Increased Risk Of Colorectal Cancer Research Articles

Colorectal cancer: risk factors and potential of dietary probiotics in its prevention

Cancer is the leading cause of human death worldwide. In spite of medical advancements, cancer cases are rising globally where Colorectal Cancer (CRC) frequency is third in position in males and second in females. Colorectal cancer (CRC) is a disease where abnormal growth of cells occurs in the colon and rectal area of the alimentary canal. Factors like food habits, smoking, alcohol consumption, obesity, gut dysbiosis, etc. increase CRC risk. The CRC patients suffer not only from painful surgical treatments but also bear the side effects of palliative radiotherapy, chemotherapy, and therapeutic drugs used for the same. Dietary probiotics have great potential in the prevention and management of CRC due to their anticancer properties. The present review discusses the various risk factors of colorectal cancer and important role of probiotic supplements to prevent it. It highlights some of the proposed mechanisms of probiotics for their protective role against CRC. The prevention through modifiable risk factors and probiotic dietary supplements can save the patients from the trauma of the disease. Probiotics regulate gut dysbiosis and prevent CRC through different mechanisms, so more research work and clinical trials in humans with respect to it are expected in the future.

Gut microbiota composition in colorectal cancer patients is genetically regulated

The risk of colorectal cancer (CRC) depends on environmental and genetic factors. Among environmental factors, an imbalance in the gut microbiota can increase CRC risk. Also, microbiota is influenced by host genetics. However, it is not known if germline variants influence CRC development by modulating microbiota composition. We investigated germline variants associated with the abundance of bacterial populations in the normal (non-involved) colorectal mucosa of 93 CRC patients and evaluated their possible role in disease. Using a multivariable linear regression, we assessed the association between germline variants identified by genome wide genotyping and bacteria abundances determined by 16S rRNA gene sequencing. We identified 37 germline variants associated with the abundance of the genera Bacteroides, Ruminococcus, Akkermansia, Faecalibacterium and Gemmiger and with alpha diversity. These variants are correlated with the expression of 58 genes involved in inflammatory responses, cell adhesion, apoptosis and barrier integrity. Genes and bacteria appear to be involved in the same processes. In fact, expression of the pro-inflammatory genes GAL, GSDMD and LY6H was correlated with the abundance of Bacteroides, which has pro-inflammatory properties; abundance of the anti-inflammatory genus Faecalibacterium correlated with expression of KAZN, with barrier-enhancing functions. Both the microbiota composition and local inflammation are regulated, at least partially, by the same germline variants. These variants may regulate the microenvironment in which bacteria grow and predispose to the development of cancer. Identification of these variants is the first step to identifying higher-risk individuals and proposing tailored preventive treatments that increase beneficial bacterial populations.

The Associations of Selenoprotein Genetic Variants with the Risks of Colorectal Adenoma and Colorectal Cancer: Case-Control Studies in Irish and Czech Populations.

Background: Selenium manifests its biological effects through its incorporation into selenoproteins, which play several roles in countering oxidative and inflammatory responses implicated in colorectal carcinogenesis. Selenoprotein genetic variants may contribute to colorectal cancer (CRC) development, as we previously observed for SNP variants in a large European prospective study and a Czech case–control cohort. Methods: We tested if significantly associated selenoprotein gene SNPs from these studies were also associated with CRC risk in case–control studies from Ireland (colorectal neoplasia, i.e., cancer and adenoma cases: 450, controls: 461) and the Czech Republic (CRC cases: 718, controls: 646). Genotyping of 23 SNPs (20 in the Irish and 13 in the Czechs) was performed by competitive specific allele-specific PCR (KASPar). Multivariable adjusted logistic regression was used to assess the associations with CRC development. Results: We found significant associations with an increased CRC risk for rs5859 (SELENOF) and rs2972994 (SELENOP) in the Irish cohort but only with rs4802034 (SELENOV) in the Czechs. Significant associations were observed for rs5859 (SELENOF), rs4659382 (SELENON), rs2972994 (SELENOP), rs34713741 (SELENOS), and the related Se metabolism gene variant rs2275129 (SEPHS1) with advanced colorectal neoplasia development. However, none of these findings retained significance after multiple testing corrections. Conclusions: Several SNPs previously associated with CRC risk were also associated with CRC or colorectal neoplasia development in either the Irish or Czech cohorts. Selenoprotein gene variation may modify CRC risk across diverse European populations, although the specific variants may differ.

Recent Advances in the Treatment of Colorectal Cancer: A Review.

