Elevated Risk Of Colorectal Cancer Research Articles

The Yield of Colonoscopy in the Evaluation of Constipation: An Age-Based Analysis of Outcome.

Background: Chronic constipation, a prevalent gastrointestinal complaint, exhibits rising incidence and diverse clinical implications, especially among the aging population. This study aims to assess colonoscopy performance in chronic constipation across age groups, comprehensively evaluating diagnostic yield and comparing results with average-risk controls. Methods: A retrospective analysis was conducted on 50,578 colonoscopy procedures performed over 12 years, including 5478 constipated patients. An average-risk control group (n = 4100) was included. Data extracted from electronic medical records covered demographics, operational aspects, and colonoscopy findings. The primary outcome measures included the diagnosis rate of colorectal cancer (CRC), polyp detection rate (PDR), and inflammatory bowel disease (IBD) diagnoses in constipated patients versus controls, with age-based and multivariate analyses. Results: Constipated patients exhibiting lower rates of adequate bowel preparation (92.7% vs. 85.3%; p < 0.001) and a lower cecal intubation rate. No significant variances between CRC and PDR were observed between constipated and controls, except for a potential of a slightly elevated CRC risk in constipated patients older than 80 (2.50% vs. 0% in controls; p = 0.07). Multivariate analysis demonstrated, across all age groups, that constipation did not confer an increased risk for CRC or polyp detection. Younger constipated patients exhibited a higher rate of IBD diagnoses (1.7% vs. 0.1% in controls; p < 0.001). Conclusions: Constipation did not confer an increased risk for CRC or polyps, among any age groups, except for a potential signal of elevated CRC risk in patients older than 80; additionally, it was associated with higher rates of IBD in younger patients.

Impact of ambient air pollution on colorectal cancer risk and survival: insights from a prospective cohort and epigenetic Mendelian randomization study

This study investigates the associations between air pollution and colorectal cancer (CRC) risk and survival from an epigenomic perspective. Using a newly developed Air Pollutants Exposure Score (APES), we utilized a prospective cohort study (UK Biobank) to investigate the associations of individual and combined air pollution exposures with CRC incidence and survival, followed by an up-to-date systematic review with meta-analysis to verify the associations. In epigenetic two-sample Mendelian randomization analyses, we examine the associations between genetically predicted DNA methylation related to air pollution and CRC risk. Further genetic colocalization and gene-environment interaction analyses provided different insights to disentangle pathogenic effects of air pollution via epigenetic modification. During a median 12.97-year follow-up, 5767 incident CRC cases among 428,632 participants free of baseline CRC and 533 deaths in 2401 patients with CRC were documented in the UK Biobank. A higher APES score was associated with an increased CRC risk (HR, 1.03, 95% CI= 1.01-1.06; P=0.016) and poorer survival (HR, 1.13, 95% CI= 1.03-1.23; P=0.010), particularly among participants with insufficient physical activity and ever smokers (Pinteraction > 0.05). A subsequent meta-analysis of seven observational studies, including UK Biobank data, corroborated the association between PM2.5 exposure (per 10μg/m3 increment) and elevated CRC risk (RR,1.42, 95% CI= 1.12-1.79; P=0.004; I2=90.8%). Genetically predicted methylation at PM2.5-related CpG site cg13835894 near TMBIM1/PNKD and cg16235962 near CXCR5, and NO2-related cg16947394 near TMEM110 were associated with an increased CRC risk. Gene-environment interaction analysis confirmed the epigenetic modification of aforementioned CpG sites with CRC risk and survival. Our study suggests the association between air pollution and CRC incidence and survival, underscoring the possible modifying roles of epigenomic factors. Methylation may partly mediate pathogenic effects of air pollution on CRC, with annotation to epigenetic alterations in protein-coding genes TMBIM1/PNKD, CXCR5 and TMEM110. Xue Li is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), the National Nature Science Foundation of China (No. 82204019) and Healthy Zhejiang One Million People Cohort (K-20230085). ET is supported by a Cancer Research UK Career Development Fellowship (C31250/A22804). MGD is supported by the MRC Human Genetics Unit Centre Grant (U127527198).

