Ornithine decarboxylase G316A genotype is prognostic for colorectal adenoma recurrence and predicts efficacy of aspirin chemoprevention.

PURPOSE: The chemopreventive activity of aspirin in colorectal neoplasia may be explained in part by its effect on polyamine metabolism. The ornithine decarboxylase (ODC) G316A polymorphism affects polyamine metabolism through altered expression of ODC. We investigated the influence of ODC G316A on the chemopreventive activity of aspirin in colorectal adenoma (CRA) recurrence. EXPERIMENTAL DESIGN: We genotyped ODC G316A in 546 individuals in the United Kingdom Colorectal Adenoma Prevention trial of aspirin for CRA recurrence prevention and pooled our findings with data from two other randomized intervention trials. RESULTS: The United Kingdom Colorectal Adenoma Prevention participants with homozygous ODC 316AA genotype were at reduced CRA recurrence risk [relative risk (RR), 0.43; 95% confidence interval (95% CI), 0.16-1.15], particularly if also exposed to aspirin (RR, 0.24; 95% CI, 0.03-1.71). In the pooled analysis of 2,207 individuals, those with homozygous ODC 316AA genotype were at significantly reduced CRA recurrence risk (RR, 0.68; 95% CI, 0.47-0.99). Following stratification by genotype and aspirin exposure, individuals with homozygous wild-type or heterozygous genotypes derived modest benefit from aspirin (RR, 0.85; 95% CI, 0.72-1.01), whereas in those with both ODC 316AA genotype and aspirin exposure recurrence risk was halved (RR, 0.52; 95% CI, 0.29-0.91). CONCLUSION: The ODC G316A genotype is prognostic for CRA recurrence and predictive of an enhanced response to aspirin in preventing recurrence. This variant has the potential to be a clinically useful genetic marker to identify individuals likely to derive the greatest benefit from aspirin chemoprevention.     

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.     

Dairy products, polymorphisms in the vitamin D receptor gene and colorectal adenoma recurrence

Vitamin D receptor (VDR) activation inhibits proliferation and angiogenesis in the colorectal epithelium, and inhibits metastasis of colorectal tumors. Polymorphisms in the VDR gene alter receptor cellular levels and functioning, and may confer altered susceptibility to colorectal neoplasia. We aimed to investigate the influence of VDR polymorphisms and dietary factors impacting on vitamin D metabolism on colorectal adenoma (CRA) recurrence. Data on dietary intakes of calcium, vitamin D and dairy products were collected from 853 participants in the United Kingdom Colorectal Adenoma Prevention trial, a randomized trial of aspirin and folate for CRA recurrence prevention. The VDR Cdx2, FokI, BsmI, ApaI and TaqI polymorphisms were genotyped in 546 participants with available DNA, and gene-diet interaction analyses performed in 480. Dairy product intake was inversely related to CRA recurrence risk independent of calcium and vitamin D [relative risk (RR) = 0.64; 95% confidence intervals (CIs): 0.47-0.88, for subjects in the highest compared to lowest intake tertile, p(trend) = 0.005]. Milk accounted for 60% of dairy product intake, and on analysis of milk and nonmilk dairy products separately recurrence risk in individuals in the highest tertile of milk intake was half that of lowest tertile individuals (RR = 0.52; 95% CI: 0.38-0.72, p(trend) = 3.2 x 10(-5)), whereas nonmilk dairy products did not influence recurrence. VDR polymorphism genotypes and haplotypes did not directly alter recurrence risk, but the reduction in risk associated with high dairy product intake was confined to individuals with ApaI aA/AA genotype (p(interaction) = 0.02). These findings indicate dairy products, and in particular milk, have chemopreventive activity against CRA recurrence.     

Genetic variants of UGT1A6 influence risk of colorectal adenoma recurrence.