Colorectal cancer (CRC) is the third most common cancer worldwide, and surgical treatment remains the first-line treatment to provide a cure. In addition to the aging population, obesity, low physical activity, and smoking habits increase CRC risk. Despite advances in surgical techniques, chemotherapy, and radiotherapy, colorectal cancer remains the second leading cause of cancer-related deaths worldwide. For early-stage CRC, endoscopic treatment, including endoscopic mucosal resection and endoscopic submucosal dissection, has been performed. However, lymph node dissection is an integral part of surgical treatment for advanced-stage cancer because of the high incidence of lymph node metastasis. Conventional open surgery has evolved into laparoscopic and robotic surgery. Although prospective studies have confirmed the safety and feasibility of laparoscopic surgery for CRC, relevant treatment models of transverse colon cancer and rectal cancer still need to be further explored and validated. Furthermore, multidisciplinary treatment is needed to cure CRC completely. This review aimed to provide an update on recent advances in the surgical treatment of CRC.

Alcohol consumption, polygenic risk score, and early- and late-onset colorectal cancer risk.

SummaryBackgroundEvidence is lacking on the impact of alcohol consumption on colorectal cancer (CRC) risk (overall and by age at diagnosis) by polygenic risk score (PRS) levels, and it is unclear how the magnitude of CRC risk associated with alcohol consumption compares to the magnitude of genetically determined risk.MethodsMultiple logistic regression was used to assess the association between alcohol consumption and colorectal cancer (CRC) across PRS levels based on 140 CRC-related loci among 5104 CRC cases and 4131 controls from a large population-based case-control study. We compared the effects for alcohol consumption and PRS on CRC risk using the “Genetic Risk Equivalent (GRE)” for effective risk communication. Specific analyses were conducted for early-onset CRC (EOCRC, <55 years) and late-onset CRC (LOCRC, ≥55 years).FindingsHigh alcohol consumption, and to a lower extent, also alcohol abstinence were associated with increased CRC risk. Compared to low alcohol consumption (0·1-<25 g/d), lifetime average alcohol consumption ≥25 g/d was more strongly associated with EOCRC [odds ratio (OR) 1·8, 95% confidence interval (CI) 1·2–2·8] than with LOCRC risk (OR 1·3, 95% CI 1·1–1·4) (P-value for interaction with age =0·011). Interactions between alcohol consumption and PRS did not reach statistical significance for either EOCRC or LOCRC risk. The estimated impact of high lifetime alcohol consumption on EOCRC was equivalent to the effect of having 47 percentiles higher PRS (GRE 47, 95% CI 12–82), stronger than the impact on LOCRC (GRE 18, 95% CI 8–29).InterpretationExcessive alcohol use was strongly associated with EOCRC risk, independent of PRS levels. Abstaining from heavy drinking could reduce risk for CRC, in particular for EOCRC to an extent that would be equivalent to having a much lower genetically determined risk.FundingThe first author (X.C.) was supported by the Guangzhou Elite Project (GEP). The DACHS study was supported by grants from the German Research Council (BR 1704/6–1, BR1704/6–3, BR 1704/6–4, BR 1704/6–6, CH 117/1–1, BR 1704/17–1, HO 5117/2–1) and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01GL1712).

Evaluating the Potential of Polygenic Risk Score to Improve Colorectal Cancer Screening.

Colorectal cancer has high incidence and associated mortality worldwide. Screening programs are recommended for men and women over 50. Intermediate screens such as fecal immunochemical testing (FIT) select patients for colonoscopy with suboptimal sensitivity. Additional biomarkers could improve the current scenario. We included 2,893 individuals with a positive FIT test. They were classified as cases when a high-risk lesion for colorectal cancer was detected after colonoscopy, whereas the control group comprised individuals with low-risk or no lesions. 65 colorectal cancer risk genetic variants were genotyped. Polygenic risk score (PRS) and additive models for risk prediction incorporating sex, age, FIT value, and PRS were generated. Risk score was higher in cases compared with controls [per allele OR = 1.04; 95% confidence interval (CI), 1.02-1.06; P < 0.0001]. A 2-fold increase in colorectal cancer risk was observed for subjects in the highest decile of risk alleles (≥65), compared with those in the first decile (≤54; OR = 2.22; 95% CI, 1.59-3.12; P < 0.0001). The model combining sex, age, FIT value, and PRS reached the highest accuracy for identifying patients with a high-risk lesion [cross-validated area under the ROC curve (AUROC): 0.64; 95% CI, 0.62-0.66]. This is the first investigation analyzing PRS in a two-step colorectal cancer screening program. PRS could improve current colorectal cancer screening, most likely for higher at-risk subgroups. However, its capacity is limited to predict colorectal cancer risk status and should be complemented by additional biomarkers. PRS has capacity for risk stratification of colorectal cancer suggesting its potential for optimizing screening strategies alongside with other biomarkers.