Age-related cholesterol and colorectal cancer progression: Validating squalene epoxidase for high-risk cases.

As people age, the risk and progression of colorectal cancer (CRC), along with cholesterol levels, tend to increase. Nevertheless, epidemiological studies on serum lipids and CRC have produced conflicting results. We previously demonstrated that the reduction of squalene epoxidase (SQLE) due to accumulated cholesterol within cells accelerates CRC progression through the activation of the β-catenin pathway. This study aimed to investigate the mechanism by which age-related cholesterol accumulation within tissue accelerates CRC progression and to assess the clinical significance of SQLE in older individuals with elevated CRC risk. Using machine learning-based digital image analysis with fluorescence-immunohistochemistry, we assessed SQLE, GSK3βpS9 (GSK3β activity inhibition through serine 9 phosphorylation at GSK3β), p53 wild-type (p53WT), and p53 mutant (p53MT) levels in CRC tissues. Our analysis revealed a significant reduction in SQLE, p53WT, and p53MT and increase in GSK3βpS9 levels, all associated with the substantial accumulation of intra-tissue cholesterol in aged CRCs. Cox analysis underscored the significant influence of SQLE on overall survival and progression-free survival in grade 2-3 CRC patients aged over 50. SQLE and GSK3βpS9 consistently exhibited outstanding prognostic and diagnostic performance, particularly in older individuals. Furthermore, combining SQLE with p53WT, p53MT, and GSK3βpS9 demonstrated a robust diagnostic ability in the older population. In conclusion, we have identified that individuals aged over 50 face an increased risk of CRC progression due to aging-linked cholesterol accumulation within tissue and the subsequent reduction in SQLE levels. This study also provides valuable biomarkers, including SQLE and GSK3βpS9, for older patients at elevated risk of CRC.

Machine learning framework to extract the biomarker potential of plasma IgG N-glycans towards disease risk stratification

Effective management of chronic diseases and cancer can greatly benefit from disease-specific biomarkers that enable informative screening and timely diagnosis. IgG N-glycans found in human plasma have the potential to be minimally invasive disease-specific biomarkers for all stages of disease development due to their plasticity in response to various genetic and environmental stimuli. Data analysis and machine learning (ML) approaches can assist in harnessing the potential of IgG glycomics towards biomarker discovery and the development of reliable predictive tools for disease screening. This study proposes an ML-based N-glycomic analysis framework that can be employed to build, optimise, and evaluate multiple ML pipelines to stratify patients based on disease risk in an interpretable manner. To design and test this framework, a published colorectal cancer (CRC) dataset from the Study of Colorectal Cancer in Scotland (SOCCS) cohort (1999–2006) was used. In particular, among the different pipelines tested, an XGBoost-based ML pipeline, which was tuned using multi-objective optimisation, calibrated using an inductive Venn-Abers predictor (IVAP), and evaluated via a nested cross-validation (NCV) scheme, achieved a mean area under the Receiver Operating Characteristic Curve (AUC-ROC) of 0.771 when classifying between age-, and sex-matched healthy controls and CRC patients. This performance suggests the potential of using the relative abundance of IgG N-glycans to define populations at elevated CRC risk who merit investigation or surveillance. Finally, the IgG N-glycans that highly impact CRC classification decisions were identified using a global model-agnostic interpretability technique, namely Accumulated Local Effects (ALE). We envision that open-source computational frameworks, such as the one presented herein, will be useful in supporting the translation of glycan-based biomarkers into clinical applications.

Longitudinal adherence to surveillance for late effects of cancer treatment: a population-based study of adult survivors of childhood cancer.

