Development Of Colonic Adenomas Research Articles

Optimal glycaemic control and the reduced risk of colorectal adenoma and cancer in patients with diabetes: a population-based cohort study

ObjectiveWhether varying degrees of glycaemic control impact colonic neoplasm risk in patients with diabetes mellitus (DM) remains uncertain.DesignPatients with newly diagnosed DM were retrieved from 2005 to 2013. Optimal glycaemic...

Expression of apoptosis repressor with caspase recruitment domain (ARC) in familial adenomatous polyposis (FAP) adenomas and its correlation with DNA mismatch repair proteins, p53, Bcl-2, COX-2 and beta-catenin

BackgroundColorectal familial adenomatous polyposis (FAP) adenomas exhibit a uniform pathogenetic basis caused by a germline mutation in the adenomatous polyposis gene (APC), but the molecular changes leading to their development are incompletely understood. However, dysregulated apoptosis is known to substantially affect the development of colonic adenomas. One of the key regulatory proteins involved in apoptosis is apoptosis repressor with caspase recruitment domain (ARC).MethodsThe expression of nuclear and cytoplasmic ARC in 212 adenomas from 80 patients was analyzed by immunohistochemistry. We also compared expression levels of ARC with the expression levels of p53, Bcl-2, COX-2, and MMR proteins. Statistical analyses were performed by Spearman’s rank correlation and linear regression test.ResultsARC was overexpressed in the nuclei and cytoplasm of most FAP adenomas investigated. Cytoplasmic ARC staining was moderately stronger (score 2) in 49.1% (n = 104/212) and substantially stronger (score 3) in 32.5% (n = 69/212) of adenomas compared to non-tumorous colorectal mucosa. In 18.4% (n = 39/212) of adenomas, cytoplasmic ARC staining was equivalent to that in non-tumorous mucosa.Nuclear expression of ARC in over 75% of cells was present in 30.7% (n = 65/212) of investigated adenomas, and nuclear expression in 10–75% of cells was detected in 62.7% (n = 133/212). ARC expression in under 10% of nuclei was found in 6.6% (n = 14/212) of adenomas.The correlation between nuclear ARC expression and cytoplasmic ARC expression was highly significant (p = 0.001). Moreover, nuclear ARC expression correlated positively with overexpression of Bcl-2, COX-2 p53 and β-catenin. Cytoplasmic ARC also correlated with overexpression of Bcl-2. Sporadic MMR deficiency was detected in very few FAP adenomas and showed no correlation with nuclear or cytoplasmic ARC.ConclusionsOur results demonstrated that both cytoplasmic and nuclear ARC are overexpressed in FAP adenomas, thus in a homogenous collective. The highly significant correlation between nuclear ARC and nuclear β-catenin suggested that ARC might be regulated by β-catenin in FAP adenomas. Because of its further correlations with p53, Bcl-2, and COX-2, nuclear ARC might play a substantial role not only in carcinomas but also in precursor lesions.98uN_KvtZQTaRuojLZPqfUVideo

Increased BMI, Sedentary Lifestyle & Metabolic Syndrome as Independent Risk Factors for Development of Colorectal Adenomas: A Prospective Study

