Chapter Three - Chemopreventive Role of Dietary Phytochemicals in Colorectal Cancer

IntroductionHigher intake levels of dietary calcium have been shown to be associated with decreased risk of colorectal cancer (CRC) development in several prospective studies. However, very little information is available on the CRC risk association of circulating calcium concentrations, particularly since elevated serum calcium has been associated in some settings with metabolic dysfunction and diabetes, factors which appear to be related to higher CRC risk.Material and methodsIn order to explore this question, we conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to investigate the association between serum calcium levels and the risk of colorectal cancer (CRC) development. 975 first incident CRC cases were matched to 975 matched controls from within the cohort by sex, age, study centre, length of follow-up and some additional relevant variables. Serum calcium levels were measured using reflection X-ray fluorescence spectrometry on the pre-diagnostically-collected serum samples from cases and matched controls.Conditional logistic regression was used to calculate multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CIs).Results and discussionsHigher levels of serum calcium were associated with reduced risk of CRC (OR Q5vs.Q1=0.69, 95% CI: 0.48–0.99; p trend=0.02). Sub-group analyses by anatomical sub-site suggest that the observed inverse cancer risk association is apparent in the colon (OR Q5vs.Q1=0.61, 95% CI: 0.38–0.98; p trend=0.04) and not in the rectum (OR Q5vs.Q1=0.99, 95% CI: 0.53–1.85; p trend=0.54) where the association appeared to be non-linear. The magnitude of the association in the colon is similar to that observed with dietary calcium at the same anatomical site. Stratified analysis by sex is suggestive of a stronger association for men than women.ConclusionIn conclusion, elevated serum calcium levels are inversely associated with risk of CRC development, with some evidence for heterogeneity by anatomical sub-site and sex. Additional studies are necessary to confirm these findings and to further investigate potential underlying mechanisms for the role of serum calcium in CRC development.

PO-103 Can we eat to prevent colorectal cancer?

Serrated Colorectal Neoplasia: From Sideshow to Center Stage

Many epidemiological studies have studied the associations between adiponectin rs1501299G/T, rs822395A/C, and rs822396A/G polymorphisms and risk of cancer development, while conflicting results have been reported. Therefore, we conducted a meta-analysis to assess the associations. We retrieved the following databases: Medline, Embase, Web of Science, and Wanfang, and the latest update date was 15th of August 2012. Odds ratio (OR) and corresponding 95 % confidence interval (95 % CI) were calculated by using fixed- or random-effect model. Overall, there were 13 case-control studies consisting of 7,902 subjects for adiponectin rs1501299G/T, seven studies consisting of 6,209 subjects for rs822395A/C, and seven studies consisting of 5,791 subjects for rs822396A/G polymorphism in this study. Combined analyses indicated that neither adiponectin rs822395A/C nor rs822396A/G was associated with risk of cancer incidence (OR (95 % CI) 0.91 (0.77-1.77), P z test = 0.26 for CC vs. AA and 0.96 (0.87-1.05) for C carriers vs. A carriers, P z test = 0.33 for rs822395A/C; 0.88 (0.53-1.47) for GG vs. AA, P z test = 0.63 and 0.94 (0.84-1.04) for G carriers vs. A carriers, P z test = 0.24 for rs822396A/G polymorphism). Similarly, combined analysis also indicated that adiponectin rs1501299G/T polymorphism was not associated with risk of cancer development (OR (95 % CI) 0.86 (0.73-1.01) for TT vs. GG, P z test = 0.07 and 1.17 (0.98-1.39), P z test = 0.08). However, when stratified analyses were conducted, the result indicated that T allele was significantly associated with increased cancer risk for Caucasians (OR (95 % CI) 1.28 (1.06-1.64) and P z test = 0.01 for G carriers vs. T carriers) and associated with increased risk of colorectal cancer development while with decreased risk of prostate cancer incidence compared to G allele (OR (95 % CI) 1.34 (1.14-1.57), P z test < 0.01 for G carriers vs. T carriers for colorectal cancer; 0.80 (0.65-0.97), P z test = 0.03 for TG vs. GG for prostate cancer). In summary, this meta-analysis indicated that adiponectin rs1501299G/T, rather than rs822395A/C and rs822396A/G polymorphism, was associated with risk of cancer development, especially for colorectal and prostate cancer.

Does Colon Polyp Surveillance Improve Patient Outcomes?