Adult survivors of childhood cancer are at elevated risk of morbidity and mortality compared to the general population, but their adherence to lifelong periodic surveillance is suboptimal. We aimed to examine adherence to surveillance guidelines for high-yield tests and identify risk factors for nonadherence in adult survivors of childhood cancer. In this retrospective, population-based cohort study, we used health care administrative data from Ontario, Canada, to identify adult survivors of childhood cancer diagnosed between 1986 and 2014 who were at elevated risk of therapy-related colorectal cancer, breast cancer, or cardiomyopathy. Using a Poisson regression framework, we assessed longitudinal adherence and predictors of adherence to the Children's Oncology Group surveillance guideline. Among 3241 survivors, 327 (10%), 234 (7%), and 3205 (99%) were at elevated risk for colorectal cancer, breast cancer, and cardiomyopathy, respectively. Within these cohorts, only 13%, 6%, and 53% were adherent to recommended surveillance as of February 2020. During a median follow-up of 7.8 years, the proportion of time spent adherent was 14% among survivors at elevated risk for colorectal cancer, 10% for breast cancer, and 43% for cardiomyopathy. Significant predictors of adherence varied across the risk groups, but higher comorbidity was associated with adherence to recommended surveillance. Survivors of childhood cancer in Ontario are rarely up to date for recommended surveillance tests. Tailored interventions beyond specialized clinics are needed to improve surveillance adherence.

Screening inhibitors against the Ef-Tu of Fusobacterium nucleatum: a docking, ADMET and PBPK assessment study.

The oral pathogen Fusobacterium nucleatum has recently been associated with an elevated risk of colorectal cancer (CRC), endometrial metastasis, chemoresistance, inflammation, metastasis, and DNA damage, along with several other diseases. This study aimed to explore the disruption of protein machinery of F. nucleatum via inhibition of elongation factor thermo unstable (Ef-Tu) protein, through natural products. No study on Ef-Tu inhibition by natural products or in Fusobacterium spp. exists till todate. Ef-Tu is an abundant specialized drug target in bacteria that varies from human Ef-Tu. Elfamycins target Ef-Tu and hence, Enacyloxin IIa was used to generate pharmacophore for virtual screening of three natural product libraries, Natural Product Activity and Species Source (NPASS) (n = 30000 molecules), Tibetan medicinal plant database (n = 54 molecules) and African medicinal plant database (n > 6000 molecules). Peptaibol Septocylindrin B (NPC141050), Hirtusneanoside, and ZINC95486259 were prioritized from these libraries as potential therapeutic candidates. ADMET profiling was done for safety assessment, physiological-based pharmacokinetic modeling in human and mouse for getting insight into drug interaction with body tissues and molecular dynamics was used to assess stability of the best hit NPC141050 (Septocylindrin B). Based on the promising results, we propose further in vitro, in vivo and pharmacokinetic testing on the lead Septocylindrin B, for possible translation into therapeutic interventions.

P423 Incidence of Colorectal Cancer among Patients with Ulcerative Colitis in the Middle East: A Systematic Review and Meta-Analysis

Abstract Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal inflammation of the colon. A well-documented long-term complication of UC is an increased risk of developing colorectal cancer (CRC). The Middle Eastern population, with its unique genetic and environmental factors, presents a distinctive context for the investigation of CRC risk in UC patients. This meta-analysis aims to systematically evaluate and synthesize the available data on the incidence of CRC among UC patients in the Middle East Methods A comprehensive literature search was conducted, identifying relevant studies from various databases and sources. A total of 12 studies met the inclusion criteria and were subjected to quantitative synthesis. The primary outcome measure was the incidence of CRC among UC patients in the Middle East. A random-effects model was used for data synthesis. Heterogeneity was assessed using the I^2 statistic. Results The meta-analysis included a total of 12 studies, comprising 13,881 UC patients in the Middle East. The overall estimated incidence of CRC in this population was 1.41% (95% confidence interval [CI]: 1.32% to 1.50%). Notably, there was substantial heterogeneity across the studies (I² = 100%). Conclusion This meta-analysis provides insights into the incidence of CRC among UC patients in the Middle East. The findings underscore the significance of recognizing and addressing the elevated risk of CRC in UC patients, particularly in the context of unique genetic and environmental factors in the Middle East. Further research is needed to refine risk assessment and optimize preventive strategies in this specific population. Ultimately, this study serves as a vital resource for clinicians and researchers seeking to combat the burden of CRC in Middle Eastern UC patients.