<i>Background</i>: Several risk factors for development of colorectal adenomas has been studied over the years. But the effect of increased BMI, sedentary lifestyle and metabolic syndrome on the development of colorectal adenoma has been minimally studied. This study describes the influence of increased BMI, sedentary lifestyle & metabolic syndrome on the prevalence of colorectal adenoma. Secondary objective was to determine whether these factors influence the progression of benign adenomas into advanced adenomas or not. <i>Methods</i>: A total of 697 consecutive cases were included. Asymptomatic subjects aged more than 40 years who were undergoing their first colonoscopy were included in the study. Patients with a history of colonic neoplasia, IBD, colonoscopic polypectomy or colectomy were excluded from the study. Details of colonoscopy, polypectomy and histology were recorded. Data were analyzed by SPSS version 22.0. Chi-square (X²) test was done to assess the association of different risk factors with the development of colonic adenomas. Odds ratio (OR) along with its 95% CI was calculated for every individual risk factor under evaluation. A p-value<0.05 was considered as significant. <i>Result</i>: Colonic polyps were detected in 153 (21.95%) subjects. Out of these 153 subjects 81 (11.62%) had histologically proved adenomas. Benign adenomas were detected in 63 (9.03%) cases, whereas advanced adenomas were detected in 18 (2.58%) cases. A BMI of≥30 showed an OR of 2.94 (1.64-4.24) for the development of colorectal adenomas. Presence of metabolic syndrome showed an OR of 1.74 (1.14-2.34) for the development of adenomas. Sedentary lifestyle showed an OR of 1.91 (1.31-2.51) for the development of colorectal adenomas. An age of≥50 years also showed significant effect (OR=1.39) on the development of colonic adenomas. Lastly the presence of increased BMI, sedentary lifestyle and metabolic syndrome was identified as individual risk factors for the progression of adenoma towards advanced adenomas with an OR of 1.67, 2.14 & 2.92 respectively. <i>Conclusion</i>: This study demonstrates that increased BMI, sedentary lifestyle and metabolic syndrome are associated with increased risk of development of colorectal adenomas. Moreover, increasing age (>50 years) also contribute to the increased risk of development of colorectal adenomas. And lastly it has been showed that increased BMI, sedentary lifestyle and metabolic syndrome individually contribute to the increased risk of progression of benign colonic adenomas to a more advanced adenoma.

Black raspberries attenuate colonic adenoma development in Apc Min mice: Relationship to hypomethylation of promoters and gene bodies.

Recent studies have suggested that in addition to promoter region, DNA methylation in intragenic and intergenic regions also changes during physiological processes and disease. The current study showed that feeding of black raspberries (BRBs) to ApcMin mice suppressed colon and intestinal tumors. MBDCap-seq suggested that dietary BRBs hypomethylated promoter, intragenic, and intergenic regions. Annotation of those regions highlighted genes in pathways involved in immune regulation, inflammatory signaling, production of nitric oxide and reactive oxygen species, and progression of colorectal cancer. BRB phytochemicals (e.g., ellagic acid, anthocyanins, oligosaccharides) and their gut bacterial metabolites (e.g., urolithin, protocatechuic acid, short-chain fatty acids) inhibited DNMT1 and DNMT3B activities in a cell-free assay. Our results suggest that BRBs’ hypomethylating activities result from the combined effects of multiple BRB phytochemicals and their gut bacterial metabolites. Because similar substances are found in many plant products, our results with BRBs might also apply to commonly consumed fruits and vegetables.

Type 2 diabetes impacts colorectal adenoma detection in screening colonoscopy

Background: Diabetes is associated with an increased risk of colorectal cancer (CRC). We conducted a retrospective analysis of adenoma detection rates (ADR) in initial screening colonoscopies to further investigate the role of diabetes in adenoma detection. Methods: A chart review was performed on initial average risk screening colonoscopies (ages 45–75) during 2012–2015. Data collected included basic demographics, insurance, BMI, family history of CRC, smoking, diabetes, and aspirin use. Multivariable generalized linear mixed models for binary outcomes were used to examine the relationship between diabetes and variables associated with CRC risk and ADR. Results: Of 2865 screening colonoscopies, 282 were performed on patients with type 2 diabetes (T2DM). Multivariable analysis suggested that T2DM (OR = 1.49, 95% CI:1.13–1.97, p = 0.0047) was associated with an increased ADR, as well as smoking, older age, higher BMI and male sex (all p < 0.05). For patients with T2DM, those not taking diabetes medications were more likely to have an adenoma than those taking medication (OR = 2.38, 95% CI:1.09–5.2, p = 0.03). Conclusion: T2DM has an effect on ADR after controlling for multiple confounding variables. Early interventions for prevention of T2DM and prescribing anti-diabetes medications may reduce development of colonic adenomas and may contribute to CRC prevention.

Inflammation, etiologies and Model for End-stage Liver Disease score: What makes liver disease patients susceptible to developing colorectal neoplasia?