PURPOSE: The UDP glucuronosyltransferase 1A6 (UGT1A6) and cytochrome P450 2C9 (CYP2C9) enzymes participate in the metabolism of nonsteroidal anti-inflammatory drugs, endogenous substances, and carcinogens. Functional polymorphisms of UGT1A6 (T181A and R184S) and CYP2C9 (R144C and I359L) have been reported to modify the protective effect of aspirin on colorectal adenoma risk. We aimed to further investigate the effect of these genetic variants on the development of colorectal neoplasia. EXPERIMENTAL DESIGN: We examined the relationship between UGT1A6 and CYP2C9 genotype and colorectal adenoma recurrence in 546 patients participating in a randomized placebo-controlled aspirin intervention trial. RESULTS: Although colorectal adenoma recurrence was not significantly influenced by CYP2C9 genotype, carriers of variant UGT1A6 alleles were at significantly reduced risk of colorectal neoplasia recurrence [relative risk (RR), 0.68; 95% confidence interval (95% CI), 0.52-0.89]. This risk reduction was also evident when the analysis was confined to advanced neoplasia recurrence (RR, 0.71; 95% CI, 0.47-1.09). When patients were stratified by genotype and aspirin intervention, those with variant UGT1A6 alleles were at reduced recurrence risk irrespective of whether they received aspirin or placebo (RR, 0.62; 95% CI, 0.42-0.92 and RR, 0.63; 95% CI, 0.44-0.91, respectively). CONCLUSIONS: These findings confirm that UGT1A6 variants influence colorectal carcinogenesis independent of aspirin intake and suggest that they may have clinical value in secondary prevention programs for patients diagnosed with colorectal adenoma.     

Polymorphisms in prostaglandin synthase 2/cyclooxygenase 2 (PTGS2/COX2) and risk of colorectal cancer

Inflammation plays a key role in the development of colorectal cancers. We have investigated the relationship between PTGS2 (COX2) polymorphisms and colorectal cancer risk in a hospital based case-control study. We recruited 292 patients with colorectal cancer and 274 controls from new patients admitted to Bellvitge Hospital, Barcelona, Spain, from 1996 to 1998. Subjects responded to a questionnaire on risk factors. Genotypes of the eight more frequent polymorphisms of PTGS2 were determined. Two polymorphisms are located in the promoter sequence, one in the untranslated region of exon 1, one in exon 3, one in intron 5, two in the untranslated region of exon 10, and one downstream of the last polyadenylation (poly-A) signal. Associations were analysed with logistic regression models assuming a dominant effect for rare variants to increase statistical power. An association was detected between colorectal cancer and a polymorphism in the untranslated region of exon 10 of PTGS2, with an odds ratio (OR) of 2.49, 95% confidence interval (CI) of 1.17-5.32, P=0.01. A nearby polymorphism downstream of the last poly-A signal also showed a nonsignificant increase in risk (OR 2.17, 95% CI 0.99-4.78, P=0.05). Analysis of haplotypes confirmed that individuals with these variants were at increased risk of colorectal cancer (OR compared to the most frequent haplotype: 2.17, 95% CI 0.97-4.84, P=0.06) Interactions between PTGS2 genotype and use of nonsteroidal anti-inflammatory drugs and risk of colorectal cancer were also explored.     

PTGS2 (COX-2) -765G > C promoter variant reduces risk of colorectal adenoma among nonusers of nonsteroidal anti-inflammatory drugs.

Prostaglandin H synthase 2 (PTGS2) or cyclooxygenase-2 (COX-2) has been shown to play a key role in the regulation of inflammation, and its inhibition is associated with a reduced risk of colon cancer. The PTGS2 (COX-2) -765G > C promoter variant is located in a putative SP1 binding site and reduces PTGS2 expression. In a Minnesota-based case-control study of cases with adenomatous (n = 494) or hyperplastic polyps (n = 186) versus polyp-free controls (n = 584), we investigated the role of the PTGS2 -765G > C promoter polymorphism. Multiple logistic regression analysis was used, adjusting for age, body mass index, caloric intake, alcohol, fiber, sex, hormone use, and smoking. For colorectal adenoma, odds ratios (OR) compared with PTGS2 -765GG as reference were GC 1.00 [95% confidence interval (95% CI), 0.74-1.35] and CC 0.53 (95% CI, 0.22-1.28). For hyperplastic polyps, the comparable adjusted odds ratios were GC 0.97 (95% CI, 0.65-1.46) and CC 0.24 (95% CI, 0.05-1.11). Risk associated with the -765G > C variant differed by aspirin or other nonsteroidal anti-inflammatory drug (NSAID) use. Among nonusers of aspirin or other NSAIDs, the CC genotype conferred a significant decrease in risk of adenoma (OR, 0.26; 95% CI, 0.07-0.89). Use of aspirin or other NSAIDs reduced risk of adenoma only among those with the -765GG (wild type) and possibly -765CG genotypes (OR, 0.66; 95% CI, 0.48-0.92 and OR, 0.64; 95% CI, 0.40-1.02, respectively). These data suggest that COX-2 expression or activity may be beneficially suppressed, and risk of colorectal polyps reduced, by aspirin or other NSAIDs in PTGS2 -765GG (wild type) individuals and by the -765 CC variant genotype in nonusers of NSAIDs.     