Insulin resistance and impaired insulin secretion and gastrointestinal cancer risk in Korean adults: Preliminary results from Korean Genome and Epidemiology study.

761 Background: To date, few studies conducted on the effect of insulin resistance or insulin secretory function on cancer risk in non-diabetic population. This study evaluated whether insulin resistance and/or insulin secretory function affect gastrointestinal cancer risk in the Korean population. Methods: We analyzed data from Korean Genome and Epidemiology Study, Korea Association Resource dataset. It consists of 10,030 participants aged 40-69y observed from 2001 to 2018. The risk of all cancers, and gastrointestinal cancers were assessed. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Homeostasis Model Assessment of Beta-cell function (HOMA-β) were used as indicators of insulin resistance and insulin secretory function. Results: In the final dataset, 8,649 individuals without previous history of any cancers were included. During an average follow-up of 15 years, 415 subjects (4.8%) developed cancers. Compared to the low HOMA-IR/high HOMA-β group (reference), diabetic patients had the highest risk of overall cancers, followed by high HOMA-IR/low HOMA-β group (Adjusted hazard ratio[95% confidence interval]: 1.74 [1.11 - 2.75] and 1.40 [0.96 – 2.06], respectively) Among gastrointestinal cancers, the risk of gastric cancer was higher in the low HOMA-IR/low HOMA-β and high HOMA-IR/high HOMA-β groups (1.92 [1.06 - 3.47] and 2.27 [1.26 - 4.06], respectively) When further analyzed by HOMA-β stratified by quartiles, the lowest quartile (Q1) showed an increased risk of gastric cancer compared to the highest-quartile (Q4; 1.84 [0.98 – 3.46], p = 0.06) In contrast, no significant results were observed regarding the colorectal cancer risk, when analyzed based on HOMA-IR and HOMA-β. However, when further analyzed by HOMA-IR stratified by quartiles, the highest quartile (Q4) exhibited a significantly elevated colorectal cancer risk compared to the lowest quartile (Q1; 2.14 [1.11 - 4.11], P for trend = 0.04). Conclusions: Insulin resistance and impaired insulin secretion function may increase the risk of cancer, but the underlying mechanisms may differ by cancer type.

Colorectal Cancer Risk Prediction Using the rs4939827 Polymorphism of the SMAD7 Gene in the Romanian Population.

Colorectal cancer (CRC) is globally recognized as a prevalent malignancy known for its significant mortality rate. Recent years have witnessed a rising incidence trend in colorectal cancer, emphasizing the necessity for early diagnosis. Our study focused on examining the impact of the SMAD7 gene variant rs4939827 on the risk of colorectal cancer occurrence. The composition of our study group included 340 individuals, comprising 170 CRC diagnosed patients and 170 healthy controls. We performed genotyping of all biological samples using the TaqMan assay on the ABI 7500 Real-Time PCR System (Applied Biosystems, Waltham, MA, USA). This investigation focused on the rs4939827 gene variant, assessing its association with CRC risk and clinicopathological characteristics. Genotyping results for the SMAD7 gene variant rs4939827 revealed a 42.6% prevalence of the C allele in CRC patients (p = 0.245) and a 22.8% prevalence of the T allele in control subjects (p = 0.109). This study concluded that there was an elevated risk of CRC in the dominant model for CC/CT+TT, with a p-value of 0.113 and an odds ratio (OR) of 2.781, within a 95% confidence interval (CI) of 0.998 to 3.456. The findings of our research indicate a correlation between variants of the SMAD7 gene and the likelihood of developing colorectal cancer in our study population. Consequently, these results could be instrumental in facilitating early diagnosis of colorectal cancer utilizing information on single-nucleotide polymorphism (SNP) and genetic susceptibility to the disease.

