Meat consumption, ornithine decarboxylase gene polymorphism, and outcomes after colorectal cancer diagnosis.
ABSTRACT: BACKGROUND:Dietary arginine and meat consumption are implicated in colorectal cancer (CRC) progression via polyamine-dependent processes. Polymorphism in the polyamine-regulatory gene, ornithine decarboxylase 1 (Odc1, rs2302615) is prognostic for CRC-specific mortality. Here, we examined joint effects of meat consumption and Odc1 polymorphism on CRC-specific mortality. MATERIALS AND METHODS:The analytic cohort was comprised of 329 incident stage I-III CRC cases diagnosed 1994-1996 with follow- up through March 2008. Odc1 genotyping was conducted using primers that amplify a 172-bp fragment containing the polymorphic base at +316. Dietary questionnaires were administered at cohort entry. Multivariate Cox proportional hazards regression analysis for CRC-specific mortality was stratified by tumor, node, metastasis (TNM) stage, and adjusted for clinically relevant variables, plus meat consumption (as a continuous variable, i.e., the number of medium-sized servings/week), Odc1 genotype, and a term representing the meat consumption and Odc1 genotype interaction. The primary outcome was the interaction of Odc1 and meat intake on CRC-specific mortality, as assessed by departures from multiplicative joint effects. RESULTS:Odc1 genotype distribution was 51% GG, 49% GA/AA. In the multivariate model, there was a significant interaction between meat consumption and Odc1 genotype, P-int = 0.01. Among Odc1 GA/AA CRC cases in meat consumption Quartiles 1-3, increased mortality risk was observed when compared to GG cases (adjusted hazards ratio (HR) = 7.06 [95% CI 2.34-21.28]) - a difference not found among cases in the highest dietary meat consumption Quartile 4. CONCLUSIONS:Effects of meat consumption on CRC-specific mortality risk differ based on genetic polymorphism at Odc1. These results provide further evidence that polyamine metabolism and its modulation by dietary factors such as meat may have relevance to CRC outcomes.
Project description:Activity of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is required for normal growth and is elevated in many cancers, including colorectal cancer. We examined associations of the +316 ODC1 single nucleotide polymorphism (SNP) with colorectal cancer-specific survival among colorectal cancer cases, and then investigated its functional significance in colon cancer cells.The study included 400 incident stage I-III colorectal cancer cases from the population-based University of California Irvine Gene-Environment Study of Familial Colorectal Cancer (diagnosed from 1994 to 1996 with follow-up through March 2008). The primary outcome was colorectal cancer-specific survival dependent on ODC1 (rs2302615) genotype (GG versus GA/AA). In human colon cancer cell lines, ODC1 allele-specific binding of E-box transcription factors was determined via Western blotting and chromatin immunoprecipitation assays. ODC1 allele-specific promoter activity was determined using promoter constructs in combination with vectors expressing either the transcriptional activator c-MYC or the repressor MAD1.Genotype-specific survival differences were observed among colorectal cancer cases: compared with cases with the ODC1 GG genotype (hazards ratio, 1; reference) the adjusted colorectal cancer-specific survival hazards ratio was 2.02 (95% confidence interval, 1.17-3.50) for ODC1 GA/AA cases (P = 0.012). In colon cancer cells, the ODC1 SNP, flanked by two E-boxes, predicts ODC1 promoter activity. The E-box activator c-MYC and repressors MAD1 and MAD4 preferentially bind to ODC1 minor A-alleles, compared with major G-alleles, in cultured cells.These results have implications for conditional regulation of polyamine homeostasis and suggest a model in which the ODC1 SNP may be protective for colon adenoma recurrence and detrimental for survival after colon cancer diagnosis.