AimResearch has identified patients with chronic liver disease as a risk group for colorectal neoplasia. In this study, we aimed to identify liver disease subgroups at enhanced risk of developing colorectal neoplasia, as well as causal factors.MethodsThe present retrospective study included patients with chronic liver disease undergoing colonoscopy during liver transplantation evaluations, and liver‐healthy patients as part of the German screening protocol. We assessed inflammatory laboratory values, Model for End‐stage Liver Disease score, portal hypertension, and liver disease etiologies as explanatory variables. Outcomes included polyps, adenomas, high‐risk situations, and colorectal cancer, tested in uni‐ and multivariable analyses.ResultsA total of 1046 patients were included, 407 with liver disease, 639 without. Alcohol‐toxic, metabolic, cryptogenic, non‐alcoholic fatty liver disease, and hepatocellular carcinoma were significantly associated with colorectal neoplasia, as were low compared with high Model for End‐stage Liver Disease scores. Portal hypertension showed no associations with neoplasia. Inflammatory markers were associated with colorectal neoplasia, independent of liver disease severity.ConclusionsLow Model for End‐stage Liver Disease score, inflammatory markers, and certain etiologies were associated with colorectal neoplasia. Our findings suggest that inflammation may play an important role in the development of colonic adenomas in patients with chronic liver disease. Findings need to be confirmed in prospective studies, but may allow risk stratification and, possibly, development of prophylactic treatments.

Genome-wide DNA methylation analysis of colorectal adenomas with and without recurrence reveals an association between cytosine-phosphate-guanine methylation and histological subtypes.

Aberrant methylation of DNA is supposed to be a major and early driver of colonic adenoma development, which may result in colorectal cancer (CRC). Although gene methylation assays are used already for CRC screening, differential epigenetic alterations of recurring and nonrecurring colorectal adenomas have yet not been systematically investigated. Here, we collected a sample set of formalin-fixed paraffin-embedded colorectal low-grade adenomas (n = 72) consisting of primary adenomas without and with recurrence (n = 59), recurrent adenomas (n = 10), and normal mucosa specimens (n = 3). We aimed to unveil differentially methylated CpG positions (DMPs) across the methylome comparing not only primary adenomas without recurrence vs primary adenomas with recurrence but also primary adenomas vs recurrent adenomas using the Illumina Human Methylation 450K BeadChip array. Unsupervised hierarchical clustering exhibited a significant association of methylation patterns with histological adenoma subtypes. No significant DMPs were identified comparing primary adenomas with and without recurrence. Despite that, a total of 5094 DMPs (false discovery rate <0.05; fold change >10%) were identified in the comparisons of recurrent adenomas vs primary adenomas with recurrence (674; 98% hypermethylated), recurrent adenomas vs primary adenomas with and without recurrence (241; 99% hypermethylated) and colorectal adenomas vs normal mucosa (4179; 46% hypermethylated). DMPs in cytosine-phosphate-guanine (CpG) islands were frequently hypermethylated, whereas open sea- and shelf-regions exhibited hypomethylation. Gene ontology analysis revealed enrichment of genes associated with the immune system, inflammatory processes, and cancer pathways. In conclusion, our methylation data could assist in establishing a more robust and reproducible histological adenoma classification, which is a prerequisite for improving surveillance guidelines.

Serum MicroRNA profile in patients with colon adenomas or cancer

BackgroundColon cancer, one of the most common causes of cancer-related deaths, arises from adenomatous polyps. In these years, circulating microRNAs (miRNAs) have attracted increasing attention as novel biomarkers for colon cancers. The dysregulated circulating miRNAs in patients with colon adenomas has not been well-understood.MethodsHere, we aimed to identify miRNA profile in the serum of patients with colon adenomas or colon cancer by using microarray. Then we validated eight differentially expressed miRNAs (DEMs) by qRT-PCR and predicted their targets.ResultsWe identified 26 DEMs from Adenomas versus Normal comparison (11 up-regulations and 15 down-regulations), 72 DEMs from Cancer versus Normal comparison (19 up-regulations and 53 down-regulations) and 17 DEMs from Cancer versus Adenomas comparison (4 up-regulations and 13 down-regulations). Moreover, three DEMs identified from Cancer versus Normal comparison were included in the list of DEMs identified from Cancer versus Adenomas comparison, and may be specific diagnostic biomarkers for colon cancer. Five down-regulated miRNAs identified from Cancer versus Normal comparison were included in the list of DEMs identified from Adenomas versus Normal comparison, and may be important for the development of colon polyps and cancer.ConclusionsWe discovered 8 circulating miRNAs associated with colon adenomas and colon cancer, and these miRNAs may potentially serve as noninvasive screening biomarkers for colon cancer. Our study is useful for expanding our understanding in the development of colon adenomas and colon cancer, and thus provide novel insights into colon cancer pathogenesis and prevention.

