Higher Risk Of Colorectal Adenoma Research Articles

Body mass index and the prevalence of high-risk colorectal adenomas in a population undergoing screening colonoscopy in Alberta, Canada.

There is limited evidence regarding body mass index (BMI) as an early marker of high-risk adenoma (HRA) at the time of screening colonoscopy. Because high-risk adenomas (HRA) can develop into colorectal cancer (CRC), BMI could serve as an important clinical predictor of future risk of CRC. We examined data from 1831 adults undergoing screening colonoscopy at the Forzani & MacPhail Colon Cancer Screening Center in Alberta, Canada. We fit multivariable logistic regression models to examine the association between BMI and HRA. Non-linear relationships for BMI on HRA were also evaluated using restricted cubic splines. The mean BMI in patients with HRA was 28.2kg/m2 compared to 27.4kg/m2 in patients without adenomas (t test: p=0.003). In the adjusted models, those with a BMI over 30kg/m2 had 1.45 (95% CI 1.05-2.00) times the odds of HRA detected during colonoscopy compared to those with a BMI below 25kg/m2. Examining BMI as continuous, the odds of HRA were 1.20 (95% CI 1.04-1.37) times higher for every 5kg/m2 increase in BMI. The findings of this study suggest that excess body mass is associated with higher risk of HRA among a screening population and may be useful an early marker of future disease.

Association between Atherosclerosis and High-Risk Colorectal Adenomas based on Cardio-Ankle Vascular Index and Ankle-Brachial Index.

Colorectal adenomas are precancerous lesions that may lead to colorectal cancer. Recent studies have shown that colorectal adenomas are associated with atherosclerosis. The cardio-ankle vascular index (CAVI) and ankle-brachial index (ABI) are noninvasive methods for evaluating atherosclerosis. This study examined the association between atherosclerosis and high-risk colorectal adenomas based on the CAVI and ABI. The data of patients aged ≥50 years who had a colonoscopy and CAVI and ABI measurements from August 2015 to December 2021 at the Kangwon National University Hospital were analyzed retrospectively. After the colonoscopy, subjects were divided into no, overall, and high-risk (size ≥1 cm, high-grade dysplasia or villous adenoma, three or more adenomas) adenoma groups based on the pathology findings. The data were subjected to univariate and multivariate logistic regression analyses. Among the 1,164 subjects, adenomas and high-risk adenomas were found in 613 (52.6%) and 118 (10.1%) patients, respectively. The rate of positive ABI (<0.9) and positive CAVI (≥9.0) were significantly higher in the high-risk adenoma group (22.0% and 55.9%) than in the no adenoma (12.3% and 39.6%) and the overall adenoma group (15.7% and 44.0%) (p=0.008 and p=0.006, respectively). Multivariate analysis revealed a positive CAVI and smoking status to be significantly associated with high-risk adenoma with an odds ratio of 1.595 (95% confidence interval 1.055-2.410, p=0.027) and 1.579 (1.072-2.324, p=0.021), respectively. In this study, a significant correlation between positive CAVI and high-risk adenomas was observed. Therefore, CAVI may be a significant predictor for high-risk colorectal adenoma.

MAFLD with central obesity is associated with increased risk of colorectal adenoma and high-risk adenoma

ObjectiveTo analyze the risk factors associated with colorectal adenoma and to investigate the associations of metabolism-related fatty liver disease (MAFLD) with obesity, colorectal adenoma and high-risk adenoma.MethodsA total of 1395 subjects were enrolled and divided into a colorectal adenoma group (593 subjects) and a control group (802 subjects) according to the inclusion and exclusion criteria. The characteristics of patients in the colorectal adenoma group and the control group were compared by the chi-square test. Univariate and multivariate logistic analyses were used to analyze independent risk factors and associations with different MAFLD subtypes. Colorectal adenoma characteristics and the proportion of patients with high-risk colorectal adenoma were also compared.ResultsHigh-density lipoprotein (HDL-C) was significantly lower in patients in the colorectal adenoma group than in those in the control group (P < 0.001). Logistic regression analysis revealed that age, obesity status, central obesity status, hypertension status, diabetes status, fatty liver status, smoking history, BMI, waist circumference, triglyceride level, HDL-C level, fasting blood glucose level and degree of hepatic steatosis were all independent risk factors for colorectal adenoma. Notably, MAFLD was associated with a significantly increased risk of colorectal adenoma in patients with central obesity (P < 0.001). In addition, obesity, central obesity, diabetes, fatty liver and degree of hepatic steatosis were all shown to be independent risk factors for high-risk colorectal adenoma. In addition, a greater proportion of MAFLD patients with central obesity than those without central obesity had high-risk colorectal adenoma.ConclusionMAFLD and central obesity are independently associated with the development of colorectal adenoma. MAFLD with central obesity is associated with an increased risk of colorectal adenoma and high-risk adenoma.