A Prospective Analysis of Red and Processed Meat Intake in Relation to Colorectal Cancer in the Black Women's Health Study

BackgroundBlack Americans have the highest incidence of colorectal cancer (CRC) of any racial/ethnic group in the United States. High intake of red and processed meats has been associated with an increased CRC risk in predominately White populations. However, 3 prior studies in Black populations, who have been reported to have high intakes of red and processed meats, have reported no associations. Data on a possible association between CRC risk and SFAs and MUFAs, the primary types of fat in red and processed meats, are inconclusive. ObjectivesWe prospectively assessed intakes of processed and unprocessed red meat, SFAs, and MUFAs in relation to CRC risk, utilizing data from the Black Women's Health Study (BWHS, 1995–2018). MethodsDietary data were derived from validated FFQs completed in 1995 and 2001. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression. ResultsAmong 52,695 BWHS participants aged 21–69 y at baseline and followed for ≤22 y, 564 women developed incident CRC. Unprocessed red meat intake was associated with a 33% increased CRC risk per 100 g/d (HR: 1.33; 95% CI: 1.03–1.71). Examination of CRC anatomic sites revealed that unprocessed red meat was associated with 2-times increased rectal cancer risk (HR: 2.22; 95% CI: 1.15–4.26). There was no evidence of an interaction with age (pinteraction = 0.4), but unprocessed red meat intake was only associated with a significant increased risk of late-onset CRC (≥50 y of age, HR: 1.41; 95% CI: 1.05–1.88). Processed red meat and total SFA and MUFA intakes were not associated with CRC risk. ConclusionsUnprocessed red meat intake was associated with an increased CRC risk in the present study, the first positive evidence that red meat plays a role in the etiology of CRC in Black women. The findings suggest prevention opportunities.

Prospective Associations of Circulating Bile Acids and Short-Chain Fatty Acids With Incident Colorectal Cancer.

Human studies investigating the prospective relationship between microbial metabolites and colorectal cancer (CRC) risk are lacking. We tested whether higher serum bile acids (BAs) and lower short-chain fatty acids (SCFAs) were associated with CRC risk. In baseline serum collected more than 30 years before a CRC diagnosis, we quantified concentrations of 15 BAs and 6 SCFAs using targeted liquid chromatography with tandem mass spectrometry assays in 1:1 matched cases and controls from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (men: n = 262 cases; women: n = 233 cases) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (men: n = 598 cases). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for BA and SCFA quartiles and summary measures with CRC overall and by anatomic location using multivariable conditional logistic regression models. PLCO analyses were stratified by sex. All statistical tests were 2-sided. In PLCO women, 7 BAs were strongly associated with increased CRC risk, including the secondary BAs, deoxycholic (ORQ4 v Q1 = 2.85, 95% CI = 1.45 to 5.60, Qtrend = 0.011), glycodeoxycholic (OR Q4 v Q1 = 3.45, 95% CI = 1.79 to 6.64, Qtrend = 0.006), taurodeoxycholic (OR Q4 v Q1 = 2.36, 95% CI = 1.22 to 4.55, Qtrend = 0.023), and glycolithocholic acid (ORQ4 v Q1 = 2.71, 95% CI = 1.41 to 5.22, Qtrend = 0.015). Women in the highest compared with lowest quartile of total SCFAs had a 45% lower risk of CRC (OR = 0.55, 95% CI = 0.31 to 0.98, Ptrend = .03). Associations for total BAs and SCFAs were strongest among women with proximal colon cancer. No statistically significant associations were observed for BA or SCFA measures among men. Serum concentrations of BAs, particularly downstream microbial metabolites of cholic acid, were strongly associated with increased risk of CRC among women.