Primary systemic therapy for operable breast cancer patients: the need for the new generation of trial design

Genetic polymorphisms are responsible for inter-individual variation and diversity and have been recently considered as the main genetic elements involved in the development and progression of cancer. We examined associations between common germline genetic variants in 7 genes involved in folate metabolism, cell proliferation and apoptosis, prostaglandin synthesis, detoxification of compounds and inflammation, and disease-free survival among women diagnosed with invasive breast cancer. DNA from up to 432 women was genotyped for 8 polymorphisms. The genotypes of each polymorphism were tested for association with disease-free survival using univariate and multivariate Cox regression analysis. The model was adjusted for known breast cancer prognostic factors. The rare allele of the IL-10 592C>A polymorphism was significantly associated with reduced disease-free survival (P = 0.018, risk ratio of recurrence (RR) = 1.45, 95% confidence interval (CI) = 1.06–1.98), which was not attenuated after adjusting for age at diagnosis, tumor size, lymph node status, clinical stage, histological grade, estrogen receptor status, progesterone receptor status, and treatment modalities (P = 0.019, RR = 1.48, 95% CI = 1.066–2.044). No association was found between MTHFR 677C>T, TGFB1 29T>C, FASLG 844C>T, FAS 1377G>A, FAS 670A>G, PTGS2 8473T>C and SULT1A1 638G>A polymorphisms and disease-free survival. Our data suggest that the rare allele of IL-10 592C>A may be a potential prognostic marker in breast cancer for disease-free survival.     

Inflammatory cytokine gene polymorphisms, nonsteroidal anti-inflammatory drug use, and risk of adenoma polyp recurrence in the polyp prevention trial.

BACKGROUND: Pro- and anti-inflammatory cytokine genes may be important in the maintenance and progression of colorectal cancer. It is possible that single-nucleotide polymorphisms in inflammatory genes may play a role in chronic colonic inflammation and development of colorectal adenomas. Furthermore, common variants in cytokine genes may modify the anti-inflammatory effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in the prevention of colorectal cancer. METHODS: We examined the association between cytokine gene polymorphisms and risk of recurrent adenomas among 1,723 participants in the Polyp Prevention Trial. We used logistic regression to calculate odds ratios (OR) for the association between genotype, NSAID use, and risk of adenoma recurrence. RESULTS: Cytokine gene polymorphisms were not statistically significantly associated with risk of adenoma recurrence in our study. We observed statistically significant interactions between NSAID use, IL-10 -1082 G>A genotype, and risk of adenoma recurrence (P = 0.01) and multiple adenoma recurrence (P = 0.01). Carriers of the IL-10 -1082 G>A variant allele who were non-NSAID users had a statistically significant decreased risk of multiple adenoma recurrence (OR, 0.43; 95% confidence interval, 0.24-0.77) as well as a nonsignificant 30% decreased risk of any adenoma recurrence. In contrast, NSAID users who were carriers of the IL-10 -1082 G>A variant allele were at an increased risk of any adenoma recurrence (OR, 1.55; 95% confidence interval, 1.00-2.43). CONCLUSION: These findings suggest that individuals who are carriers of the IL-10 -1082 G>A variant allele may not benefit from the chemoprotective effect of NSAIDs on adenoma polyp recurrence.     