BackgroundAKT, also called protein kinase B, is a serine-threonine kinase that functions as a mediator of PI3K-Akt-mTOR signaling pathway and plays an important role in an array of cellular processes. Many single nucleotide polymorphisms (SNP) in AKT gene have been observed to be associated with various types of cancers. In the current research the association of a functional SNP rs1130233 in AKT, depicting G to A transition, was studied with AKT activation, DNA damage, an early response B-cell translocation gene 2 (Btg2) expression and risk of colorectal cancer (CRC) development.Patients and methodsA total 197 population-based controls and 200 CRC patients were genotyped for SNP rs1130233. AKT expression, activation and BTG2 expression were determined in GG, AG and AA genotype carriers. DNA damage was determined through comet assay.ResultsThe heterozygous AG genotype (55.67%) was more prevalent in the local population compared to homozygous wild type GG (37.78%) and homozygous AA genotypes (6.55%). Moreover, AG and AA alleles were observed to be significant contributors (P = 0.01, OR = 1.80, CI = 1.18 to 2.74, and P = 0.001, OR = 5.00, CI = 1.90 to 13.18, respectively) in increasing the risk of CRC. The immunoblot analysis revealed that G to A transition decreased the expression and activation of AKT. Moreover, AG and AA genotypes of AKT1 rs1130233 showed a significant increase in DNA damage and Btg2 expression.ConclusionsThe data concludes that G to A substitution is a risk factor for CRC development involving a decrease in AKT expression and activation and increase in DNA damage.

Will Virtual Colonoscopy Replace Optical Colonoscopy for Colorectal Cancer Screening?

Association of TP53 codon 72 and CDH1 genetic polymorphisms with colorectal cancer risk in Bangladeshi population

The global burden of obesity is increasing, as are colorectal cancer (CRC) incidence and mortality. To assess the association between body mass index (BMI) and risks of incident CRC and CRC-related death in the Asian population. This cohort study includes data pooled from 17 prospective cohort studies included in The Asia Cohort Consortium. Cohort enrollment was conducted from January 1, 1984, to December 31, 2002. Median follow-up time was 15.2 years (IQR, 12.1-19.2 years). Data were analyzed from January 15, 2023, through January 15, 2024. Body mass index, calculated as weight in kilograms divided by height in meters squared. The primary outcomes were CRC incidence and CRC-related mortality. The risk of events is reported as adjusted hazard ratios (AHRs) and 95% CIs for incident CRC and death from CRC using the Cox proportional hazards regression model. To assess the risk of incident CRC, 619 981 participants (mean [SD] age, 53.8 [10.1] years; 52.0% female; 11 900 diagnosed incident CRC cases) were included in the study, and to assess CRC-related mortality, 650 195 participants (mean [SD] age, 53.5 [10.2] years; 51.9% female; 4550 identified CRC deaths) were included in the study. A positive association between BMI and risk of CRC was observed among participants with a BMI greater than 25.0 to 27.5 (AHR, 1.09 [95% CI, 1.03-1.16]), greater than 27.5 to 30.0 (AHR, 1.19 [95% CI, 1.11-1.29]), and greater than 30.0 (AHR, 1.32 [95% CI, 1.19-1.46]) compared with those with a BMI greater than 23.0 to 25.0 (P < .001 for trend), and BMI was associated with a greater increase in risk for colon cancer than for rectal cancer. A similar association between BMI and CRC-related death risk was observed among participants with a BMI greater than 27.5 (BMI >27.5-30.0: AHR, 1.18 [95% CI, 1.04-1.34]; BMI >30.0: AHR, 1.38 [95% CI, 1.18-1.62]; P < .001 for trend) and was present among men with a BMI greater than 30.0 (AHR, 1.87 [95% CI, 1.49-2.34]; P < .001 for trend) but not among women (P = .15 for trend) (P = .02 for heterogeneity). In this cohort study that included a pooled analysis of 17 cohort studies comprising participants across Asia, a positive association between BMI and CRC incidence and related mortality was found. The risk was greater among men and participants with colon cancer. These findings may have implications to better understand the burden of obesity on CRC incidence and related deaths in the Asian population.