Establishment of a large-scale patient-derived high-risk colorectal adenoma organoid biobank for high-throughput and high-content drug screening

BackgroundColorectal adenoma (CA), especially high-risk CA (HRCA), is a precancerous lesion with high prevalence and recurrence rate and accounts for about 90% incidence of sporadic colorectal cancer cases worldwide. Currently, recurrent CA can only be treated with repeated invasive polypectomies, while safe and promising pharmaceutical invention strategies are still missing due to the lack of reliable in vitro model for CA-related drug screening.MethodsWe have established a large-scale patient-derived high-risk colorectal adenoma organoid (HRCA-PDO) biobank containing 37 PDO lines derived from 33 patients and then conducted a series of high-throughput and high-content HRCA drug screening.ResultsWe established the primary culture system with the non-WNT3a medium which highly improved the purity while maintained the viability of HRCA-PDOs. We also proved that the HRCA-PDOs replicated the histological features, cellular diversity, genetic mutations, and molecular characteristics of the primary adenomas. Especially, we identified the dysregulated stem genes including LGR5, c-Myc, and OLFM4 as the markers of adenoma, which are well preserved in HRCA-PDOs. Based on the HRCA-PDO biobank, a customized 139 compound library was applied for drug screening. Four drugs including metformin, BMS754807, panobinostat and AT9283 were screened out as potential hits with generally consistent inhibitory efficacy on HRCA-PDOs. As a representative, metformin was discovered to hinder HRCA-PDO growth in vitro and in vivo by restricting the stemness maintenance.ConclusionsThis study established a promising HRCA-PDO biobank and conducted the first high-throughput and high-content HRCA drug screening in order to shed light on the prevention of colorectal cancer.

Correlation between Metabolite of Prostaglandin E2 and the incidence of colorectal adenomas.

Colorectal cancer is a common malignancy, and the incidence and mortality rates continue to rise. An important factor in the emergence of inflammation-induced colorectal carcinogenesis is elevated cyclooxygenase-2. Prostaglandin E2 (PGE2) over-production is frequently equated with cyclooxygenase-2 gene over-expression. PGE2 can be assessed by measuring the level of prostaglandin's main metabolite, PGE-M, in urine. Colorectal adenoma is a precancerous lesion that can lead to colorectal cancer. We conducted research to evaluate the association between urinary levels of the PGE-M and the risk of colorectal adenomas. In a western Chinese population, we identified 152 cases of adenoma and 152 controls patients without polyps. Adenoma cases were categorized into control, low-risk and high-risk groups. There was no significant change in PGE-M levels, between the control group and the low-risk adenoma group. In the high-risk group, the PGE-M levels were 23% higher than the control group. When compared to people with the lowest urine PGE-M levels (first quartile), people with greater urinary PGE-M levels had a higher chance of developing high-risk colorectal adenomas, with an adjusted odds ratio (95% CI) of 1.65 (0.76-3.57) in the fourth quartile group, (p= 0.013). We conclude urinary PGE-M is associated with the risk of developing high-risk adenomas. Urinary PGE-M level may be used as a non-invasive indicator for estimating cancer risk.

Dietary xenobiotics, (poly)phenols and fibers: Exploring associations with gut microbiota in socially vulnerable individuals.