Risk modification of colorectal adenoma by CYP7A1 polymorphisms and the role of bile acid metabolism in carcinogenesis

Cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in the conversion of cholesterol to bile acids, is a postulated gene modifier of colorectal cancer risk and target for the therapeutic bile acid, ursodeoxycholic acid (UDCA). We investigated associations between CYP7A1 polymorphisms and fecal bile acids, colorectal adenoma (CRA), and UDCA efficacy for CRA prevention. Seven tagging, single-nucleotide polymorphisms (SNP) in CYP7A1 were measured in 703 (355 UDCA, 348 placebo) participants of a phase III chemoprevention trial, of which 495 had known baseline fecal bile acid concentrations. In the placebo arm, participants with two minor G(rs8192871) alleles (tag for a low activity promoter polymorphism at -204) had lower odds of high secondary bile acids (OR = 0.26, 95% CI: 0.10-0.69), and CRA at 3 years' follow-up (OR = 0.41, 95% CI: 0.19-0.89), than AA carriers. Haplotype construction from the six polymorphic SNPs showed participants with the third most common haplotype (C(rs10957057)C(rs8192879)G(rs8192877)T(rs11786580)A(rs8192871)G(rs13251096)) had higher odds of high primary bile acids (OR = 2.34, 95% CI: 1.12-4.89) and CRA (OR = 1.89, 95% CI: 1.00-3.57) than those with the most common CTACAG haplotype. Furthermore, three SNPs (rs8192877, rs8192871, and rs13251096) each modified UDCA efficacy for CRA prevention, and CCGTAG-haplotype carriers experienced 71% lower odds of CRA recurrence with UDCA treatment, an effect not present for other haplotypes (test for UDCA-haplotype interaction, P = 0.020). Our findings support CYP7A1 polymorphisms as determinants of fecal bile acids and risk factors for CRA. Furthermore, UDCA efficacy for CRA prevention may be modified by genetic variation in CYP7A1, limiting treatment benefit to a subgroup of the population.     

The role of cytokine gene polymorphisms in colorectal cancer and their interaction with aspirin use in the northeast of Scotland.

The reduced risk of colorectal cancer associated with cyclooxygenase enzyme inhibitors, such as aspirin and other nonsteroidal anti-inflammatory drugs, strongly suggests that chronic inflammation is a key mediator in the development of colorectal cancer. This complements recent molecular evidence demonstrating an association between a number of proinflammatory genetic polymorphisms and risk of colorectal cancer. We assessed polymorphisms in the IL-1, IL-10, TNF-A, and TGF-B genes in a population-based case-control study of colorectal cancer cases (n = 264) and frequency-matched controls (n = 408) in the Northeast of Scotland and analyzed their interaction with regular aspirin use. There was no evidence of a relation between any of the individual polymorphisms, or pairs of polymorphisms, and risk of colorectal cancer. There was a significant interaction between the IL-10-592 C/A polymorphism and aspirin use (Pinteraction = 0.03). Carriers of the variant IL-10-592 (A) allele, who produce less of the anti-inflammatory cytokine interleukin-10, had a statistically significant 50% reduced risk of colorectal cancer when taking regular aspirin (odds ratio, 0.5; 95% confidence interval, 0.25-0.97), whereas risk was not reduced in carriers of the A allele who did not use aspirin, or among aspirin users with the CC genotype. It is possible that carriers of the mutant IL-10-592 allele are more likely to derive anti-inflammatory and chemopreventive benefits from aspirin in the presence of a lower production of their own endogenous anti-inflammatory interleukin-10. These results suggest that host genetics may play a role in predicting response to chemopreventive strategies. Confirmation of these findings in other populations is required.     

Statin use and colorectal cancer risk according to molecular subtypes in two large prospective cohort studies

Use of statins is hypothesized to reduce colorectal cancer risk but the evidence remains inconsistent. This may be partly explained by differential associations according to tumor location or molecular subtypes of colorectal cancer. We examined the association between statin use and colorectal cancer risk according to tumor location, KRAS mutation status, microsatellite instability (MSI) status, PTGS2 (COX-2) expression, or CpG island methylator phenotype (CIMP) status in two large prospective cohort studies, the Nurses' Health Study and Health Professionals Follow-up Study. We applied Cox regression to a competing risks analysis. We identified 1,818 colorectal cancers during 1990 to 2006. Compared with nonusers, current statin use was not associated with colorectal cancer [relative risk (RR) = 0.99, 95% CI = 0.86-1.14] or colon cancer (RR = 1.10, 95% CI = 0.94-1.29) but was inversely associated with rectal cancer (RR = 0.59, 95% CI = 0.41-0.84, P(heterogeneity) < 0.001). When we examined the association within strata of KRAS mutation status, we found no association with KRAS-mutated cancers (RR = 1.20, 95% CI = 0.87-1.67) but did observe a possible inverse association among KRAS wild-type cancers (RR = 0.80, 95% CI = 0.60-1.06, P(heterogeneity) = 0.06). The association did not substantially differ by PTGS2 expression, MSI status, or CIMP status. Current statin use was not associated with risk of overall colorectal cancer. The possibility that statin use may be associated with lower risk of rectal cancer or KRAS wild-type colorectal cancer requires further confirmation.     