Circulating levels of insulin-like growth factor binding protein 3 (IGFBP3) are modulated by functional variants of IGFBP3 and therefore may be associated with higher risk of colorectal cancer development. However, few studies have investigated the role of IGFBP3 polymorphisms in colorectal cancer in Chinese individuals. In this study, two common polymorphisms of IGFBP3 were determined by the Taqman genotyping platform in 202 Chinese colorectal cancer cases diagnosed between 2006 and 2008 and 212 cancer-free population controls. Data showed that the genotype distribution of G2133C (rs2864746), but not A-202C (rs2864744), was significantly different between cancer cases and controls. Unconditional logistic regression analyses revealed that participants carrying the G2133C GC heterozygote or CC homozygote had a significant 1.55-fold increased risk of colorectal cancer development in an allele dose-responsive manner. However, there was no evidence of a dose-effect relationship between number of variants and risk for CRC occurrence. Data suggest that the exon 1 G2133C missense variant of IGFBP3 may be a susceptibility factor for colorectal cancer in Chinese subjects. Larger studies are warranted to validate our findings in a Chinese population.

Two major screening models are currently available in the world for colorectal cancer: systematic screening and opportunistic screening. Systematic screening covers all segments of the population in a certain area and requires the participation of specialized institutions and professionals as well as huge financial support. It is a population-based active screening. Opportunistic screening targets those who seek medical treatment and screens for disease of interest during patients’ treatment or examination. Compared with systematic screening, opportunistic screening has the advantages of good compliance and no need for additional examination with slightly increased cost. The key to opportunistic screening for colorectal cancer is to identify the population at high risk for colorectal cancer and determine who need such screening. The criteria for identification of high-risk population for colorectal cancer include mainly family history, personal history, laboratory testing, and age: 遖 hereditary non-polyposis colorectal cancer (HNPCC) family members aged ≥ 10 years; 遘 individuals with first-degree relatives with familial polyposis aged ≥10 years; 遞 individuals with first-degree relatives with colorectal cancer and aged ≥ (the age of the diagnosis of colorectal cancer in the affected relatives minus 10 years ) (i.e. first-degree relatives who are 10 years younger than a colorectal cancer patient are at high risk for the cancer. For example, the first-degree relatives aged 50 years or older of a 60-year-old colorectal cancer patient are high-risk population for colorectal cancer.); 遨 previous history of colorectal cancer or colorectal adenoma; 遯 ulcerative colitis or Crohn’s disease unhealed for more than 10 years; 遶 history of biliary tract disease or cholecystectomy for more than 10 years; 隨 history of lower abdominal radiotherapy for more than 10 years; 遲 history of chronic schistosomiasis in the colon; 邂 history of chronic appendicitis; 遽 unexplained positive fecal occult blood test; 11 unexplained elevated serum CEA level; and 12 age of 50 years and older. Development of screening models for colorectal cancer depends on disease risk stratification of individuals in the population. The risk of colorectal cancer development in individuals in a natural population with no symptoms of colorectal cancer is stratified into four levels: 遖 Level III high risk. Individuals in this subgroup have the highest risk and about 5% of colorectal cancer cases occur in this population, who should undergo screening every 3 months to 1 year. 遘 Level II high risk. About 15-20% of colorectal cancer cases occur in this population, who should undergo screening every 1 to 5 years. 遞 Level I high risk. About 70% to 80% of colorectal cancer cases occur in this population, who should undergo screening at a frequency of 5 to 10 years. Stratifying the population at high risk for colorectal

Objective MicroRNAs are small endogenous, non-coding, single-stranded posttranscriptional RNA molecules. The discovery of microRNAs has made new contributions to cancer diagnosis and treatment. These microRNAs reported as a responsible for colorectal cancer development with several epigenetic changes. In this study, it was aimed to evaluate the relationship between the polymorphism of miR-196a-2 polymorphism rs11614913 and colorectal cancer in Turkish population. Methods Two hundred colorectal cancer patient (124 colon cancer and 76 rectal cancer) and 240 health control individuals were included in our study, which was planned as a hospital based retrospective cohort study. MiR-196a2 polymorphism in peripheral blood samples has been determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) method. Significance of the results has been evaluated by using SPSS (20.0 SPSS Inc., Chicago, IL, USA.) statistical program. Results miR-196a2 C / C + C / T genotypes was found to be associated with the risk of colorectal cancer development (p: 0.001; OR: 2.04, 95% CI: 1.293-3.236). The subgroup analysis, showed that the C / C + C / T genotype increased the risk of colon cancer development 2.11 times (p: 0.016; 95% CI: 1.136-3.918) and rectal cancer 2.86 times (p: 0.011; 95% CI:1.242-6.592). The relationship between any clinicopathological features of colorectal cancer and the frequency of the C / C + C / T genotype of miR196a2 was not statistically significant (p&gt; 0.05). Conclusion This study supports that miR-196a2's C / C + C / T genotypes is related with increased colorectal cancer development risk.