Project description:The ornithine decarboxylase-1 (ODC1) polymorphism at position +316 affects binding by transcriptional activators and repressors and modulates the risk of metachronous colorectal adenomas, particularly in association with aspirin use. We investigated the effects of ODC1 after treatment with difluoromethylornithine (eflornithine)/sulindac or placebo. Two hundred twenty-eight colorectal adenoma patients in a randomized phase III trial were genotyped for ODC1. We used Wilcoxon rank sums tests on non-normally distributed continuous variables across two genotype groups, ?(2) or Fisher exact test to assess the association between baseline categorical variables and genotype group, and log binomial regression for the primary (adenoma recurrence) and secondary outcomes (tissue polyamine response, cardiovascular toxicity, gastrointestinal toxicity, and ototoxicity). All statistical tests were two-sided. In binomial regression models with variables age, sex, race, aspirin use, treatment, and ODC1 genotype, treatment was the only statistically significant factor associated with differences in adenoma recurrence or tissue polyamine response. A statistically significant interaction was detected between ODC1 genotype and treatment with respect to adenoma recurrence (placebo group: GG, 50%, AA/GA: 34%; treatment group: GG, 11%, AA/GA, 21%; P(interaction) = .038). Excess ototoxicity was observed among ODC1 AA patients receiving treatment, but the interaction of genotype and treatment on ototoxicity was not statistically significant (P = .45).
Project description:Improvements in colorectal cancer (CRC) detection and treatment have led to greater numbers of CRC survivors, for whom there is limited evidence on which to provide dietary guidelines to improve survival outcomes. Higher intake of red and processed meat and lower intake of fibre are associated with greater risk of developing CRC, but there is limited evidence regarding associations with survival after CRC diagnosis. Among 3789 CRC cases in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, pre-diagnostic consumption of red meat, processed meat, poultry and dietary fibre was examined in relation to CRC-specific mortality (n 1008) and all-cause mortality (n 1262) using multivariable Cox regression models, adjusted for CRC risk factors. Pre-diagnostic red meat, processed meat or fibre intakes (defined as quartiles and continuous grams per day) were not associated with CRC-specific or all-cause mortality among CRC survivors; however, a marginal trend across quartiles of processed meat in relation to CRC mortality was detected (P 0·053). Pre-diagnostic poultry intake was inversely associated with all-cause mortality among women (hazard ratio (HR)/20 g/d 0·92; 95 % CI 0·84, 1·00), but not among men (HR 1·00; 95 % CI 0·91, 1·09) (P for heterogeneity=0·10). Pre-diagnostic intake of red meat or fibre is not associated with CRC survival in the EPIC cohort. There is suggestive evidence of an association between poultry intake and all-cause mortality among female CRC survivors and between processed meat intake and CRC-specific mortality; however, further research using post-diagnostic dietary data is required to confirm this relationship.
Project description:BACKGROUND:It is postulated that both individual genotype and environmental factors such as diet may modify the risk of developing colorectal cancer (CRC). The influences of GST gene polymorphism and red meat intake on CRC occurrence in the Polish population were analyzed in this study. METHODS:Genotyping was performed with the qPCR method. RESULTS:A high frequency of meat consumption was associated with an over 2-fold increase in the risk of colorectal cancer odds ratio (OR) adjusted for sex and age = 2.4, 95% confidence interval (CI); 1.3-4.4). However, after analyzing the genetic profiles, in the absence of polymorphisms of all three analyzed genes, there was no association between a high frequency of meat consumption and the occurrence of CRC. In the case of GSTM1 gene polymorphism, the high frequency of meat consumption increased the risk of CRC by almost more than 4 times (OR adjusted for sex and age = 3.8, 95% CI: 1.6-9.1). For GSTP1 gene polymorphism, a 3-fold increase in CRC risk was observed with a high frequency of meat consumption (OR adjusted for sex and age = 3.4, 95% CI: 1.4-8.1). In the case of GSTT1 gene polymorphism, the increase in risk of CRC was not statistically significant (OR adjusted for sex and age = 1.9, 95% CI: 0.4-8.5). CONCLUSIONS:The frequency of red meat intake in non-smokers increases the risk of colon cancer in the case of GST gene polymorphisms.