Colorectal cancer among farmers in the AGRICAN cohort study

ObjectivesSpecific farming types and tasks have rarely been studied in relation to colorectal cancer (CRC). We evaluated associations between 5 types of livestock and 13 types of crops in relation to CRC and its subsites within the Agriculture and Cancer (AGRICAN) study. MethodsAGRICAN cohort includes 181,842 agricultural workers living in 11 French geographical areas. Data on farming types and tasks was collected by self-administered questionnaires. We identified 2 609 CRC, 972 right colon, 689 left colon and 898 rectal incident cancer cases during follow-up from 2005 to 2015. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). ResultsSignificantly increased CRC risk was observed for farmers producing horses (HR=1.18, 95% CI 1.06–1.31), sunflower (HR=1.23, 95% CI 1.03–1.45) and field vegetables (HR=1.18, 95% CI 1.02–1.36). Positive associations were also observed for pig, poultry and wheat/barley. Some associations were observed only for specific subsites: left colon cancer was associated with fruit growing (HR=1.36, 95% CI 1.09–1.70) and potato (HR=1.28, 95% CI 1.05–1.57). Tasks related to livestock (animal care, insecticide treatment, disinfection of milking equipment and building) or to crop (haymaking, sowing, pesticide treatment, seed treatment, harvesting) were also associated with CRC. Duration and size of farming types/task increased the risk for some of the associations. Analysis stratified by sex suggested an interaction with several farming types/task. ConclusionsThe current study showed original and positive findings for several farming types and tasks and CRC risk, overall and by subsites.

Red and Processed Meat Intake, Polygenic Risk Score, and Colorectal Cancer Risk.

High red and processed meat intake (RPMI) is an established risk factor for colorectal cancer (CRC). We aimed to assess the impact of RPMI on CRC risk according to and in comparison with genetically determined risk, which was quantified by a polygenic risk score (PRS). RPMI and potential confounders (ascertained by questionnaire) and a PRS (based on 140 CRC-related loci) were obtained from 5109 CRC cases and 4134 controls in a population-based case–control study. Associations of RPMI with CRC risk across PRS levels were assessed using logistic regression models and compared to effect estimates of PRS using “genetic risk equivalent” (GRE), a novel metric for effective risk communication. RPMI multiple times/week, 1 time/day, and >1 time/day was associated with 19% (95% CI 1% to 41%), 41% (18% to 70%), and 73% (30% to 132%) increased CRC risk, respectively, when compared to RPMI ≤ 1 time/week. Associations were independent of PRS levels (pinteraction = 0.97). The effect of RPMI > 1 time/day was equivalent to the effect of having 42 percentiles higher PRS level (GRE 42, 95% CI 20–65). RPMI increases CRC risk regardless of PRS levels. Avoiding RPMI can compensate for a substantial proportion of polygenic risk for CRC.

Pairwise association of key lifestyle factors and risk of colorectal cancer: a prospective pooled multicohort study.

Several lifestyle factors are associated with an increased risk of colorectal cancer (CRC). Although lifestyle factors co-occur, in most previous studies these factors have been studied focusing upon a single risk factor or assuming independent effects between risk factors. To examine the pairwise effects and interactions of smoking, alcohol consumption, physical inactivity, and body mass index (BMI) with risk of subsequent colorectal cancer (CRC). We used METCA cohort data (pooled data from seven population-based Finnish health behavior survey studies during years 1972-2015) consisting of 171 063 women and men. Participants' smoking, alcohol consumption, physical inactivity and BMI measures were gathered, and participants were categorized into those exposed and those not exposed. The incidence of CRC was modeled by Poisson regression with main and interaction effects of key lifestyle factors. The cohort members were followed-up through register linkage to the Finnish Cancer Registry for first primary CRC case until the end of 2015. Follow-up time was 1715, 690 person years. The highest pairwise CRC risk was among male smokers who had overweight (BMI ≥ 25 kg/m2 ) (HR 1.75, 95% CI 1.36-2.26) and women who had overweight and consumed alcohol (HR 1.45, 95% CI 1.14-1.85). Overall, among men the association of lifestyle factors and CRC risk was stronger than among women. In men, both having overweight and being a smoker combined with any other adverse lifestyle factor increased CRC risk. Among women, elevated CRC risks were observed for those who were physically inactive and who consumed alcohol or had overweight. No statistically significant interactions were detected between pairs of lifestyle factors. This study strengthens the evidence of overweight, smoking, and alcohol consumption as CRC risk factors. Substantial protective benefits in CRC risk can be achieved by preventing smoking, maintaining BMI to <25 kg/m2 and not consuming alcohol.

Alcohol consumption, DNA methylation and colorectal cancer risk: Results from pooled cohort studies and Mendelian randomization analysis.

