High Incidence Of Colon Cancer Research Articles

Colorectal cancer prediction via histopathology segmentation using DC-GAN and VAE-GAN

Colorectal cancer ranks as the third most common form of cancer in the United States. The Centres of Disease Control and Prevention report that males and individuals assigned male at birth (AMAB) have a slightly higher incidence of colon cancer than females and those assigned female at birth (AFAB) Black humans are more likely than other ethnic groups or races to develop colon cancer. Early detection of suspicious tissues can improve a person's life for 3-4 years. In this project, we use the EBHI-seg dataset. This study explores a technique called Generative Adversarial Networks (GAN) that can be utilized for data augmentation colorectal cancer histopathology Image Segmentation. Specifically, we compare the effectiveness of two GAN models, namely the deep convolutional GAN (DC-GAN) and the Variational autoencoder GAN (VAE-GAN), in generating realistic synthetic images for training a neural network model for cancer prediction. Our findings suggest that DC-GAN outperforms VAE-GAN in generating high-quality synthetic images and improving the neural network model. These results highlight the possibility of GAN-based data augmentation to enhance machine learning models’ performance in medical image analysis tasks. The result shows DC-GAN outperformed VAE-GAN.

Abstract 314: Intratumor genetic heterogeneity dictates metastatic subclones in stage II colon cancer

Abstract The high incidence of colon cancer (CC) worldwide is a major health concern. Although surgery and adjuvant chemotherapy are effective to a high extent in lymph-node negative colon cancers, there are still some 10-15% of patients that show disease relapse within the next 5-year period after intended curative surgery. We hypothesize that genomic instability and intratumor heterogeneity fuel the formation of subclonal populations in the primary tumor that might promote metastasis. In the current study, we assessed the presence of intratumor heterogeneity in CC using multiplex interphase FISH (miFISH) and whole-exome sequencing (WES) to evaluate samples obtained from primary stage II colon tumors and their patient-matched associated liver metastases using multi-region sampling (N=9). In combination with genome-wide copy-number changes obtained from WES analysis, miFISH allowed the simultaneous quantification of copy-numbers for nine CC relevant genes and a centromeric ploidy control probe in intact tumor nuclei derived from archival patient material. Our preliminary data on the four cases analyzed so far, revealed high similarities regarding copy-number changes and ploidy between primary tumor and metastatic samples for three of the cases. While two of these cases showed either triploid or highly aneuploid genomes with different degrees of genomic instability and subclonality among them, the third case displayed a diploid content for both matched lesions. Intriguingly, as seen by miFISH and WES, loss of CDX2 in the primary tumor might have originated the main clonal population giving rise to metastasis in this latter case. Conversely, the fourth case analyzed exhibited a triploid baseline for the primary tumor while the metastasis revealed a diploid population. Interestingly, despite higher absolute copy numbers in the primary tumor, there was an overlap of five of the gains and losses observed for the major clone populations of the tumor and metastasis by miFISH. However, two of the highly clonal gains observed in the tumor, namely the EGFR and MYC gain, were not present in the metastasis. Altogether, in addition to the ploidy change, results indicated major discrete copy-number changes from primary tumor to metastasis in this patient. In summary, we show here that the combined analysis of WES and miFISH is able to describe the subclonal composition of copy-number alterations in primary tumors and their patientmatched liver metastases. Future perspectives also include the assessment of subclonality affecting single-nucleotide variants to complete the genomic landscape of tumor evolution and clonal development in this patient cohort with the goal to better understand the nature of these early metastases. Citation Format: Sanam Yaghoubi, Kerstin Heselmeyer-Haddad, Ivan Archilla, Carolina Parra, Darawalee Wangsa, Giancarlo Castellano, Sara Lahoz, Veronica Pablo-Fontecha, Daniela Hirsch, Wei-Dong Chen, Thomas Ried, Miriam Cuatrecasas, Paul S. Meltzer, Jordi Camps. Intratumor genetic heterogeneity dictates metastatic subclones in stage II colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 314.