Hepatitis B virus infection and risk of colorectal cancer: a large, population-based cohort study from Israel.

Recent population-based studies have suggested a possible link between hepatitis B (HBV) infection and extra-hepatic malignancies. We aimed to evaluate the association between HBV and colorectal cancer (CRC) using a large, population-based cohort study utilizing data from a large health maintenance organization (HMO). The study included patients with non-cirrhotic HBV based on relevant ICD-9-CM codes and supportive serology identified from the HMO's database. Age-, sex-, ethnicity-, and BMI-matched non-HBV patients in a 1:10 ratio were included in the control group. We assessed the overall diagnosis rate of CRC and hepatocellular carcinoma (HCC) during the study period and calculated the diagnosis rate of CRC in each age category (≤50, 51-70, and ≥70) in both groups. A total of 3430 HBV patients and 34,300 controls were included in the study. The mean age, sex, BMI, and ethnic composition were similar, and the rates of family history of CRC did not differ between both groups. The overall follow-up period was 134±16 months. The diagnosis rate of HCC (1.6% vs. 0.1%; P<0.0001) was significantly higher in the HBV patients. However, the proportion of CRC was comparable for both groups (0.6% vs. 0.8%, P=0.404), which was evident in all age subgroups. Our findings suggest that HBV infection is associated with an increased risk of HCC diagnosis but is not linked to an elevated risk of CRC. These findings may inform future clinical practice and research regarding the relationship between HBV and extrahepatic malignancies.

The Contribution of DNA Ligase 4 Polymorphisms to Colorectal Cancer.

While numerous biomarkers associated with genetic susceptibility to colorectal cancer (CRC) have been identified and validated through epidemiological studies, the specific influence of DNA ligase 4 (Lig4) genotypes remains unexplored. This study aimed to elucidate the hitherto unexamined relationship between Lig4 genotypes and CRC risk. The genotypes of Lig4 rs1805388 were determined applying the polymerase chain reaction-restriction fragment length polymorphism methodology. The potential association between these genotypes and CRC risk was assessed in a Taiwanese population comprising 362 CRC cases and an equal number of age- and sex-matched controls. In the genotypic analysis, the distribution of CC, CT, and TT genotypes for Lig4 rs1805388 among CRC cases was 54.7%, 38.1%, and 7.2%, respectively. This distribution was not significantly different from the controls, which exhibited genotypic frequencies of 57.2%, 36.7%, and 6.1%, respectively (p for trend=0.7314). Analysis of allelic distribution indicated that individuals carrying the T allele of Lig4 rs1805388 displayed a slightly elevated CRC risk compared to those carrying the C allele (odds ratio=1.10, 95% confidence interval=0.87-1.39, p=0.4685). The variant genotypes of Lig4 rs1805388 may not serve as predictive markers for CRC risk in the Taiwanese population.