Alcohol consumption is thought to be one of the modifiable risk factors for colorectal cancer (CRC). However, the causality and mechanisms by which alcohol exerts its carcinogenic effect are unclear. We evaluated the association between alcohol consumption and CRC risk by analyzing data from 32 cohort studies and conducted two‐sample Mendelian randomization (MR) analysis to examine for casual relationship. To explore the effect of alcohol related DNA methylation on CRC risk, we performed an epigenetic MR analysis with data from an epigenome‐wide association study (EWAS). We additionally performed gene‐alcohol interaction analysis nested in the UK Biobank to assess effect modification between alcohol consumption and susceptibility genes. We discovered distinct effects of alcohol on CRC incidence and mortality from the meta‐analyses, and genetic predisposition to alcohol drinking was causally associated with an increased CRC risk (OR = 1.79, 95% CI: 1.23‐2.61) using two‐sample MR approaches. In epigenetic MR analysis, two alcohol‐related CpG sites (cg05593667 and cg10045354 mapped to COLCA1/COLCA2 gene) were identified causally associated with an increased CRC risk (P < 8.20 × 10−4). Gene‐alcohol interaction analysis revealed that carriage of the risk allele of the eQTL (rs3087967) and mQTL (rs11213823) polymorphism of COLCA1/COLCA2 would interact with alcohol consumption to increase CRC risk (P Interaction = .027 and P Interaction = .016). Our study provides comprehensive evidence to elucidate the role of alcohol in CRC and highlights that the pathogenic effect of alcohol on CRC could be partly attributed to DNA methylation by regulating the expression of COLCA1/COLCA2 gene.

Metabolic Dysfunction-Associated Fatty Liver Disease Increases Colon Cancer Risk: A Nationwide Cohort Study.

INTRODUCTION:The association between nonalcoholic fatty liver disease (NAFLD) and colorectal cancer (CRC) has been controversial. Using the new consensus-driven definition, we evaluated the association of metabolic dysfunction–associated fatty liver disease (MAFLD) with the risk of developing CRC.METHODS:From a nationwide health screening database, we included 8,933,017 participants (48.6% male) aged 40–64 years between 2009 and 2010. Participants were categorized by the presence of fatty liver disease (FLD)—NAFLD and MAFLD, separately—and by the combination of the 2 definitions: neither FLD, NAFLD only, MAFLD only, or both FLD. The primary outcome was the development of CRC.RESULTS:Among the participants, 2,517,330 (28.2%) had NAFLD, and 3,337,122 (37.4%) had MAFLD, whereas 2,465,151 (27.6%) met both NAFLD and MAFLD definitions. Over a median follow-up period of 10.1 years, 60,888 new CRC cases developed. NAFLD and MAFLD were each associated with a significantly higher risk of developing CRC. When the neither FLD group was the reference, multivariable-adjusted hazard ratios (95% confidence interval) for CRC were 1.16 (1.06–1.28) in the NAFLD only group, 1.18 (1.16–1.20) in the both FLD group, and 1.32 (1.28–1.35) in the MAFLD only group. The presence of advanced liver fibrosis further increased CRC risk in each FLD group.DISCUSSION:FLD was associated with a higher risk of CRC development. CRC risk was higher in the presence of MAFLD, especially when accompanied by liver fibrosis.

Abstract PO-180: Synergistic interplay between genetic characteristics of glucose homeostasis and long-term exposure to cigarette smoking in development of African American colorectal cancer

Abstract Background: Colorectal cancer (CRC) is the leading cause of cancer diagnosis and death in women in the United States and other westernized countries and approximately 90% of new cases and deaths occur in women 50 years old and older. African American (AA) women have the highest CRC incidence and mortality rates among all races/ethnic female groups. Also, CRC is the third most common cancer diagnosis and cause of cancer deaths in AA women. Insulin resistance (IR) or glucose intolerance is a critical biologic mechanism for the development of CRC owing to obesity in postmenopausal women. Whereas IR and excessive adiposity are more prevalent in AA women than in white women, AA women are under-represented in genome-wide studies for systemic regulation of IR and the association with CRC risk. Methods: Having examined 780 genome-wide IR single-nucleotide polymorphisms (SNPs) available in the Women's Health Initiative Database for Genotypes and Phenotypes (WHI dbGaP) SNP Health Association Resource (SHARe) among 4,692 AA women, we tested for a causal inference between genetically elevated IR and CRC risk in a Mendelian randomization (MR) framework. Further, by incorporating 35 CRC-associated lifestyle factors, we established a prediction model on the basis of gene–environment interactions to generate risk profiles for CRC with the most influential genetic and lifestyle factors and eventually estimated their combined and joint effects on CRC risk. Results: In the pooled MR analysis, the genetically elevated IR was associated with 9 times increased risk for CRC. By addressing the variation of individual SNPs in CRC risk in the prediction model, we detected 4 fasting glucose–specific SNPs in GCK, PCSK1, and MTNR1B and 4 lifestyles, including smoking, aging, prolonged lifetime exposure to endogenous estrogen, and high fat intake, as the most predictive markers for CRC risk. Our joint test for those risk genotypes and lifestyles with smoking revealed the synergistically increased CRC risk, more substantially in women with longer-term exposure to cigarette smoking. Conclusion: Our findings may improve CRC prediction ability among medically under-represented AA women and highlight genetically informed preventive interventions (e.g., smoking cessation; CRC screening to longer-term smokers) for those women at high risk with risk genotypes and behavioral patterns. Citation Format: Su Yon Jung. Synergistic interplay between genetic characteristics of glucose homeostasis and long-term exposure to cigarette smoking in development of African American colorectal cancer [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-180.