ObjectivesAlthough xenobiotics derived from food processing may cause modifications in the composition of the gut microbiota (GM) evidence is scarce. The aim of this study is to evaluate the impact of potential dietary carcinogens as heterocyclic amines (HAs), polycyclic aromatic hydrocarbons (PAHs), nitrates, nitrites, nitroso compounds and acrylamide, in combination to fibers (poly)phenols on the GM composition in a group of materially deprived subjects.Study designTransversal observational study in a sample of 19 subjects recipients of Red Cross food aid. Dietary information was recorded by means of 3 non-consecutive 24 h recalls. Questions focused on the type of cooking and the extent of cooking and roasting were included. Information on potential carcinogens was mainly obtained from the European Prospective Investigation into Cancer and Nutrition (EPIC) and Computerized Heterocyclic Amines Resource for Research in Epidemiology of Disease (CHARRED) Carcinogen Databases. Microbial composition was determined by 16S ribosomal RNA gene sequencing in fecal samples.ResultsHigher levels of Lachnospiraceae and Eggerthellaceae families were found in individuals consuming less than 50 ng/day of 2-amino-3,8 dimethylimidazo (4,5,f) quinoxaline (MeIQx) (considered as lower risk dose for colorectal adenoma) while those consuming more than 40 ng/day of 2-amino-1-methyl-6-phenylimidazo (4,5,b) pyridine (PhIP) (higher risk for colorectal adenoma) showed lower relative abundance of Muribaculaceae and greater presence of Streptococcaceae and Eubacterium coprostanoligenes group.ConclusionThe associations identified between diet and processing by-products on GM in this study could be used as potential targets for the designing of dietary interventions tailored to this collective.

Reusing a prepaid health plan’s fecal immunochemical tests for microbiome associations with colorectal adenoma

An altered colonic microbiota probably increases colorectal adenoma (CRA) and cancer (CRC) risk, but large, unbiased fecal collections are needed to examine the relationship of gut microbiota diversity and composition to colorectal carcinogenesis. This study assessed whether fecal immunochemical tests (FITs) from CRA/CRC screening may fulfill this requirement. Using FIT, self-collected by members of Kaiser Permanente Hawaii (KPH), as well as interspersed quality control (QC) specimens, DNA was extracted and amplified to generate 16S rRNA microbiome profiles rarified at 10,000 reads. CRA/CRC were diagnosed by colonoscopy and histopathology. Covariates were from electronic KPH records. Of 921 participants’ FIT devices, 538 (58%) yielded at least 10,000 rRNA reads and 1016 species-level variants mapped to 46 genera. Of the 538 evaluable participants, 63 (11.7%) were FIT-negative per protocol, and they were considered negative for CRA/CRC. Of the 475 FIT + participants, colonoscopy and pathologic review revealed that 8 (1.7%) had CRC, 71 (14.9%) had high-risk CRA, 107 (22.5%) had low-risk CRA, and 289 (60.8%) did not have CRA/CRC. Men were 2.27-fold [95% confidence interval (CI) 1.32–3.91] more likely than women to be FIT+ . Men also had 1.96-fold (CI 1.24–3.07) higher odds of low-risk CRA, with similar trends for high-risk CRA and CRC. CRA/CRC were not associated with overweight, obesity, diabetes, or antibiotic prescriptions in this study. QC analysis across 24 batches of FIT devices revealed QC outliers in four batches. With or without exclusion of the four QC-outlier batches, as well as lenient (1000-read) rarefaction, CRA/CRC had no consistent, statistically significant associations with fecal microbiome alpha diversity, beta diversity or genera relative abundance. CRA/CRC had expected associations with male sex but not with microbiome metrics. Fecal microbiome profiling using DNA extracted from at-home collected, re-used FIT devices is feasible, albeit with substantial challenges. Using FITs for prospective microbiome studies of CRA/CRC risk should consider the impact of the current findings on statistical power and requisite sample sizes.

Arterial stiffness is associated with high-risk colorectal adenomas and serrated lesions: A cross-sectional study in a Taiwanese population

BackgroundLittle is currently known about the association between arterial stiffness and colorectal serrated lesions. This study was aimed toward an investigation of the association between arterial stiffness and colorectal precancerous lesions, including colorectal adenomas and serrated lesions. Methods7262 eligible adult subjects who underwent health check-ups with colonoscopies and brachial-ankle pulse wave velocity (baPWV) were recruited. Patients were categorized as polyp-free, low-risk and high-risk adenomas, and low-risk and high-risk serrated lesions based on the presence of polyps. The severity of arterial stiffness was categorized into four subgroups based on the baPWV quartile. ResultsAfter adjusting for multiple covariates, the baPWV values were found to be positively correlated with the occurrence of low-risk adenomas. With respect to high-risk polyps, the third and highest baPWV quartiles were significantly associated with the occurrence of both high-risk adenomas and high-risk serrated lesions. A more significant association was found in the highest baPWV quartiles combined with smoking in cases classified with high-risk serrated lesions. ConclusionsIncreased arterial stiffness was independently associated with precancerous colorectal lesions, not only adenomas but also high-risk serrated lesions. Individuals with increased arterial stiffness, especially those who are smokers, should be more aware of the risk of colorectal cancer.