Su1764 - Poorly Controlled Diabetes and Morbid Obesity Increase the Risk of Precancerous Colonic Adenoma Development in Initial Colonoscopies

Su1764 - Poorly Controlled Diabetes and Morbid Obesity Increase the Risk of Precancerous Colonic Adenoma Development in Initial Colonoscopies

Loss of free fatty acid receptor 2 enhances colonic adenoma development and reduces the chemopreventive effects of black raspberries in ApcMin/+ mice.

We previously showed that black raspberries (BRBs) have beneficial effects in human colorectal cancer and a mouse model of colorectal cancer (ApcMin/+). The current study investigated the role of free fatty acid receptor 2 (FFAR2) in colon carcinogenesis and whether the FFAR2 signaling pathway contributes to BRB-mediated chemoprevention in mice. FFAR2 (also named GPR43) is a member of the G-protein-coupled receptor family that is expressed in leukocytes and colon. ApcMin/+ and ApcMin/+-FFAR2-/- mice were given a control diet or the control diet supplemented with 5% BRBs for 8 weeks. FFAR2 deficiency promoted colonic polyp development, with 100% incidence and increased polyp number and size. The ApcMin/+ mice developed colonic tubular adenoma, whereas the ApcMin/+-FFAR2-/- mice developed colonic tubular adenoma with high-grade dysplasia. FFAR2 deficiency also enhanced the cAMP-PKA-CREB-HDAC pathway, downstream of FFAR2 signaling, and increased activation of the Wnt pathway, and raised the percentage of GR-1+ neutrophils in colonic lamina propria (LP) and increased infiltration of GR-1+ neutrophils into colonic polyps. BRBs suppressed colonic polyp development and inhibited the cAMP-PKA-CREB-HDAC and Wnt pathways in the ApcMin/+ mice but not the ApcMin/+-FFAR2-/- mice. They also increased the percentage of GR-1+ neutrophils and cytokine secretion in colonic LP and decreased the infiltration of GR-1+ neutrophils and IL-1β expression in colon polyps of ApcMin/+ mice but not ApcMin/+-FFAR2-/- mice. These results suggest that loss of FFAR2 drives colon tumorigenesis and that BRBs require functional FFAR2 to be chemopreventive. BRBs have the potential to modulate the host immune system, thereby enhancing the antitumor immune microenvironment.

Black raspberries suppress colonic adenoma development in ApcMin/+ mice: relation to metabolite profiles.

Freeze-dried black raspberries (BRBs) have demonstrated chemopreventive effects in a dietary intervention trial with human colorectal cancer patients. The aim of this study was to investigate BRB-caused metabolite changes using the Apc(Min/+) mouse as a model of human colorectal cancer. Wild-type (WT) mice were fed control diet, and Apc(Min/+) mice were fed either control diet or control diet supplemented with 5% BRBs for 8 weeks. Colonic and intestinal polyp size and number were measured. A non-targeted metabolomic analysis was conducted on colonic mucosa, liver and fecal specimens. Eight weeks of BRB treatment significantly decreased intestinal and colonic polyp number and size in Apc(Min/+) mice. The apc gene mutation significantly changed 52 metabolites in colonic mucosa associated with increased amino acid and decreased lipid metabolites, as well as 39 liver and 8 fecal metabolites. BRBs significantly reversed 23 apc-regulated metabolites, including 13 colonic mucosa, 8 liver and 2 fecal metabolites that were involved in amino acid, glutathione, lipid and nucleotide metabolism. Of these, changes in eight metabolites were linearly correlated with decreased colonic polyp number and size in BRB-treated Apc(Min/+) mice. Elevated levels of putrescine and linolenate in Apc(Min/+) mice were significantly decreased by BRBs. Ornithine decarboxylase expression, the key enzyme in putrescine generation, was fully suppressed by BRBs. These results suggest that BRBs produced beneficial effects against colonic adenoma development in Apc(Min/+) mice and modulated multiple metabolic pathways. The metabolite changes produced by BRBs might potentially reflect the BRB-mediated chemopreventive effects in colorectal cancer patients.