1001. Chronic Colonization with Toxigenic Clostridioides difficile Strains Drives Colonic Tumorigenesis in Mice

BackgroundLong-term effects of chronic and/or recurrent C. difficile infections (CDI) are not well understood, and any potential role of CDI in colorectal cancer (CRC) risk is presently unknown. While pursuing efforts to identify novel procarcinogenic microbes, we identified two mucosal slurries from CRC patients (3728T and 3752T) that were tumorigenic in germ-free (GF) ApcMin/+ mice. Surprisingly, both of these CRC patient slurries were positive for C. difficile by 16S rRNA amplicon sequencing. Given the ability of other chronic infections to promote tumorigenesis (e.g., H. pylori), we hypothesized that chronic colonization with C. difficile could promote tumorigenesis in the colon. MethodsA consortium of 30 bacterial isolates including a toxigenic tcdA+ tcdB+ C. difficile strain (CIm_3728T) was cultured from GF ApcMin/+ mice gavaged with the 3728T slurry. This consortium was gavaged into additional GF ApcMin/+ mice with or without C. difficile strains CIm_3728T, CIm_3752T (isolated from mice gavaged with the 3752T slurry), or isogenic tcdA/tcdB mutants of the M7404 R027 strain. Single cell RNA sequencing (scRNAseq), high dimensional (HD) flow cytometry, and fluorescence in situ hybridization (FISH) with EUB338 and Cd198 probes were performed on distal colons from mice gavaged with either complex CRC slurries or the 3728T isolates with CIm_3728T.Results C. difficile strains drove tumorigenesis of the 3728T isolate mixture (Fig. 1A,B). Tumorigenesis was associated with early procarcinogenic signaling and spatial changes including induction of Wnt signaling in colonic epithelial progenitor cells by scRNAseq, IL-17 induction in immune cells by HD flow cytometry, and bacterial biofilm invasion deep into epithelial crypts by FISH. Tumorigenesis correlated with chronic colonization with toxigenic strains of C. difficile and was toxin-dependent, as toxin mutant strains (M7404 tcdA-tcdB-) did not induce tumors.Figure 1. C. difficile strains from CRC patients induce distal colonic tumorigenesis in germ-free (GF) ApcMin/+ mice. A consortium of 30 bacteria, including C. difficile, were isolated from mice gavaged with the 3728T human CRC mucosal slurry. These isolates were then gavaged into additional GF ApcMin/+ mice, with or without C. difficile isolates from mice gavaged with the 3728T slurry or 3752T slurry. (A) Colonic tumor numbers in GF ApcMin/+ mice at 10 wk p.i. demonstrate that C. difficile (Cd) drives the tumorigenesis of this 30-member bacterial consortium. (B) Gross tumors can be observed in the colon of a representative mouse gavaged with the 3728T isolates with the CIm_3728T (top) or CIm_3752T (middle) strain of C. difficile but not in a mouse gavaged with the isolates lacking C. difficile (bottom).ConclusionToxigenic C. difficile strains isolated from human CRC mucosal slurries were pro-carcinogenic in mice, suggesting that C. difficile is a potential driver of CRC. Given the public health burden of C. difficile, further studies are warranted to determine whether C. difficile infections (initial, recurrent, and chronic asymptomatic) increase CRC risk in patients.Disclosures Jada Domingue, PhD, AstraZeneca (Employee) James White, PhD, Personal Genome Diagnostics (Consultant) Patricia J. Simner, PhD, Accelerate Diagnostics (Grant/Research Support)Affinity Biosensors (Grant/Research Support)BD Diagnostics (Consultant, Grant/Research Support)GeneCapture (Consultant)OpGen, Inc (Consultant, Grant/Research Support)Shionogi, Inc (Consultant) Karen C. Carroll, MD, MeMed (Scientific Research Study Investigator)Meridian Diagnostics, Inc. (Grant/Research Support)Pattern Diagnostics (Advisor or Review Panel member)Scanogen, Inc. (Advisor or Review Panel member) Karen C. Carroll, MD, Pattern Diagnostics, Inc. (Individual(s) Involved: Self): Grant/Research Support; Scanogen, Inc. (Individual(s) Involved: Self): Consultant Cynthia L. Sears, MD, Bristol Myers Squibb (Grant/Research Support)Ferring (Advisor or Review Panel member)Janssen (Grant/Research Support)

Association of circulating short chain fatty acid levels with colorectal adenomas and colorectal cancer.