Compliance with follow-up guidelines after high-risk colorectal polyp removal: a population-based study

After high-risk colorectal adenoma removal, colorectal cancer risk remains higher than that in the general population. Depending on polyp characteristics, a 3-month or 3-year follow-up colonoscopy is recommended, and clear follow-up instructions must be given to the patient. Our primary aim was to evaluate compliance with French follow-up recommendations. Second, we evaluated the impact of how the information was given and if patients actually underwent their control colonoscopy according to the instructions given. We collected data from the Burgundy polyp population-based registry and medical records from the endoscopy centers of the area. Between June 30, 2014 and July 1, 2015, 405 patients were included in this study. Written follow-up instructions were provided to 345 patients (85.2%), and 184 of them (53.3%) complied with guidelines. For 29.9% the interval to follow-up colonoscopy was longer than recommended, and for 6.4% the interval was shorter. Among the 303 patients who had clear follow-up instructions, 42.2% had their control colonoscopy and 83.6% respected the stipulated interval. Follow-up instructions were found in the colonoscopy report in at least 49% of cases. Compliance with follow-up guidelines was poor: Inappropriate intervals were often longer than recommended. Patients with written follow-up instructions and those who underwent follow-up colonoscopy mostly followed these instructions. Ensuring compliance with guidelines and giving written instructions to patients should be primary goals to achieve effective follow-up. Gastroenterologist training should be improved in this way.

The Risk of Colorectal Adenoma in Nonalcoholic or Metabolic-Associated Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease associated with various metabolic disorders. Metabolic dysfunction-associated fatty liver disease (MAFLD) emphasizes metabolic dysfunction in NAFLD. Although the relationship between NAFLD and colorectal adenomas has been suggested, the effect of MAFLD on colorectal adenoma has yet to be investigated. In this study, we examined the relationship between NAFLD/MAFLD and colorectal adenoma in comparison with other metabolic factors. Methods: Examinees who underwent colonoscopy and abdominal ultrasonography on the same day from January 2012 to December 2012 were included. NAFLD was diagnosed according to the findings of ultrasonography. The Fibrosis-4 (FIB-4) index was used as a surrogate marker for advanced hepatic fibrosis. A logistic regression model was used to analyze the risk of NAFLD/MAFLD for colorectal adenoma. Results: The prevalence of NAFLD and MAFLD was 37.5% and 32.8%, respectively. In the multivariate analysis, male sex, older age, diabetes, and smoking increased the risk of colorectal adenoma. NAFLD and MAFLD were the most important risk factors for colorectal adenoma only in females [adjusted odds ratio (OR) 1.43 and 95% confidence interval (CI) 1.01–2.03, and OR 1.55, 95% CI 1.09–2.20, respectively]. NAFLD and MAFLD with an advanced fibrosis index were significantly associated with an increased risk of colorectal adenoma. (NAFLD: OR 1.38, 95% CI, 1.04–1.83, p = 0.027; MAFLD: OR 1.45, 95% CI, 1.13–1.96, p = 0.004, respectively). Conclusion: NAFLD and MAFLD were significantly associated with a higher risk of colorectal adenomas, especially in females. NAFLD and MAFLD with advanced fibrosis were associated with an increased risk of colorectal adenoma. Colonoscopic examinations may be emphasized for patients with NAFLD/MAFLD, for women, or patients with the presence of hepatic fibrosis.

Evaluation of a 92 multiplex protein panel in detection of colorectal cancer and high-risk adenoma in 784 symptomatic individuals.

Blood-based protein biomarkers for detection of colorectal cancer (CRC) have been submitted to intense research to improve the full potential in screening for CRC. The aim was to explore the diagnostic performance of 92 proteins related to inflammation and carcinogenesis in detection of CRC or precancerous lesions. Blood-samples were collected from 4,698 individuals undergoing colonoscopy. An explorative unmatched case-control study was designed with 294 cases (individuals with CRC or high-risk colorectal adenoma) and 490 controls (individuals with low-risk colorectal adenoma, non-malignant findings or clean colorectum at colonoscopy). Protein profiling was performed by multiplex proximity extension assay. Statistical analyses were performed as univariate and multivariate logistic regression analyses. Univariably, CSF-1, MMP12 and IL8 demonstrated superior performance in discrimination of individuals with CRC. Recurrently, IL8 was included as contributor in majority of multivariate models discriminating individuals with CRC. The multivariate evaluation in discrimination of individuals with CRC demonstrated AUC=ROC 0.82, sensitivity = 0.39 at specificity = 0.80. Discrimination of individuals with late stage CRC from individuals with clean colorectum demonstrated AUC=ROC 0.90, sensitivity = 0.58 at specificity = 0.80. A subset of biomarker candidates, specifically IL8, investigated in the present study suggest a potential as blood-based biomarkers in screening of CRC.