Type 2 Diabetes and Colorectal Cancer Risk

ImportanceType 2 diabetes and colorectal cancer (CRC) disproportionately burden indviduals of low socioeconomic status and African American race. Although diabetes is an emerging CRC risk factor, associations between diabetes and CRC in these populations are understudied.ObjectiveTo determine if diabetes is associated with CRC risk in a cohort representing understudied populations.Design, Setting, and ParticipantsThis cohort study uses data from the prospective Southern Community Cohort Study in the US, which recruited from 2002 to 2009 and completed 3 follow-up surveys by 2018. Of about 85 000 participants, 86% enrolled at community health centers, while 14% were enrolled via mail or telephone from the same 12 recruitment states. Participants with less than 2 years of follow-up, previous cancer diagnosis (excluding nonmelanoma skin cancer) at enrollment, missing enrollment diabetes status, diabetes diagnosis before age 30, and without diabetes at enrollment with no follow-up participation were excluded. Data were analyzed from January to September 2023.ExposuresPhysician-diagnosed diabetes and age at diabetes diagnosis were self-reported via survey at enrollment and 3 follow-ups.Main Outcomes and MeasuresDiabetes diagnosis was hypothesized to be positively associated with CRC risk before analysis. Incident CRC was assessed via state cancer registry and National Death Index linkage. Hazard ratios and 95% CIs were obtained via Cox proportional hazard models, using time-varying diabetes exposure.ResultsAmong 54 597 participants, the median (IQR) enrollment age was 51 (46-58) years, 34 786 (64%) were female, 36 170 (66%) were African American, and 28 792 (53%) had income less than $15 000 per year. In total, 289 of 25 992 participants with diabetes developed CRC, vs 197 of 28 605 participants without diabetes. Diabetes was associated with increased CRC risk (hazard ratio [HR], 1.47; 95% CI, 1.21-1.79). Greater associations were observed among participants without colonoscopy screening (HR, 2.07; 95% CI, 1.16-3.67) and with smoking history (HR, 1.62; 95% CI, 1.14-2.31), potentially due to cancer screening differences. Greater associations were also observed for participants with recent diabetes diagnoses (diabetes duration &amp;amp;lt;5 years compared with 5-10 years; HR, 2.55; 95% CI, 1.77-3.67), possibly due to recent screening.Conclusions and RelevanceIn this study where the majority of participants were African American with low socioeconomic status, diabetes was associated with elevated CRC risk, suggesting that diabetes prevention and control may reduce CRC disparities. The association was attenuated for those who completed colonoscopies, highlighting how adverse effects of diabetes-related metabolic dysregulation may be disrupted by preventative screening.

NTHL1 Gene Mutations in Polish Polyposis Patients-Weighty Player or Vague Background?

Multiple polyposes are heterogeneous diseases with different underlying molecular backgrounds, sharing a common symptom: the presence of transforming into cancerous intestinal polyps. Recent reports have indicated biallelic mutations in the NTHL1 gene, which is involved in base excision repair (BER), as predisposing to an elevated risk of colorectal cancer (CRC). We aimed to evaluate the significance of the p.Q82* truncating variant in predisposition to intestinal polyposis by assessing its frequency in polyposis patients. We genotyped 644 Polish patients and 634 control DNA samples using high-resolution melting analysis (HRM) and Sanger sequencing. We found the p.Q82* variant in four polyposis patients; in three, it was homozygous (OR = 6.90, p value = 0.202). Moreover, the p.R92C mutation was detected in one patient. We also looked more closely at the disease course in patients carrying NTHL1 mutations. Two homozygous patients also presented other neoplasia. In the family case, we noticed the earlier presence of polyps in the proband and early hepatoblastoma in his brother. We cannot univocally confirm the relationship of p.Q82* with an increased risk of CRC. However, homozygous p.Q82* was more frequent by 10-fold in patients without other mutations identified, which makes NTHL1 gene screening in this group reasonable.

Association Between Helicobacter pylori, Adverse Gynecological and Pregnancy Outcomes, and Some Cancers: An Overview of Metanalyses