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.     

Inflammation-related gene polymorphisms and colorectal adenoma.

Chronic inflammation has been reported to be a risk factor for colorectal neoplasia. The propensity to mount an inflammatory response is modified by germ line variation in cytokine and other inflammation-related genes. We hypothesized that a proinflammatory genotype would be positively associated with colorectal adenoma, a precursor of colorectal cancer. We investigated the association of colorectal adenoma with 19 single nucleotide polymorphisms in a range of important proinflammatory (IL1B, IL6, IL8, TNF, and LTA) and anti-inflammatory (IL4, IL10, and IL13) cytokines and other inflammation-related genes (PTGS2 and PPARG) in a case-control study of risk factors for colorectal polyps in which all participants (ages 18-74 years) had undergone colonoscopy or sigmoidoscopy. The study sample comprised 244 cases of colorectal adenoma and 231 polyp-free controls. Compared with being homozygous for the common allele, heterozygosity at the IL1B -31 (C>T) locus was associated with an odds ratio (OR) for colorectal adenoma of 1.8 [95% confidence interval (95% CI), 1.2-2.9]. Homozygous carriers of the IL8 -251-A allele were at 2.7-fold increased risk of adenoma (95% CI, 1.5-4.9) compared with homozygosity for the common T allele, whereas carriage of at least one IL8 -251-A allele conferred a 1.5 increased odds of disease (95% CI, 1.0-2.4). Among non-nonsteroidal anti-inflammatory drug users, there was a statistically significant association between the IL10 -819-T/T genotype and adenoma compared with the common IL10 -819-C/C genotype (OR, 3.9; 95% CI, 1.1-13.6), which was not evident among nonsteroidal anti-inflammatory drug users (OR, 0.7; 95% CI, 0.3-1.5; P(interaction) = 0.01). These exploratory data provide evidence that polymorphic variation in genes that regulate inflammation could alter risk for colorectal adenoma.     

Interleukin-1beta gene in esophageal, gastric and colorectal carcinomas

Interleukin (IL)-1 gene polymorphisms are associated with development of gastric atrophy and with increased risk of gastric carcinoma. A -31C to T base transition in the promoter region of this gene is involved in carcinogenic changes within the stomach, especially in Helicobacter pylori infected individuals. We examined association between IL-1 locus polymorphisms and risk of esophageal, gastric and colorectal carcinomas in Japanese patients with H. pylori infection. IL-1B and IL-1RN polymorphisms were analyzed in 136 controls, 75 patients with esophageal carcinoma, 186 patients with gastric carcinoma, 69 patients with colorectal carcinoma, and 18 patients with ulcerative colitis (UC). For IL-1B-511 and -31 polymorphisms were determined by fluorescence-based polymerase chain reaction single-strand conformation polymorphism analysis. For IL-1 receptor antagonist gene (IL-1RN), penta-allelic variable number of tandem repeats (VNTR) was determined by PCR-standard agarose gel electrophoresis. For gastric carcinoma, IL-1B-511 heterozygotes (OR, 0.48; 95% CI, 0.3-0.9; p=0.0115) and T carriers (OR, 0.52; 95% CI, 0.3-1.0; p=0.0185) had a significantly reduced risk of carcinoma. For colorectal carcinoma, IL-1B-511 heterozygotes (OR, 0.34; 95% CI, 0.2-0.7; p=0.0028) and T carriers (OR, 0.43; 95% CI, 0.2-0.9; p=0.0015) had a significantly low risk of carcinoma. No significant difference was observed in the frequencies of IL-1B-31C/T and IL-1RN genotypes between controls and the esophageal carcinoma patients. Our results shows that IL-1B-511C/T and T carrier state may indicate less risk for gastric and colorectal carcinoma in the Japanese population.     