RNA-sequencing identification and validation of genes differentially expressed in high-risk adenoma, advanced colorectal cancer, and normal controls.

Distinct gene expression patterns that occur during the adenoma-carcinoma sequence need to be determined to analyze the underlying mechanism in each step of colorectal cancer progression. Elucidation of biomarkers for colorectal polyps that harbor malignancy potential is important for prevention of colorectal cancer. Here, we use RNA sequencing to determine gene expression profile in patients with high-risk adenoma treated with endoscopic submucosal dissection by comparing with gene expression in patients with advanced colorectal cancer and normal controls. We collected 70 samples, which consisted of 27 colorectal polyps, 24 cancer tissues, and 19 normal colorectal mucosa. RNA sequencing was performed on an Illumina platform to select differentially expressed genes (DEGs) between colorectal polyps and cancer, polyps and controls, and cancer and normal controls. The Kyoto Gene and Genome Encyclopedia (KEGG) and gene ontology (GO) analysis, gene-concept network, GSEA, and a decision tree were used to evaluate the DEGs. We selected the most highly expressed genes in high-risk polyps and validated their expression using real-time PCR and immunohistochemistry. Compared to patients with colorectal cancer, 82 upregulated and 24 downregulated genes were detected in high-risk adenoma. In comparison with normal controls, 33 upregulated and 79 downregulated genes were found in high-risk adenoma. In total, six genes were retrieved as the highest and second highest expressed in advanced polyps and cancers among the three groups. Among the six genes, ANAX3 and CD44 expression in real-time PCR for validation was in good accordance with RNA sequencing. We identified differential expression of mRNAs among high-risk adenoma, advanced colorectal cancer, and normal controls, including that of CD44 and ANXA3, suggesting that this cluster of genes as a marker of high-risk colorectal adenoma.

Gender difference in metabolic syndrome and incident colorectal adenoma: A prospective observational study (KCIS No.42).

This community-based study aimed to elucidate whether there is a gender difference in the effect of metabolic syndrome (MetS) and its individual components on an elevated risk for incident colorectal adenoma.A prospective cohort study was conducted by enrolling 59,767 subjects aged 40 years or older between 2001 and 2009 in Keelung, Taiwan, to test this hypothesis, excluding those with a prior history of colorectal cancer and those with colorectal cancer diagnosed at the first screening. Cox proportional hazards regression models were used to assess the effect of MetS in terms of a dichotomous classification, each individual component and the number of components for males and females.Colorectal adenoma was present in 2.7% (n = 652) of male participants and 1.1% (n = 403) of female participants. The prevalence rate of MetS was 26.7% and 23.3% for males and females, respectively. The effect of MetS on colorectal adenoma was statistically significant and similar for the 2 genders, with an adjusted hazard ratio (aHR) of 1.33 (95% CI: 1.13–1.58) in males and 1.33 (95% CI: 1.06–1.66) in females after adjustment for confounders. However, MetS led to higher risk of advanced colorectal adenoma in men than in women. Regarding the effect of each component of MetS on colorectal adenoma, abnormal waist circumference and hypertriglyceridemia led to an elevated risk of colorectal adenoma in both genders. A rising risk of colorectal adenoma among females was noted in those with a moderately higher level of glycemia (100–125 mg/dL, aHR = 1.44, 95% CI: 1.12–1.85). Hypertriglyceridemia and high blood pressure were associated with an increased risk of advance colorectal adenoma in males.Both male and female subjects with MetS had a higher risk of colorectal adenoma. The contributions from individual components of MetS varied by gender. These findings suggest that the possible risk reduction of colorectal adenoma through metabolic syndrome-based lifestyle modifications may differ between genders.