Sox9 Induction, Ectopic Paneth Cells, and Mitotic Spindle Axis Defects in Mouse Colon Adenomatous Epithelium Arising From Conditional Biallelic Apc Inactivation

We generated transgenic mice in which human CDX2 gene elements control expression of a tamoxifen-regulated Cre protein (CDX2P-CreER(T2)) to allow for inducible gene targeting in intestinal epithelium. After tamoxifen dosing of CDX2P-CreER(T2) mice, Cre activity was detected in the distal ileal, cecal, colonic, and rectal epithelium, with selected crypt base, transit amplifying, and surface cells all capable of activating Cre function. Four weeks after tamoxifen dosing of CDX2P-CreER(T2) mice carrying a Cre-activated fluorescent reporter, single crypts were uniformly fluorescence positive or negative, reflecting Cre activation in crypt stem cells. Biallelic inactivation of the Apc tumor suppressor gene via the CDX2P-CreER(T2) transgene in colon epithelium led to acute alterations in cell proliferation, apoptosis, and morphology, along with mitotic spindle misorientation, β-catenin nuclear localization, and induction of the intestinal stem cell markers Lgr5 and Musashi-1 and the Sox9 transcription factor. Normal mouse colon epithelium lacks Paneth cells, a key small intestine niche cell type, and Paneth cell differentiation is dependent on Sox9 function. In Apc-deficient colon epithelium, ectopic Paneth-like cells were seen outside the crypt base, such as new crypt budding sites. Our data indicate Apc inactivation via CDX2P-CreER(T2) targeting in mouse colon epithelium is sufficient to induce adenomatous changes and the generation of Paneth-like cells from neoplastic progenitors, with potentially significant roles in colon adenoma development and progression.

Prevention of colorectal cancer and dietary management.

This systematic review focuses on dietary and lifestyle risk factors for colorectal cancer (CRC) prevention and chemoprevention among high-risk populations. We searched PubMed for English-language articles about dietary components, lifestyle risk factors, and chemoprevention agents in relation to colorectal cancer and their references published from 1980 through 2013. We reviewed articles jointly for the most clinically important information, emphasizing randomized trials and meta-analyses where available. There is convincing evidence that intake of garlic, vitamin B6 and magnesium, active living, maintaining a healthy weight and waist, avoiding or reducing red meat, alcohol, and smoking, as well as hormone replacement therapy among women may significantly protect against developing colorectal cancer. There is less consistent evidence for fruit and vegetable intake (fiber and folate), fish and Omega-3 fatty acids, selenium, dairy, calcium and vitamin D. For high-risk populations, aspirin have been shown to protect against the development of colonic adenomas and CRC, while a minimal effective dose remains unclear. Colorectal cancer can be prevented in general population through dietary and lifestyle interventions, and aspirin may be a good choice of chemoprevention agent among high risk individuals.

Sa1515 Should We Keep HIV Infected Patients in the Average-Risk Screening Category? a Sub-Analysis of the Comp (Colonoscopy Outcomes in Minority Population) Registry Data

Should We Keep HIV Infected Patients in the Average-Risk Screening Category? a Sub-Analysis of the Comp (Colonoscopy Outcomes in Minority Population) Registry Data Manhal Olaywi*, Shashideep Singhal, Kinesh Changela, Deepanshu Jain, Devin Lane, Mojdeh Momeni, Mahesh Krishnaiah, Sushil Duddempudi, Sury Anand Gastorenterology, The Brooklyn Hospital Center, Brooklyn, NY Introduction: Human Immunodeficiency Virus (HIV) infected patients have altered immune system and host defenses that affect their predisposition to cancers. There is limited literature to elucidate the effect of HIV on colorectal carcinogenesis and precancerous colonic adenomas. The analysis was targeted to determine the differences in development of colonic adenomas in HIV infected subjects in comparison to general population. Methods: The subjects with HIV were selected from the COMP registry at our institution using ICD 9 code. Subjects presenting for screening colonoscopy age 50 to 75 years were included, while colonoscopies done for evaluation of symptoms or surveillance of prior malignancy were excluded. The demographic, clinical, and pathological data of study subjects were analyzed using SPSS statistical software to compare HIV positive and control group. Results: A total of 1775 colonoscopies met the inclusion criteria with 115 subjects who were identified as HIV positive and 1660 in control group. Racial distribution was African Americans 58%, Hispanics 32% and 10% others. There was a predominance of males in the HIV group 60% in comparison to control group 40% (p 0.01). There were no other significant differences in demographics of HIV group in comparison to controls. A significantly higher proportion of HIV patients had poor bowel preparation 14.8% in comparison to control group 9.5% (p 0.05), hence were excluded from the analysis to exclude the confounding effect. The adenoma detection rate (ADR) for the HIV group 13% was lower 13% in comparison to the controls 23.6% (P 0.001). The advanced adenoma detection rate (AaDR) was also lower in the HIV group 7.8%, while it was 14% in the control group (P 0.03). On a multivariate analysis HIV positivity was independently associated with lower ADR and AaDR. Conclusion: In our study, the prevalence of pre-malignant colonic adenomas and advanced adenomas in HIV-infected patients was lower than the HIV negative patients. These data support the current practice of screening HIV-infected according to the average-risk screening guidelines.

