Right-sided adenomas had higher CASP3 LI than left colorectal adenomas (p = 0.008). Significant differences in cyclin D1 LI, p21 LI and survivin LI were also observed across histopathologic subtypes of serrated lesions. Conclusions Our findings demonstrate different patterns of regulatory protein expression in adenomas than serrated lesions, especially involving apoptosis

Serum endotoxins and flagellin and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort

Background: Chronic inflammation and oxidative stress are thought to be involved in colorectal cancer development. These processes may contribute to leakage of bacterial products, such as lipopolysaccharide (LPS) and flagellin, across the gut barrier. The objective of this study, nested within a prospective cohort, was to examine associations between circulating LPS and flagellin serum antibody levels and colorectal cancer risk. Methods: A total of 1,065 incident colorectal cancer cases (colon, n = 667; rectal, n = 398) were matched (1:1) to control subjects. Serum flagellin- and LPS-specific IgA and IgG levels were quantitated by ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (CI), adjusting for multiple relevant confouding factors. Results: Overall, elevated anti-LPS and anti-flagellin biomarker levels were not associated with colorectal cancer risk. After testing potential interactions by various factors relevant for colorectal cancer risk and anti-LPS and anti-flagellin, sex was identified as a statistically significant interaction factor (Pinteraction < 0.05 for all the biomarkers). Analyses stratified by sex showed a statistically significant positive colorectal cancer risk association for men (fully-adjusted OR for highest vs. lowest quartile for total anti-LPS + flagellin, 1.66; 95% CI, 1.10–2.51; Ptrend, 0.049), whereas a borderline statistically significant inverse association was observed for women (fully-adjusted OR, 0.70; 95% CI, 0.47–1.02; Ptrend, 0.18). Conclusion: In this prospective study on European populations, we found bacterial exposure levels to be positively associated to colorectal cancer risk among men, whereas in women, a possible inverse association may exist. Impact: Further studies are warranted to better clarify these preliminary observations