The influence of UGT1A6 variants and aspirin use in a randomized trial of celecoxib for prevention of colorectal adenoma

Aspirin and celecoxib prevent colorectal adenoma recurrence. Genetic variants in the UGT1A6 enzyme are associated with delayed aspirin metabolism and greater chemopreventive efficacy. We examined the effect of combining aspirin and celecoxib in relation to UGT1A6 T181A and R184S variants among 1,647 patients in the Adenoma Prevention with Celecoxib (APC) trial who were stratified according to the use of low-dose aspirin after removal of adenomas and randomized to placebo, 200-mg twice daily, or 400-mg twice daily celecoxib for 3 years. Patients underwent follow-up colonoscopies at 1 and 3 years to assess on-treatment efficacy. At 5 years, 538 patients underwent a colonoscopy to assess risk of recurrence after treatment was discontinued for at least 1 year. During treatment, the relative risk (RR) of recurrent adenoma was 0.68 [95% confidence interval (CI), 0.59-0.79] for 200-mg twice daily celecoxib and 0.54 (95% CI, 0.46-0.64) for 400-mg twice daily celecoxib compared with placebo. Aspirin use was not independently associated with recurrent adenoma (RR, 0.98, 95% CI, 0.86-1.15). These results did not vary according to UGT1A6 genotype. However, among those with a variant UGT1A6 genotype on aspirin, the RR of adenoma was 1.60 (95% CI, 0.81-3.15) after withdrawal of 200-mg twice daily and 1.98 (95% CI, 1.06-3.70) after withdrawal of 400-mg twice daily celecoxib compared with withdrawal of placebo. In contrast, there was no increased risk associated with discontinuing celecoxib among any other groups. Concurrent use of low-dose aspirin does not influence the efficacy of celecoxib in adenoma prevention. However, discontinuing celecoxib among aspirin-using individuals who initially developed adenoma despite a UGT1A6 variant genotype resulted in rapid reemergence of disease.     

Genetic variants in the UGT1A6 enzyme, aspirin use, and the risk of colorectal adenoma

Genetic variation in the uridine diphosphate glucuronosyltransferase 1A6 (UGT1A6) enzyme is associated with impaired metabolism of aspirin. To determine whether polymorphisms in the UGT1A6 enzyme modulate the protective benefit of regular aspirin use on colorectal adenoma, we conducted a prospective, nested case-control study of 1062 women who provided blood specimens and detailed data on aspirin use before undergoing lower endoscopy. All statistical tests were two sided. Although UGT1A6 genotype was not associated with overall adenoma risk (multivariable odds ratio [OR] = 1.10, 95% confidence interval [CI] = 0.85 to 1.41), functional variant genotypes statistically significantly modified the effect of aspirin on adenoma (P(interaction) = .02). Among the 616 women with variant genotypes, regular use of aspirin (two or more standard tablets per week) was associated with a decreased risk of adenoma (multivariable OR for adenoma = 0.66 [95% CI = 0.45 to 0.95], OR = 0.63 [95% CI = 0.43 to 0.91] for 0.5-7 standard tablets per week and OR = 0.41 [95% CI = 0.24 to 0.71] for more than 7 tablets per week; P(trend) = .001). In contrast, among women with wild-type genotypes, regular aspirin use was not associated with a reduced risk nor did they obtain any additional benefit with higher doses (P(trend) = .50). These results were consistent among women with advanced adenomas (P(interaction) = .003). Thus, functional polymorphisms in the UGT1A6 enzyme statistically significantly modify the effect of aspirin on colorectal neoplasia, and certain subsets of the population, defined by genotype, may obtain differential benefit from aspirin chemoprevention.     