855 Racial Differences in Outcome of Colonoscopy in Young Adults (

Identification and removal of colonic adenomas is the corner stone of our colorectal cancer prevention program. There has been a concern of earlier development of colonic adenomas in adults < 50 years of age especially in high risk ethnic groups. There are very limited studies done to determine the yield of colonoscopy in young minority adults.

Abstract 3710: Targeted inhibition of arginase-1 may underline the suppression of the development of colonic neoplasia in a transgenic APC Min mouse model.

Abstract Colorectal cancer (CRC) is the third-leading malignancy in the United States. This year alone, about 141,210 new cases of colorectal cancer will be diagnosed and more than 49,380 people will die from the disease. Strategies have focused on early screening practices and the prevention of the development of colonic adenomas that serve as precursors of invasive colon cancers. We have recently showed that chloroquine (CQ) an anti-malarial and anti-rheumatoid agent has the capacity to competitively inhibit intracellular arginase-1 (ARG-1) and that this inhibition increases the nuclear localization of the cell cycle regulator p53 protein in colon cancer cell lines. However, the mechanism of CQ-induced inhibition of ARG-1 that results in the up-regulation of p53 is unclear. The goal of the current study was to examine the chemopreventive efficacy of CQ in the development of colonic neoplasia and to further evaluate the possible mechanism(s) of action. In this regard, six weeks old Apc(Min/+) mice were treated daily (except Saturdays and Sundays) with 0-50 mg CQ/kg body wt. via oral gavage for forty days. Post-treatment, mice were sacrificed and jejunum and colon were retrieved and preserved in 10% formalin for observation of any gross pathological changes. The results of this study showed an increased in prevalence of colonic adenomas in untreated mice compared with treated mice (&amp;lt; 0.05). Interestingly, histochemical analysis showed significant numbers of adenomas with high-grade dysplasia (as evidenced by the presence of increased fibrous tissue core) in untreated control mice in comparison with drug-treated mice (&amp;lt;0.05).Since emerging studies have identified the overexpression of ARG-1 in a variety of human malignancies, including cancer of the colon, we then investigated the impact of CQ on ARG-1 levels. To this end, HT-29 cells were co-incubated with CQ (0-50 μM) for 24 h and the levels of ARG-1 were determined by western blot assay. Surprisingly, our result showed that CQ-induced inhibition of ARG-1 level corresponded to the diminution of β-catenin protein via to its phosphorylation. Further immuno- fluorescence analysis showed an increased level of nuclear localization of GFP tagged p53 (GFP-p53) and p21 in transiently transfected HT-29 cells upon CQ treatment. The observation that targeting ARG-1 results in a corresponding decrease in β-catenin level is intriguing, since the Wnt/β-catenin signaling is fundamental to colon carcinogenesis and spontaneous tumorigenesis in Apc(Min/+) mice and patients with familial adenomatous polyposis.In conclusion, our cumulative findings indicate that CQ ameliorates the development of colonic neoplasia and that the inhibition of ARG-1 and β-catenin may contribute to its chemopreventive effects in intestinal tumorigenesis. Citation Format: Efe W. Iyamu, Mohammad S. Niaz, Aramandla Ramesh, Amos Sakwe, Kieosha Williams, Billy R. Ballard, Samuel E. Adunyah. Targeted inhibition of arginase-1 may underline the suppression of the development of colonic neoplasia in a transgenic APC Min mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3710. doi:10.1158/1538-7445.AM2013-3710

Racial differences in measures of obesity and risk of colon adenoma.