Project description:Ornithine decarboxylase (ODC1), a critical regulatory enzyme in polyamine biosynthesis, is a direct transcriptional target of MYCN, amplification of which is a powerful marker of aggressive neuroblastoma. A single nucleotide polymorphism (SNP), G316A, within the first intron of <i>ODC1</i>, results in genotypes wildtype GG, and variants AG/AA. CRISPR-cas9 technology was used to investigate the effects of AG clones from wildtype <i>MYCN</i>-amplified SK-N-BE(2)-C cells and the effect of the SNP on MYCN binding, and promoter activity was investigated using EMSA and luciferase assays. AG clones exhibited decreased <i>ODC1</i> expression, growth rates, and histone acetylation and increased sensitivity to ODC1 inhibition. MYCN was a stronger transcriptional regulator of the <i>ODC1</i> promoter containing the G allele, and preferentially bound the G allele over the A. Two neuroblastoma cohorts were used to investigate the clinical impact of the SNP. In the study cohort, the minor AA genotype was associated with improved survival, while poor prognosis was associated with the GG genotype and AG/GG genotypes in <i>MYCN</i>-amplified and non-amplified patients, respectively. These effects were lost in the GWAS cohort. We have demonstrated that the <i>ODC1</i> G316A polymorphism has functional significance in neuroblastoma and is subject to allele-specific regulation by the MYCN oncoprotein.
Project description:The polyamine-inhibitory regimen difluoromethylornithine (DFMO)+sulindac has marked efficacy in preventing metachronous colorectal adenomas. Polyamines are synthesised endogenously and obtained from dietary sources. Here we investigate dietary polyamine intake and outcomes in the DFMO+sulindac colorectal adenoma prevention trial.Dietary polyamine data were available for 188 of 267 patients completing the study. Total dietary polyamine content was derived by the sum of dietary putrescine, spermine and spermidine values and categorised into two groups: highest (>75-100%) vs the lower three quartiles (0-25, 25-50 and 50-75%). Baseline tissue polyamine concentration and ODC1 genotype were determined. Logistic regression models were used for risk estimation.A significant interaction was detected between dietary polyamine group and treatment with regard to adenoma recurrence (P=0.012). Significant metachronous adenoma risk reduction was observed after DFMO+sulindac treatment in dietary polyamine quartiles 1-3 (risk ratio (RR) 0.19; 95% confidence interval (CI) 0.08-0.42; P<0.0001) but not in quartile 4 (RR 1.51; 95% CI 0.53-4.29; P=0.44). However, a lower number of events in the placebo group within dietary quartile 4 confound the aforementioned risk estimates.These preliminary findings reveal complex relationships between diet and therapeutic prevention, and they support further clinical trial-based investigations where the dietary intervention itself is controlled.
Project description:As insulin resistance (IR) is an established risk factor for colorectal cancer (CRC), we explored the association between each of the IR-related gene polymorphisms of adiponectin (ADIPOQ) rs2241766, uncoupling protein 2 (UCP2) rs659366, and fatty acid-binding protein (FABP2) rs1799883 and CRC risk. Genotyping of blood samples and collection of lifestyle and dietary habits were performed for 400 case-control pairs. Unconditional logistic regression (ULR) was applied to assess the effects of the three single nucleotide polymorphisms (SNP), environmental factors. Both ULR and generalized multifactor dimensionality reduction (GMDR) were used to test the gene-gene and gene-environment interactions on CRC risk. Subjects carrying the ADIPOQ rs2241766 TG+GG genotype had a higher CRC risk than those carrying the TT genotype (OR?=?1.429, 95% CI 1.069-1.909). The additive and multiplicative interactions between ADIPOQ rs2241766 and FABP2 rs1799883 on CRC were found by ULR (RERI?=?0.764, 95%CI 0.218?1.311, AP?=?0.514, 95%CI 0.165?0.864, S?=?-1.745, 95%CI is unachievable, and Pmulti?=?0.017, respectively). Furthermore, the high order gene-gene interaction of the three SNPs were found by GMDR (P?=?0.0107). A significant dosage effect with an increasing number of risk genotypes was observed as the risk of CRC increased (Ptrend?=?0.037). In GMDR, the gene-environment interaction among the three SNPs and red meat consumption on CRC risk was significant (P?=?0.0107). Compared with subjects with low red meat consumption and null risk genotypes, those with high-red meat consumption and three risk genotypes had 3.439-fold CRC risk (95% CI 1.410-8.385). In conclusion, the results showed that the ADIPOQ rs2241766 TG+GG genotype increased CRC risk. Given the complexity of the carcinogen for CRC, ADIPOQ rs2241766, UCP2 rs659366, FABP2 rs1799883 and red meat consumption potentially worked together in affecting CRC risk.