Cumulative tea consumption is inversely associated with colorectal adenomas in adults: A cross-sectional study in a Taiwanese population

PurposeThis study examined the association between cumulative tea consumption over time and various colorectal adenomas as well as their pathology, number, and size. Methods7355 eligible subjects who underwent health check-ups with colonoscopies were recruited. They were classified into three groups: polyp-free, having low-risk colorectal adenomas, and having high-risk colorectal adenomas. The adenoma pathology, number, and size were collected. We defined 120 mL for each Chinese traditional teapot as a ‘cup’, and calculated the average daily cups of tea consumed. A ‘cup-year’ was defined as the daily cups multiplied by the years of tea consumption and was used to express the cumulative amount of tea consumption over time. ResultsCompared to those with no habitual tea consumption, the lowest, middle, and highest tertiles of tea consumption were found to be inversely related to low-risk colorectal adenomas. For high-risk colorectal adenomas, a negative association was found only in the group with the highest tertile of tea consumption. An inverse association between the highest tertile of tea consumption and various features of high-risk colorectal adenomas was also found for villous-rich adenomas and the presence of three or more adenomas, but was not found to be related to adenoma size ≥1 cm. ConclusionTea drinking was inversely associated with both low-risk and high-risk colorectal adenomas. Only a larger cumulative dose of ≥42 cup-years was negatively associated with high-risk colorectal adenomas, especially adenomas with villous-rich pathology and when three or more adenomas were present.

Increasing changes in visceral adiposity is associated with higher risk for colorectal adenoma: Multilevel analysis in a prospective cohort.

While many studies demonstrated an association between visceral adiposity and colorectal adenoma (CRA), the effect of longitudinal changes in body fat composition on CRA is unclear. We investigated the longitudinal association between changes in visceral adiposity and CRA occurrence. Between 2006 and 2018, 732 (62.8%) of the 1165 subjects in a prospective cohort voluntarily underwent follow-up abdominal fat computed tomography and colonoscopy. We defined incident and recurrent CRA as adenoma detected at follow-up colonoscopy from negative and positive adenoma at baseline colonoscopy, respectively. Multilevel survival analysis examined the longitudinal association between changes in visceral fat and CRA. During a median follow-up of 7.4years, 400 (54.6%) subjects developed CRA. In multivariable analysis, increasing changes in visceral adipose tissue (VAT) area were associated with higher risk of incident adenoma (hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.00-1.46 for change per 10cm2 increase; HR 1.79, 95% CI 1.08-2.97 for highest vs lowest quartile, P values for trend=0.045). Likewise, increasing changes in VAT area were independently associated with a higher risk of recurrent adenoma (HR 1.35, 95% CI 1.13-1.62 for change per 10cm2 increase; HR 1.62, 95% CI 1.04-2.52 for highest vs lowest quartile, P values for trend=0.001). Changes in subcutaneous adipose tissue area were not independently associated with CRA. Increasing changes in VAT area were longitudinally associated with a higher risk of incident and recurrent CRA, independent of risk factors, suggesting that visceral adiposity may be an important target in CRA prevention.

The Behavior of MMP-2, MMP-7, MMP-9, and Their Inhibitors TIMP-1 and TIMP-2 in Adenoma-Colorectal Cancer Sequence

Background: We and others have previously shown that matrix metalloproteinases (MMPs) play a role in colorectal cancer (CRC) invasion and metastasis. However, the serum changes of various MMPs and their inhibitors (TIMPs) have scarcely been concomitantly investigated in identical blood samples in the normal colon-adenoma-CRC sequence. Methods: The MMP-2, MMP-7, MMP-9, TIMP-1, and TIMP-2 serum antigen concentrations were determined concomitantly in 19 tumor-free control patients, 19 patients with high-risk colorectal adenoma, and 47 patients with CRC by ELISA technique. The analyzed parameters were also investigated in correlation with CRC stages. Statistical analysis with one-way ANOVA and Student’s t test was performed. p values <0.05 were considered significant. Results: Serum antigen levels of MMPs and TIMPs were significantly increased in patients with CRC and adenomas compared to controls (mean values, ng/mL) (MMP-7: 5.88, 4.44, and 2.89, respectively, p = 0.001; MMP-9: 1,075.81, 999.22, and 845.97, respectively, p = 0.01; TIMP-1: 241.80, 205.98, and 166.53, respectively, p = 0.001; TIMP-2: 83.40, 80.30, and 69.62, respectively, p = 0.01). The elevated serum MMP-7, MMP-9, TIMP-1, and TIMP-2 levels significantly correlated with advanced tumor stages (p < 0.05). No statistically significant differences were observed in MMP-2 levels. Conclusions: We demonstrate that serum antigen concentrations of MMP-7, MMP-9, TIMP-1, and TIMP-2 were significantly increased in patients with CRC and adenomas compared to controls. These results suggest that MMPs and their inhibitors TIMP-1 and TIMP-2 play an important role in CRC invasion; however, they are also activated in premalignant adenomas. Furthermore, MMP-7, MMP-9, TIMP-1, and TIMP-2 may have a potential prognostic impact in CRC.