&lt;div&gt;Abstract&lt;p&gt;Nongenetic predisposition to colorectal cancer continues to be difficult to measure precisely, hampering efforts in targeted prevention and screening. Epigenetic changes in the normal mucosa of patients with colorectal cancer can serve as a tool in predicting colorectal cancer outcomes. We identified epigenetic changes affecting the normal mucosa of patients with colorectal cancer. DNA methylation profiling on normal colon mucosa from 77 patients with colorectal cancer and 68 controls identified a distinct subgroup of normally-appearing mucosa with markedly disrupted DNA methylation at a large number of CpGs, termed as “Outlier Methylation Phenotype” (OMP) and are present in 15 of 77 patients with cancer versus 0 of 68 controls (&lt;i&gt;P&lt;/i&gt; &lt; 0.001). Similar findings were also seen in publicly available datasets. Comparison of normal colon mucosa transcription profiles of patients with OMP cancer with those of patients with non-OMP cancer indicates genes whose promoters are hypermethylated in the OMP patients are also transcriptionally downregulated, and that many of the genes most affected are involved in interactions between epithelial cells, the mucus layer, and the microbiome. Analysis of 16S rRNA profiles suggests that normal colon mucosa of OMPs are enriched in bacterial genera associated with colorectal cancer risk, advanced tumor stage, chronic intestinal inflammation, malignant transformation, nosocomial infections, and KRAS mutations. In conclusion, our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Prospective studies are needed to determine whether OMP could serve as a biomarker for an elevated epigenetic risk for colorectal cancer development.&lt;/p&gt;Prevention Relevance:&lt;p&gt;Our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Identification of OMPs in healthy controls and patients with colorectal cancer will lead to prevention and better prognosis, respectively.&lt;/p&gt;&lt;/div&gt;

&lt;div&gt;Abstract&lt;p&gt;Nongenetic predisposition to colorectal cancer continues to be difficult to measure precisely, hampering efforts in targeted prevention and screening. Epigenetic changes in the normal mucosa of patients with colorectal cancer can serve as a tool in predicting colorectal cancer outcomes. We identified epigenetic changes affecting the normal mucosa of patients with colorectal cancer. DNA methylation profiling on normal colon mucosa from 77 patients with colorectal cancer and 68 controls identified a distinct subgroup of normally-appearing mucosa with markedly disrupted DNA methylation at a large number of CpGs, termed as “Outlier Methylation Phenotype” (OMP) and are present in 15 of 77 patients with cancer versus 0 of 68 controls (&lt;i&gt;P&lt;/i&gt; &lt; 0.001). Similar findings were also seen in publicly available datasets. Comparison of normal colon mucosa transcription profiles of patients with OMP cancer with those of patients with non-OMP cancer indicates genes whose promoters are hypermethylated in the OMP patients are also transcriptionally downregulated, and that many of the genes most affected are involved in interactions between epithelial cells, the mucus layer, and the microbiome. Analysis of 16S rRNA profiles suggests that normal colon mucosa of OMPs are enriched in bacterial genera associated with colorectal cancer risk, advanced tumor stage, chronic intestinal inflammation, malignant transformation, nosocomial infections, and KRAS mutations. In conclusion, our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Prospective studies are needed to determine whether OMP could serve as a biomarker for an elevated epigenetic risk for colorectal cancer development.&lt;/p&gt;Prevention Relevance:&lt;p&gt;Our study identifies an epigenetically distinct OMP group in the normal mucosa of patients with colorectal cancer that is characterized by a disrupted methylome, altered gene expression, and microbial dysbiosis. Identification of OMPs in healthy controls and patients with colorectal cancer will lead to prevention and better prognosis, respectively.&lt;/p&gt;&lt;/div&gt;

The development of colorectal cancer (CRC) is arguably the most feared complication of ulcerative colitis. Clinical variables correlated with the development of CRC in patients with ulcerative colitis include age...