Obesity is an established risk factor for several malignancies. However, the specific measurement of obesity most relevant to colon neoplasia is still debated, and evidence has suggested gender and racial differences in this measurement. In this study, we sought to compare which measurement--BMI, waist circumference (WC), waist-to-hip ratio (WHR) or waist-to-height ratio (WHtR)--is most strongly associated with development of colon adenomas, a precursor of colon cancer, and to investigate differences in this association between racial groups. We confirmed the strong association between WHR, as a measure of central obesity, and development of colon neoplasia. In our overall analysis, patients in the highest WHR quartile showed a substantial increase in risk of colon adenomas compared to patients in the lowest WHR quartile (odds ratio (OR) = 1.82, 95% confidence interval (CI): 1.12-2.71, P(trend) = 0.0017). In stratified analyses, we noted that strongly associated obesity measures in European Americans were WC (OR = 2.38, 95% CI = 1.45-3.92, P(trend) = 0.0004) and BMI (OR = 2.18, 95% CI = 1.37-3.49, P(trend) = 0.0015), whereas in African Americans, WHR was the strongest and the only obesity measure statistically significantly associated with adenoma risk (OR = 2.12, 95% CI = 1.05-4.30, P(trend) = 0.025). Our data highlight the importance of obesity in the development of early colon neoplasia and suggest substantial racial differences in the measures of obesity most strongly associated with risk of colon adenomas.

Thrombin Supports Colitis and Colitis-Associated Cancer Pathogenesis

Abstract 2237Chronic inflammation has been recognized as a major factor in the development and progression of multiple cancers. A prime example of this is the strong association between colitis and colon cancer. However, the specific factors that regulate disadvantageous immune processes in the context of inflammation-associated cancers remain poorly defined. Growing evidence suggests that hemostatic system components, traditionally associated with the maintenance of vascular integrity and prevention of blood loss, also directly regulate inflammatory processes. Furthermore, thrombin and several thrombin targets (e.g., PARs, fibrinogen, factor XIII) have been shown to regulate tumor cell proliferation and apoptosis, support metastasis, and protect tumor cells from innate immune surveillance mechanisms in other experimental contexts. A logical extension of these findings is the hypothesis that thrombin, as a master regulator of both inflammatory processes and tumor cell biology, is a major determinant of the progression of inflammation-driven cancers such as colitis-associated colon cancer (CAC). To test this hypothesis, we induced CAC in mice carrying prothrombin levels 50% of normal (fII+/−) and WT mice in parallel using an established two step protocol consisting of azoxymethane (AOM) and dextran sodium sulfate (DSS) exposure. The modest diminution in prothrombin levels imposed by the fII+/− genotype resulted in a dramatic diminution in the number of colonic adenomas formed after AOM/DSS challenge relative to WT mice. In order to determine if the diminution in adenoma formation observed in fII+/− mice was coupled to thrombin function, wildtype mice challenged with AOM/DSS were treated with daily i.p. injections of hirudin, a direct thrombin inhibitor, or saline carrier. Similar to the finding in mice with a genetically-imposed diminution in circulating prothrombin, hirudin treatment significantly blunted adenoma formation. To determine if reduction of thrombin generation improved the inflammation preceding the development of colonic adenomas, we used a novel, highly-specific factor XI antisense oligonucleotide “gapmer” (ISIS Pharmaceuticals) to inhibit hepatic factor XI synthesis prior to DSS challenge. Gapmer-mediated diminution of fXI levels to ∼15% of normal resulted in a dramatic improvement in colitis related symptoms. Gapmer-treated mice had less intestinal bleeding and weight loss associated with DSS challenge relative to mice treated with a control oligonucleotide. Consistent with these gross observations, microscopic analyses of colonic tissue showed that fXI gapmer treatment significantly limited mucosal ulceration. Factor XI gapmer treatment also significantly diminished local levels of several inflammatory cytokines known to play a role in colon cancer progression (i.e., IL-6, IL-1β, IL-12). These results demonstrate that thrombin is a crucial driver of the pathogenesis of colitis-associated colon cancer and suggest that therapies directed at thrombin or thrombin generation could treat or prevent inflammation-driven colon cancer. As pathological inflammation has been estimated to account for as many as 1 in 5 cancer-related deaths, thrombin-directed therapies could have broad applicability to multiple malignancies. Disclosures:Mullins:Baxter: Consultancy. Monia:Isis Pharmaceuticals: Employment. MacLeod:Isis Pharmaceuticals: Employment. Revenko:Isis Pharmaceuticals: Employment. Palumbo:Novo Nordisk: Research Funding.