Abstract 1143: Circulating 27-hydroxycholesterol and risk of metachronous colorectal adenomas

Abstract Purpose: Oxysterols are cholesterol metabolites thought to play a role in basic carcinogenic mechanisms. One of the most abundant oxysterols in circulation is 27-hydroxycholesterol (27HC), which has been shown to be an endogenous selective estrogen receptor modulator and implicated in breast cancer etiology. 27HC is a ligand for liver X receptors expressed in the liver, gut, adipose tissue, and macrophages. In the colorectum, expression of these receptors suppresses cellular proliferation. It is unknown whether circulating 27HC is associated with the risk of developing colorectal neoplasia. Methods: Circulating 27HC was measured in plasma collected at baseline from participants of the Vitamin D/Calcium Polyp Prevention Study, a completed placebo-controlled randomized clinical trial of daily supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas. Participants were 2,259 men and women, 45-75 years old, diagnosed with ≥1 colorectal adenoma within 120 days prior to enrollment. Each was followed for new colorectal adenomas during a 3- or 5-year colonoscopy surveillance interval. 27HC concentrations were quantified using high-performance liquid chromatography/mass spectrometry for those who reported fasting ≥8 hours at the time of blood draw. Premenopausal women and postmenopausal women currently using hormone therapy were excluded from analyses. Risk ratios (RR) and 95% confidence intervals (CI) were estimated from log-linear regression models with adjustment for sex, age, race/ethnicity, body mass index, smoking status, family history of colorectal cancer, aspirin use, nonsteroidal anti-inflammatory drug use, and former use of postmenopausal hormone therapy. High-risk colorectal adenoma findings were defined as ≥1 advanced adenoma (≥1 cm in diameter, with 25% villous components, high-grade dysplasia, or adenocarcinoma) or ≥3 synchronous adenomas of any type. Secondary analyses considered results stratified by sex and anatomic location of lesions (proximal colon vs. distal colon/rectum). Results: In total, 27HC was measured for 1,246 participants (894 men and 352 women). Circulating 27HC was higher among men (mean, 181 ng/mL; standard deviation, SD, 49 ng/mL) than among postmenopausal women (mean, 154 ng/mL; SD, 46 ng/mL). During follow-up, 596 (46%) participants were diagnosed with ≥1 new colorectal adenoma. Circulating 27HC was associated with 9% higher risk of any colorectal adenoma per SD increase (RR, 1.09; 95% CI, 1.02-1.15; P=0.008) and 19% higher risk of high-risk colorectal adenoma findings per SD increase (RR, 1.19; 95% CI, 1.07-1.33; P=0.002). Sex-stratified results were of similar magnitude, and there were no meaningful differences according to anatomic location of adenomas. Conclusions: Circulating 27HC concentration may be a novel risk factor for metachronous colorectal adenomas. Citation Format: Michael N. Passarelli, Bonne M. Thompson, Jeffrey G. McDonald, Thomas J. Palys, Judy R. Rees, Elizabeth L. Barry, John A. Baron. Circulating 27-hydroxycholesterol and risk of metachronous colorectal adenomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1143.

High risk of colorectal polyps in men with non-alcoholic fatty liver disease: A systematic review and meta-analysis.