Short chain fatty acid (SCFAs) are bacterially derived metabolites suggested to have protective roles against colorectal cancer (CRC) development. However, there is sparse evidence from epidemiological studies in this context. Here, we assessed whether circulating SCFA concentrations varied in patients with colorectal adenomas (CRA) and CRC. Levels of seven SCFAs were extracted from plasma samples and determined by gas chromatography for 213 individuals from Ireland and the Czech Republic (CRC, n=84; CRA, n=66; controls, n=63). In the Irish CRA/CRC cohort, only levels of 2-MethylButyric acid were significantly higher in cancers compared to the adenoma and control groups (p-values=0.016 and 0.043). Using regression analysis, we observed that levels of Acetic and Propionic acid were associated with an increased CRC risk in the Czech cohort (Odd Ratio (OR): 1.02; 95% Confidence interval (CI): 1.00-1.03; OR: 1.29; 95% CI: 1.05-1.59, respectively), while i-Valeric and Valeric acid levels were associated with a decreased cancer risk (OR: 0.92; 95% CI: 0.86-0.99; OR: 0.67; 95% CI: 0.44-1.00). In the Irish cohort, levels of SCFAs were not associated with CRC risk. The association with colorectal neoplasia varied between the studied SCFAs. Future studies need to confirm these findings and address the mechanism of how these acids may promote or prevent colorectal carcinogenesis.

Diet derived polycyclic aromatic hydrocarbons and its pathogenic roles in colorectal carcinogenesis.

Polycyclic aromatic hydrocarbon (PAHs) are molecules that contaminate meat products during the high-temperature cooking of meat. This study reviewed the pathogenic roles of meat derived polycyclic aromatic hydrocarbons in the carcinogenesis of colorectal cancer (CRC). Ingested PAHs undergo xenobiotic metabolism resulting in the activation of genotoxic metabolites that can induce DNA damage in the colorectum. Genetic polymorphisms in PAH xenobiotic enzymes are linked to the risk of CRC and suggest a role for PAH-meat ingestion in carcinogenesis of colorectal malignancies. Furthermore, PAH specific DNA adducts have been identified in colorectal cancer tissue and linked to high meat intake. DNA adduct resolution is mediated by the nucleotide excision repair, and polymorphisms within genes of this repair pathway and high meat intake are associated with increased CRC risk. In the literature, there is evidence from metabolic enzyme gene variants, DNA repair genes, PAH metabolites, and epidemiological studies suggesting PAH involvement in CRC.

Proton pump inhibitors and colorectal cancer: A systematic review.

BACKGROUNDThe use of proton pump inhibitors (PPI) is common worldwide, with reports suggesting that they may be overused. Several studies have found that PPI may affect colorectal cancer (CRC) risk. AIMTo summarize current knowledge on the relationship between PPI and CRC from basic research, epidemiological and clinical studies. METHODSThis systematic review was based on the patients, interventions, comparisons, outcome models and performed according to PRISMA guidelines. MEDLINE, EMBASE, Scopus, and Web of Science databases were searched from inception until May 17, 2021. The initial search returned 2591 articles, of which, 28 studies met the inclusion criteria for this review. The studies were categorized as basic research studies (n = 12), epidemiological studies (n = 11), and CRC treatment studies (n = 5). The quality of the included studies was assessed using the Newcastle-Ottawa Scale or Cochrane Risk of Bias 2.0 tool depending on the study design. RESULTSData from basic research indicates that PPI do not stimulate CRC development via the trophic effect of gastrin but instead may paradoxically inhibit it. These studies also suggest that PPI may have properties beneficial for CRC treatment. PPI appear to have anti-tumor properties (omeprazole, pantoprazole), and are potential T lymphokine-activated killer cell-originated protein kinase inhibitors (pantoprazole, ilaprazole), and chemosensitizing agents (pantoprazole). However, these mechanisms have not been confirmed in human trials. Current epidemiological studies suggest that there is no causal association between PPI use and increased CRC risk. Treatment studies show that concomitant PPI and capecitabine use may reduce the efficacy of chemotherapy resulting in poorer oncological outcomes, while also suggesting that pantoprazole may have a chemosensitizing effect with the fluorouracil, leucovorin, oxaliplatin (FOLFOX) regimen.CONCLUSIONAn unexpected inhibitory effect of PPI on CRC carcinogenesis by way of several potential mechanisms is noted. This review identifies that different PPI agents may have differential effects on CRC treatment, with practical implications. Prospective studies are warranted to delineate this relationship and assess the role of individual PPI agents.