Patterns and Types of Colorectal Polyps Among Adults in Imo State Nigeria

Background: Colorectal cancer is one of the major health problems in the world. It used to be thought that it is a disease of people in developed countries, but recent studies has shown increasing incidence in developing countries. In Nigeria, most patients present cases late when curative resection is impossible. In order to achieve higher success, it becomes essential that knowledge and awareness for early symptoms and detection methods and screening tools have to be identified. This study aimed to elucidate the patterns and types of colorectal polyps among adults aged 40 – 65 years of age in Imo State Nigeria. Methods: The sample of the study comprised one thousand (1000) adults drawn through a multistage sampling method, and included both urban and rural dwellers from the selected communities in Imo State, Nigeria. These were screened for Fasting Occult Blood Test (FOBT). Out of the, 40 (4. 0%) of the subjects found to be positive, a further random selection was used to select 20 (50.0%) for virtual colonoscopy for detection of colorectal polyps. Results: Findings showed that there was evident in the low prevalence of colorectal polyps (20%). Also, there was a significant association between the patterns of colorectal polyp and awareness of colorectal polyp among the participants (p= 0.001; X2= 7.153). Conclusion: There are different types of colon polyps with differing tendencies to become malignant and abilities to predict the development of polyps to cancer. It is important to recognize families with members who have genetic conditions causing polyps because some of these conditions are associated with a very high incidence of colon cancer, and the cancer can be prevented if discovered early

Molecular evidence of field cancerization initiated by diabetes in colon cancer patients.

The potential involvement of type 2 diabetes mellitus (T2DM) as a risk factor for colon cancer (CC) has been previously reported. While several clinical studies show a higher incidence of CC and a lower survival rate in diabetics, others report no association. Our own experience indicates that diabetes does not seem to worsen the prognosis once the tumor is present. Despite this controversy, there are no wide‐spectrum molecular studies that delve into the impact of T2DM‐related mechanisms in colon carcinogenesis. Here, we present a transcriptomic and proteomic profiling of paired tumor and normal colon mucosa samples in a cohort of 42 CC patients, 23 of which have T2DM. We used gene set enrichment and network approaches to extract relevant pathways in diabetics, referenced them to current knowledge, and tested them using in vitro techniques. Through our transcriptomics approach, we identified an unexpected overlap of pathways overrepresented in diabetics compared to nondiabetics, in both tumor and normal mucosa, including diabetes‐related metabolic and signaling processes. Proteomic approaches highlighted several cancer‐related signaling routes in diabetics found only in normal mucosa, not in tumors. An integration of the transcriptome and proteome analyses suggested the deregulation of key pathways related to colon carcinogenesis which converged on tumor initiation axis TEAD/YAP‐TAZ as a potential initiator of the process. In vitro studies confirmed upregulation of this pathway in nontumor colon cells under high‐glucose conditions. In conclusion, T2DM associates with deregulation of cancer‐related processes in normal colon mucosa adjacent to tissue which has undergone a malignant transformation. These data support that in diabetic patients, the local microenvironment in normal colon mucosa may be a factor driving field cancerization promoting carcinogenesis. Our results set a new framework to study links between diabetes and colon cancer, including a new role of the TEAD/YAP‐TAZ complex as a potential driver.

Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria.

Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of Escherichia coli and Bacteroides fragilis Genes for colibactin (clbB) and Bacteroides fragilis toxin (bft), encoding secreted oncotoxins, were highly enriched in FAP patients' colonic mucosa compared to healthy individuals. Tumor-prone mice cocolonized with E. coli (expressing colibactin), and enterotoxigenic B. fragilis showed increased interleukin-17 in the colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone. These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria.