This meta-analysis aims to explore the risk of colorectal polyps among non-alcoholic fatty liver disease (NAFLD) patients. We searched PubMed, EMBASE, and Cochrane library databases using predefined search term to identify eligible studies (published up to 7 November 2019). Data from selected studies were extracted by using a standardized information collection form, and meta-analyses were performed using random-effects model. The statistical heterogeneity among studies (I2 ), subgroup analyses, meta-regression analyses, and the possibility of publication bias were assessed. Twenty observational (12 cross-sectional, two case-control, and six cohort) studies met the eligibility criteria, involving 142387 asymptomatic adults. In cross-sectional/case-control studies, NAFLD was found to be associated with an increased risk of colorectal polyps (odds ratio [OR]=1.34; 95% confidence interval [CI]=1.23-1.47) (including unclassified colorectal polyps, hyperplastic polyps, adenomas, and cancers) with statistically significant heterogeneity (I2 =67.8%; P<0.001). NAFLD was also associated with a higher risk of incident colorectal polyps (hazard ratio=1.60; 95% CI=1.36-1.87) with low heterogeneity (I2 =21.8%; P=0.263) in longitudinal studies. The severity of NAFLD was associated with a higher risk of colorectal adenomas (OR=1.57; 95% CI=1.30-1.88), but not colorectal cancer (OR=1.37; 95% CI=0.92-2.03). The subgroup analysis according to gender showed that NAFLD was significantly associated with a higher risk of colorectal polyps in the male population without significant heterogeneity (OR=1.47; 95% CI=1.29-1.67, I2 =0%), but not in the female population (OR=0.88; 95% CI=0.60-1.29, I2 =34.2%). NAFLD was associated with an increased risk of colorectal polyps. There was a significant difference of the relationship between genders, which suggested more precise screening colonoscopy recommendation in NAFLD patients according to gender.

Risk for Colorectal Neoplasia in Patients With Helicobacter pylori Infection: A Systematic Review and Meta-analysis.

OBJECTIVES:Helicobacter pylori may reportedly be associated with extragastric malignancy beyond gastric cancer. The present study aimed to evaluate the association between H. pylori infection and colorectal neoplasia through a systematic review and meta-analysis.METHODS:The literature search aimed to retrieve all relevant studies published up to September 2019 that examined the risk for colorectal neoplasia including colorectal adenoma, advanced adenoma, and cancer in patients with H. pylori infection. Meta-analysis was performed to calculate pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs). If publication bias was observed, the pooled OR was adjusted using the trim-and-fill method.RESULTS:Forty-eight studies including 171,045 patients were evaluated, of which 24, 8, and 31 reported H. pylori-associated risk for adenoma, advanced adenoma, and cancer, respectively. H. pylori infection was associated with a significantly higher risk for colorectal adenoma (pooled OR 1.49 [95% CI 1.37–1.62]). H. pylori infection was also associated with a higher risk for advanced colorectal adenoma (pooled OR 1.50 [95% CI 1.28–1.75]). The risk for colorectal cancer in patients with H. pylori infection was also identified (pooled OR 1.44 [95% 1.26–1.65]). Although publication bias was identified in the analysis for colorectal adenoma, the pooled estimate was not significantly changed after adjustment (pooled OR 1.39 [95% CI 1.27–1.52]).DISCUSSION:Although this meta-analysis based on the observational studies could not show causality, it demonstrated that colorectal adenoma, advanced adenoma, and cancer were all associated with H. pylori infection.

Low folate status, and MTHFR 677C > T and MTR 2756A > G polymorphisms associated with colorectal cancer risk in Thais: a case-control study

Folate plays essential roles in DNA synthesis, repair, and methylation; thus, folate status may affect carcinogenesis. Genetics polymorphisms involved in folate metabolisms have been linked with colorectal cancer (CRC) development. Therefore, we hypothesized that low folate status and related genetic polymorphisms are associated with higher risk of CRC. This case-control study enrolled 105 new cases of CRC, 101 of colorectal adenoma (CRA), and 182 controls from hospitals in Bangkok, Thailand, to examine the association between folate status and methylenetetrahydrofolate reductase (MTHFR) 677C > T, methionine synthase (MTR) 2756A > G, and methionine synthase reductase (MTRR) 66A > G with the risk of CRC and CRA. Regarding CRC risk, the lowest quartile group of serum folate and folate intake had higher risk of CRC than the highest quartile group (odds ratio [OR] = 11.45, 95% confidence interval [CI] = 4.43-29.59) and (OR = 10.29, 95% CI = 4.17-25.41). The lowest quartile group of folate intake also had a higher risk of CRA (OR = 5.22, 95% CI = 2.19-6.09). Low red blood cell folate combined with MTHFR 677C > T polymorphism statistically increased CRC risk (OR = 10.00, 95% CI = 1.36-73.42). Low folate status combined with MTR 2756A > G significantly increased CRA risk (OR = 6.43, 95% CI = 1.38-29.94). Moreover, the risk of CRC was elevated with alcohol consumption and low exercise activity when combined with low folate status (P < .05). This study supported the hypothesis that, in Thais, low folate status is associated with a higher risk of CRC, particularly among those with polymorphisms of the MTHFR 677C > T and MTR 2756 A > G genes.