Context: The number of meta-analyses published about Helicobacter pylori-associated diseases that clinicians must comprehensively know about are scarce. This overview aims to give comprehensive knowledge on the fascinating topic of Helicobacter pylori-associated diseases. Methods: The search strategy was to systematically screen the articles evaluating the association between H. pylori infection and gynecological and reproductive health issues and cancers published on the authentic databases of Scopus, MEDLINE, and Web of Sciences from the inception until 2022. Results: Fifteen meta-analyses were included in the overview. The H. pylori infections were significantly associated with general adverse pregnancy outcomes such as gestational diabetes mellitus, preeclampsia, and hyperemesis gravidarum and adverse birth outcomes such as birth defect and fetal growth restriction. H. pylori infection was not associated with a deficiency of micronutrients (B2, folate, and ferritin) but was associated with an increased risk of iron-deficiency anemia during pregnancy. In esophagus cancer, H. pylori infection was significantly reduced in adenocarcinoma but not in esophageal squamous cell carcinoma. There was no significant association between H. pylori infection and the risk of asthma. The results also indicated a significant association between H. pylori infection and an elevated risk of colorectal cancer, colorectal adenoma, and the risk of asthma and lung cancer. Results of metanalysis are not consistently reproducible regarding spontaneous abortion and pancreatic cancer. Conclusions: Our overview revealed a significant relationship between H. pylori infection and several cancers, namely colorectal, lung, and colorectal adenoma, as well as gynecological and reproductive health issues.

FIT for purpose: study protocol for a randomized controlled trial to personalize surveillance colonoscopy for individuals at elevated risk of colorectal cancer

PurposeThere is increasing demand for colorectal cancer (CRC) surveillance, but healthcare capacity is limited. The burden on colonoscopy resources could be reduced by personalizing surveillance frequency using the fecal immunochemical test (FIT). This study will determine the safety, cost-effectiveness, and patient acceptance of using FIT to extend surveillance colonoscopy intervals for individuals at elevated risk of CRC.MethodsThis multicenter, prospective, randomized controlled trial will invite participants who are scheduled for surveillance colonoscopy (due to a personal history of adenomas or a family history of CRC) and who have returned a low fecal hemoglobin (< 2 μg Hb/g feces; F-Hb) using a two-sample FIT (OC Sensor, Eiken Chemical Company) in the prior 3 years. A total of 1344 individuals will be randomized to either surveillance colonoscopy as scheduled or delayed by 1 or 2 years for individuals originally recommended a 3- or 5-year surveillance interval, respectively. The primary endpoint is incidence of advanced neoplasia (advanced adenoma and/or CRC). Secondary endpoints include cost-effectiveness and consumer acceptability of extending surveillance intervals, determined using surveys and discrete choice experiments.ConclusionThis study will establish the safety, cost-effectiveness, and acceptability of utilizing a low FIT Hb result to extend colonoscopy surveillance intervals in a cohort at elevated risk for CRC. This personalized approach to CRC surveillance will lead to a reduction in unnecessary colonoscopies, increases in healthcare savings, and a better patient experience. Trial registrationRegistration was approved on December 9, 2019 with the Australian New Zealand Clinical Trials Registry ANZCTR 12619001743156.

Age-Specific Differences in the Risk of Colorectal Precursor Lesions Among Patients with Type 2 Diabetes Undergoing Surveillance Colonoscopy.

The incidence rate of colorectal cancer (CRC) in young adults is rising in parallel with type 2 diabetes (T2D). The majority of CRC develop through two main subtypes of precursor lesions; adenomas and serrated lesions. The associations between age and T2D on development of precursor lesions remain uncertain. We studied the association of T2D with the development of adenomas and serrated lesions in individuals <50 versus ≥50 years of age, in a population undergoing long-term regular surveillance colonoscopy due to an elevated risk of CRC. A case-control study was conducted on patients who were enrolled in a surveillance colonoscopy program between 2010-2020. Findings at colonoscopy, clinical and demographic features were collected. Adjusted and unadjusted binary logistic regression assessed the association of age, T2D, sex, and other medical conditions and lifestyle-related factors with different subtypes of precursor lesions diagnosed at colonoscopy. Cox proportional hazards model analysis determined the association of T2D and other confounders with development time for precursor lesions. Cases included 412 patients <50y [mean age 38.7 (range, 24-49y)] and 824 sex-matched controls ≥50y [62.1 (50-75y)]. Individuals <50y were less likely to have been diagnosed with T2D than those ≥50y (7% vs 22%, P-value<0.001). During the follow-up period, there was no significant association between T2D and diagnosis of any precursor lesions, but when considering development time, individuals with T2D developed non-significant adenomas earlier than those without T2D (HR =1.46; 95% CI: 1.14-1.87; P-value=0.003). However, this was not independent of age or findings at index colonoscopy. T2D does not further increase the incidence of adenomas or serrated lesions in either a young or older cohort undergoing long-term surveillance colonoscopy.

Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study

BackgroundObservational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk.MethodsWe conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants.ResultsGenetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98–1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00–1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04–1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77–1.22) and colon cancer (OR: 0.97, 95% CI: 0.76–1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90–1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05).ConclusionsOur findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.

Berberine inhibits high fat diet-associated colorectal cancer through modulation of the gut microbiota-mediated lysophosphatidylcholine.

Dietary fat intake is positively associated with elevated risk of colorectal cancer (CRC). Currently, clinical treatments remian inadequate bacause of the complex pathogenesis of CRC induced by a high-fat diet (HFD). Mechanistically, imbalances in gut microbiota are associated with HFD-associated colorectal tumourigenesis. Therefore, we investigated the anti-tumor activity of berberine (BBR) in modulating the dysregulated gut microbiota and related metabolites by preforming 16S rDNA sequencing and liquid chromatography/mass spectrometry. As expected, BBR treatment significantly decreased the number of colonic polyps, ameliorated gut barrier disruption, and inhibited colon inflammation and related oncogenic pathways in AOM/DSS-induced CRC model mice fed with an HFD. Furthermore, BBR alleviated gut microbiota dysbiosis and increased the abundance of beneficial gut microorganisms, including Akkermansia and Parabacteroides, in HFD-fed CRC mice. In addition, metabolomics analysis demonstrated significantly altered the glycerophospholipid metabolism during the progression of HFD-associated CRC in mice, whereas BBR treatment reverted these changes in glycerophospholipid metabolites, particularly lysophosphatidylcholine (LPC), which was confirmed to promote CRC cell proliferation and ameliorate cell junction impairment. Notably, BBR had no clear anti-tumor effects on HFD-fed CRC model mice with gut microbiota depletion, whereas transplantation of BBR-treated gut microbiota to gut microbiota-depleted CRC mice recapitulated the inhibitory effects of BBR on colorectal tumourigenesis and LPC levels. This study demonstrated that BBR inhibited HFD-associated CRC directly through modulating gut microbiota-regulated LPC levels, thereby providing a promising microbiota-modulating therapeutic strategy for the clinical prevention and treatment of Western diet-associated CRC.

Body mass index and molecular subtypes of colorectal cancer.

Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease. We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables. Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control). In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome.

Insulin resistance and inflammation mediate the association of abdominal obesity with colorectal cancer risk.

The close association of abdominal obesity rather than general obesity with colorectal cancer (CRC) risk might be mediated by IR and inflammation, which has never been systematically explored in large-scale prospective studies. We prospectively examined the mediation effects of the fasting triglyceride-glucose (TyG) index and C-reactive protein (CRP) on the associations of obesity (general and abdominal) with CRC risk among 93,659 participants. We used the Cox proportional hazards regression models and subgroup analyses to evaluate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) of CRC. The CAUSALMED procedure was used to perform the mediation analyses. During 13.02 years of follow-up, a total of 586 CRC cases were verified. Male participants with general obesity and abdominal obesity had a 1.29-fold and a 1.28-fold increased risk of CRC. However, a significant association was only observed among female individuals with abdominal obesity. Both TyG index and CRP were associated with an elevated risk of CRC, and A significant interaction between the TyG index and CRP was found for the risk of CRC (P for interaction<0.05). CRP and the TyG index significantly mediated the positive association between abdominal obesity and CRC risk. CRP and TyG index increased the risk of CRC independently and synergistically. Mediation effects of CRP and the TyG index were found for the association between abdominal obesity and CRC risk.