Project description:A low-meat diet and regular use of nonsteroidal anti-inflammatory drugs (NSAID) have been associated with decreased mortality among colorectal cancer (CRC) patients. Here, we investigated the association between prediagnosis usual meat consumption and CRC-specific mortality, and whether meat consumption modifies the previously noted association between NSAID use and CRC-specific mortality among women in the California Teachers Study cohort. Women joining the California Teachers Study in 1995-1996 without prior CRC diagnosis, diagnosed with incident CRC during follow-up through December 2007, were eligible for inclusion. Meat intake (frequency and serving size) and NSAID use (aspirin or ibuprofen use) were ascertained via self-administered questionnaires before diagnosis. Vital status and cause of death were determined by linkage with mortality files. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios for death and 95% confidence intervals. Prediagnosis meat consumption was not associated with CRC-specific mortality among 704 CRC patients (and 201 CRC-specific deaths), comparing patients in the lowest consumption tertile (0-5.4 medium-sized servings/wk) to those in the higher consumption tertiles. Regular NSAID use (1-3 times/wk, 4-6 times/wk, daily) versus none was associated with decreased CRC-specific mortality among patients in the lowest meat consumption tertile (hazard ratio, 0.22; 95% CI, 0.06-0.82), but not among patients in the higher meat intake tertiles. The previously observed mortality risk reduction among female CRC patients associated with regular NSAID use was restricted to patients who reported low meat intake before diagnosis. These findings have implications for CRC survivorship and tertiary CRC prevention.
Project description:Meat intake has been linked to increased risk of colorectal cancer (CRC) and mortality. However, diet composition may affect the risks. We aimed to estimate associations between red and processed meat and poultry intake and risk of CRC and all-cause mortality and if they are modified by dietary quality using Cox regression analyses. Baseline dietary data were obtained from three survey rounds of the Danish National Survey on Diet and Physical Activity. Data on CRC and all-cause mortality were extracted from national registers. The cohort was followed from date of survey interview-or for CRC, from age 50 years, whichever came last, until 31 December 2017. Meat intake was analysed categorically and continuously, and stratified by dietary quality for 15-75-year-old Danes at baseline, n 6282 for CRC and n 9848 for mortality analyses. We found no significant association between red and processed meat intake and CRC risk. For poultry, increased CRC risk for high versus low intake (HR 1.62; 95%CI 1.13-2.31) was found, but not when examining risk change per 100 g increased intake. We showed no association between meat intake and all-cause mortality. The association between meat intake and CRC or mortality risk was not modified by dietary quality.
Project description:ApoE single nucleotide polymorphisms (SNPs) Cys112Arg (Epsilon-4), and Arg158Cys (Epsilon-2) have been implicated in cardiovascular and Alzheimer's disease, but their role in colorectal cancer (CRC) has not been extensively studied. We investigated whether ApoE polymorphisms alone or in combination with dietary factors selectively contribute to mismatch-repair (MMR) proficient (microsatellite stable/low or MSS/L) vs deficient (microsatellite unstable or MSI-H) CRCs. We carried out a case-control study with 906 CRC cases and 911 unaffected controls to examine the associations between ApoE polymorphisms and dietary factors and assessed their contribution to MSS/L and MSI-H CRCs. We used unconditional logistic regression to evaluate the associations between ApoE SNPs, tumour MSI status, and dietary factors after adjusting for age and sex. All statistical tests were two-sided. No significant differences in ApoE genotype frequencies were observed between CRC cases and unaffected controls. We observed that increased dietary intake of total fat, saturated fat, cholesterol, and red meat was significantly associated with CRC. Among non-ApoE4 carriers, 2-4 and >4 red meat servings/week were associated with developing MSS/L CRC (OR=1.51, 95% CI 1.10-2.07 and OR=1.80, 95% CI 1.30-2.48, respectively), whereas among ApoE4 allele carriers, four or more red meat servings/week were associated with MSI-H CRC (OR=4.62, 95% CI 1.20-17.77) when compared with the controls. ApoE isoforms modulate the risk of MSI-H and MSS/L CRCs among high red meat consumers.