Association between metabolic syndrome and its components and incident colorectal cancer in a prospective cohort study.

Metabolic syndrome (MetS) has been identified as a contributor to cancer development. However, reports concerning the association between MetS and colorectal cancer (CRC) have been inconsistent. This study investigated whether MetS, its components, and the number of components increase the risk of CRC. This was a prospective cohort study of 41,837 participants recruited from August 2002 to December 2014 from the National Cancer Center in South Korea. The participants were followed until December 2017 to identify incident CRC cases. The participants underwent laboratory tests at the baseline. Additionally, a self-administered questionnaire collected information concerning lifestyle and general characteristics at the baseline. A Cox proportional hazards model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) to explore the association between MetS and its components and CRC risk after adjustments for confounding variables. In total, 128 incident CRC cases were identified during the follow-up period. An increased CRC risk was found among participants with MetS (HR, 1.63; 95% CI, 1.08-2.44). Additionally, elevated blood pressure (HR, 1.50; 95% CI, 1.05-2.15) and a high fasting glucose level (HR, 1.80; 95% CI, 1.23-2.63) were associated with an elevated risk of CRC. Notably, an increased risk was identified among participants with abdominal obesity coexisting with another component of MetS. These results suggest that MetS is a risk factor for CRC. Greater emphasis should be placed on the importance of CRC screening among individuals with abdominal obesity coexisting with another component of MetS. Colorectal cancer (CRC) ranks as the third most common cancer type in terms of incidence. Metabolic syndrome (MetS) has been identified as a contributor to cancer development. However, the association between MetS and CRC remains controversial because of a lack of consistent findings in previous studies. In this study, the National Cholesterol Education Program's Adult Treatment Panel III guidelines are used for the diagnosis of MetS. MetS is found to be a predictor of CRC. Additionally, the importance of CRC screening among individuals with 2 components of MetS should be emphasized.

Association of HLA-G 3′UTR polymorphisms and haplotypes with colorectal cancer susceptibility and prognosis

Human leukocyte antigen (HLA)-G has been considered as an immune modulator in several types of cancers. Its genetic polymorphisms may potentially affect the risk of developing colorectal cancer (CRC). The overall purpose of this study was to analyze the implication of HLA-G 3′untranslated region (3′UTR) polymorphisms particularly 14 pb insertion/deletion (Ins/Del; rs371194629) and + 3142C/G (rs1063320) in CRC susceptibility and progression.A comparative analysis between patients (N = 233) and controls (N = 241) demonstrated that Del allele (Odds Ratios (OR) = 1.41, 95% CI = 1.091–1.819, p = 0.008), the homozygous Del/Del genotype (OR = 1.80, 95% CI = 1.205–2.664, p = 0.003) and the codominant C/G genotype (OR = 1.59, 95% CI = 1.106–2.272, p = 0.013) were associated to CRC risk. As expected, the DelG haplotype was associated with CRC susceptibility (OR = 1.47, 95% CI = 1.068–2.012, p = 0.018). Assessment of patients' survival by Kaplan-Meier analysis indicated that the Del allele and the homozygous Del/Del genotype were associated with reduced event free survival (EFS) (Respectively, p = 0.009 and p = 0.05). Interestingly, the Del allele and the homozygous Del/Del genotype have been revealed as independent prognostic factors for poor EFS in patients with CRC. Additionally, haplotypes analysis revealed that DelG haplotype was linked with significant increase in CRC risk (log-rank; EFS: p = 0.02). Inversely, the InsC haplotype was associated with a significant reduced CRC risk (log-rank; Overall survival (OS): p < 10–6; EFS: p = 0.01). Multivariate Cox regression analysis revealed that the InsC haplotype was independently associated with significantly longer EFS (p = 0.021, HR = 0.636, 95% CI = 0.433–0.935).These findings support the implication of HLA-G polymorphisms in the CRC susceptibility suggesting HLA-G as a potent prognostic and predictive indicator for CRC. Insight into mechanisms underlying HLA-G polymorphisms could allow for the development of targeted care for CRC patients according to their genetic profile.