Aspirin may be more effective in preventing colorectal adenomas in patients with higher BMI (United States)

Obesity is a risk factor for colon cancer, possibly due to elevated levels of circulating cytokines derived from adipose tissue. Aspirin, which may affect the levels of these cytokines, has been shown in randomized controlled trials to decrease the risk of colorectal adenomas. We hypothesized that the chemopreventive effect of aspirin might be greater in individuals with higher body mass index (BMI). Data were available from the Aspirin/Folate Polyp Prevention Study, a randomized controlled trial of aspirin and folic acid to prevent recurrent colorectal adenomas. Obesity was defined as BMI ≥ 30 (kg/m²), overweight as BMI of 25–29 (kg/m²) and normal weight as BMI <25 (kg/m²). For the analysis of the effect of aspirin on the recurrence of colorectal adenoma by BMI, we computed risk ratios for aspirin versus placebo within the three BMI strata using a modified Poisson model. Overall the risk reduction of adenomas with a daily dose of 325 mg aspirin was greater among subjects with higher BMI. Among obese subjects the risk ratio (RR) for advanced adenomas compared with placebo was 0.44 (95% CI 0.17–1.10), versus RR = 1.23 (95% CI 0.55–2.77) among those with normal weight. However, 81 mg aspirin daily did not interact with BMI to modify the risk of adenomas in such a fashion. The more pronounced effect of 325 mg aspirin in individuals with higher BMI suggests a possible protective role of anti-inflammatory aspirin against increased adipose-driven cytokines among obese subjects. This work was supported in part by grants from the National Institutes of Health P30 DK34987, R01 CA59005, RR000046.     

Interleukin-4 and interleukin-4 receptor polymorphisms and colorectal cancer risk

Interleukin-4 (IL-4) and interleukin-4 receptor (IL-4R) modulate inflammation and are associated with the colorectal adenoma-carcinoma progression and the metastatic capacity. IL-4 also causes a dose-dependent reduction of proliferation in colorectal cancer cells. The aim of the study was to evaluate whether genetic variants within IL4 and IL4R could affect the individual risk to develop colorectal cancer. We genotyped all the polymorphisms coding for an aminoacidic change in IL4R and we used a haplotype-tagging SNP approach for IL4. We carried out a case-control association study by genotyping, with the 5' nuclease assay, two common SNPs within IL4 (-588C>T, Ex1-168G>A) and five SNPs within IL4R (I75V, C431R, S436L, S503P, Q576R) in 377 cases of colorectal cancer and 326 controls from Spain. No statistically significant association between the SNPs investigated and colorectal cancer risk was found, as main effects. When the sub-analyses were carried out, the homozygotes for IL4 -588C>T or for Ex1-168G>A showed an increased risk for colon cancer only, with the odds ratios of 4 (95% CI 0.97-16.6; P-interaction=0.016 and 4.66 (95% CI 1.16-18.77; P-interaction=0.023), respectively. Moreover, women showed a significant increased risk associated to the IL4 rare alleles and this was clearly greater than that in men (for Ex1-168G>A: OR=1.96; 95% CI=1.11-3.47; P-interaction=0.006). However, when sub-groups are analysed, the findings should be taken with caution for the weakening of the statistical power.     

Abdominal obesity and the risk of colorectal adenoma: a meta-analysis of observational studies

Inconsistent results regarding the association between abdominal obesity and the risk of colorectal adenoma (CRA), the precursor of colorectal cancer (CRC), have been reported. To provide a quantitative assessment of this relationship, we summarized the evidence from observational studies in categorical, linear dose-response meta-analyses. We searched MEDLINE and EMBASE for studies of waist circumference (WC) and/or waist-hip ratio (WHR) and CRA risk published until the end of October 2011. Summary relative risks (SRRs) with 95% confidence intervals (CIs) were summarized using a random-effects model. Between-study heterogeneity was assessed using the Cochran's Q and I statistics. A total of 21 studies (four case-control studies, 12 cross-sectional studies, and five cohort studies) were included in this meta-analysis. Overall, the SRRs of CRA were 1.39 (95% CI: 1.24-1.56) for the highest versus the lowest level of WC and 1.22 (95% CI: 1.10-1.35) for WHR (P-value for heterogeneity 0.013 and 0.458, respectively). In linear dose-response analysis, a 10-cm increase in WC was related to an increased risk of CRA (SRR, 1.19; 95% CI, 1.13-1.26) and a 0.1-unit increment in WHR gave 1.16 (95% CI: 1.06-1.26). Subgroup analyses revealed that the increased risk of CRA in abdominally obese individuals was independent of geographic location, design, sex, and confounders: alcohol use, smoking status, and family history of colorectal cancer. However, BMI may be a confounder for the association between WC and CRA risk. These results suggest that abdominally obese individuals, both men and women, may have an increased risk of CRA.