Is H. pylori Infection Associated with Colonic Adenomas and Cancers?

Purpose: To assess the association of H. pylori infection and the incidence of colonic adenomas and carcinomas. Methods: We reviewed the Harlem Hospital endoscopy and pathology records from January 2003 - December 2007 and identified a total of 711 patients who had undergone both endoscopic gastric biopsy for H. pylori and colonoscopy for any indication at Harlem Hospital. H. pylori presence was defined by either positive CLO test and/or histologic interpretation of H. pylori presence. Colon adenomas and carcinomas were diagnosed histologically and were of any size, number and location in the colon. Results: Of the 387 patients negative for H. pylori, 83 (21.4%) had colonic adenomas. Of the 321 patients in the H. pylori positive cohort, 64 (19.6%) were found to have adenomas (p=0.64). These detection rates were consistent with the general Adenoma Detection Rate of 20.3% in all patients undergoing colonoscopy during the same time period. There was, however, an increased incidence of carcinoma observed in the H. pylori negative group compared to the the positive group (3.99% vs 1.24%; p value= 0.030). The odds ratio of colon cancer with H. pylori was 0.31 (CI 95%,0.10-0.94). Conclusion: Our study, the largest of its kind, showed no increase in the incidence of colon adenomas in patients with biopsy proven H. pylori. Surprisingly, those with H. pylori had significantly fewer colon cancers as compared to those who were negative. Both of these findings are at odds with several smaller studies which reported opposite conclusions. Further research is needed to more clearly define the influence H. pylori infection may play in the development of colon adenomas and cancers.

K‐ras exon 4A has a tumour suppressor effect on carcinogen‐induced murine colonic adenoma formation

K-ras encodes two isoforms, K-ras 4A and 4B, that are jointly affected by K-ras activating mutations, which are prevalent in colorectal cancer (CRC). CRC shows alterations in the expressed K-ras 4A : 4B isoform ratio in favour of K-ras 4B, in tumours both with and without K-ras mutations. The present study evaluated whether K-ras 4A expression can suppress colonic adenoma development in the absence of its oncogenic allele. Mice with homozygous targeted deletions of K-ras exon 4A (K-ras(tmDelta4A/tmDelta4A)) that can express the K-ras 4B isoform only, along with heterozygous K-ras(tmDelta4A/+) and wild-type mice, were given ten weekly 1,2-dimethylhydrazine (DMH) treatments to induce colonic adenomas. There was a significant increase in both the number and the size of colonic adenomas in DMH-treated K-ras(tmDelta4A/tmDelta4A) mice, with reduced survival, compared with heterozygous and wild-type mice. No K-ras mutations were found in any of the 30 tumours tested from the three groups. Lack of expression of K-ras 4A transcripts was confirmed, whereas the relative expression levels of K-ras 4B transcripts were significantly increased in the adenomas of K-ras(tmDelta4A/tmDelta4A) mice compared with K-ras(tmDelta4A/+) and wild-type mice. Immunohistochemical studies showed that adenomas of K-ras(tmDelta4A/tmDelta4A) mice had significantly increased cell proliferation and significantly decreased apoptosis with evidence of activation of MapKinase and Akt pathways, with increased phospho-Erk1/2 and both phospho-Akt-Thr308 and phospho-Akt-Ser473 immunostaining, compared with adenomas from K-ras(tmDelta4A/+) and wild-type mice. In conclusion, following DMH treatment, K-ras exon 4A deletion promoted increased number and size of colonic adenomas showing increased K-ras 4B expression, increased proliferation, decreased apoptosis, and activation of MapKinase and Akt pathways, in the absence of K-ras mutations. Therefore, K-ras 4A expression had a tumour suppressor effect on carcinogen-induced murine colonic adenoma formation, explaining the selective advantage of the altered K-ras 4A : 4B isoform ratio found in human colorectal cancer.