Biofilms provide refuge for cancerous bacteria

Colon Cancer Familial adenomatous polyposis (FAP) causes benign polyps along the colon. If left untreated, FAP leads to a high incidence of colon cancer. To understand how polyps influence tumor formation, Dejea et al. examined the colonic mucosa of FAP patients. They discovered biofilms containing

A critical discussion on diet, genomic mutations and repair mechanisms in colon carcinogenesis

Colon cancer is one of the most common malignancies and its etiology closely tied to dietary habits. Recent epidemiological data shows that colon cancer incidence is shifting to a much younger population. In this regard, some dietary components from a regular human meal might have various DNA-damaging compounds. Given that not every person endure cancer, the colonic malignancy develops throughout decades, and persistent DNA damage promotes cancer when induced at the proper intensity, a critical discussion of possible novel mechanisms by which carcinogens promote these tumors is urgently needed. Robust genomic sequencing analyses showed that low and late cell cycle expressed genes are prone to undergo mutation. Moreover, detection and repair mechanisms have a particular threshold to be activated throughout the G2/M phase, and reactivation of these devices during the M phase promotes genomic instability. Conditions of combined exposure to non-genotoxic concentrations of various carcinogens seem to act effectively through these weaknesses in genomic repair mechanisms. Therefore, we suggest that the natural tolerance of body defence mechanisms eventually become overwhelmed by the chronic exposure to different combinations and intensities of dietary mutagens leading to the high incidence of colon cancer in modern society.

NK cell count and glucotransporter 4 (GLUT4) expression in subjects with type 2 diabetes and colon cancer.

BackgroundType 2 diabetes (T2D) and colon cancer (CC) are numbered among the most common diseases in the world. The decreased activity of natural killer (NK) cells previously revealed in both mentioned pathological states may be correlated with impaired expression of GLUT4 as the major insulin-dependent glucose transporter in these cells.MethodsThe aim of this study was to evaluate GLUT4 expression and NK cells number in subjects with T2D and/or CC in comparison with control group. We evaluated 78 individuals divided into four groups: (1) patients with CC and T2DM, (2) patients with CC, (3) patients with T2DM (4) healthy control. GLUT4 expression on the surface of NK cells was measured using flow cytometry and phenotyping of NK cell was performed by immunofluorescent method.ResultsSubjects with diabetes had the highest GLUT4 expression (21.35 ± 7.2 %) in comparison with other groups (P < 0.01). The mean values of GLUT4 expression in group with CC and in patients with both T2D and CC were similar (1.4 ± 0.4 % vs 1.5 ± 1.0 %; respectively). These values were significantly lower than in control group (12.6 ± 2.9 %; P < 0.01). In patients with T2D and CC the number of NK cells (20.15 ± 6.6 %) was significantly higher than in other groups, i.e. in group with T2D (14.08 ± 5.7 %), in group with CC (9.21 ± 3.6 %) and in control group (9.48 ± 4.7 %), respectively (P < 0.01).ConclusionsIt seems that there is a need to pay more attention to the high incidence of colon cancer among patients with type 2 diabetes. Decreased GLUT4 expression observed on NK cells in patients with colon cancer may be responsible for dysfunction of these cells and the higher carcinogenic risk in type 2 diabetic subjects.

Cancer surveillance in ulcerative colitis and Crohn's disease: new strategies.

Inflammatory bowel disease (IBD) patients have a higher incidence of colon cancer than the general population. Colon cancer surveillance has traditionally involved taking numerous random biopsies to provide sufficient yield to detect dysplasia. Recently, consensus guidelines have been published which promote the use of chromoendoscopy for IBD colon cancer surveillance. This presents a new set of opportunities and challenges in the evaluation and management of dysplasia in IBD. Dysplasia, previously thought to be 'invisible' to the endoscopist, is now considered to be 'visible' in the majority of cases with the advent of the use of high-definition endoscopy and chromoendoscopy. This changes how we manage dysplastic lesions, providing the patient options for endoscopic resection rather than promoting total proctocolectomy. Implemention of chromoendoscopy may require additional training for endoscopists unfamiliar with the technique. However, if this proves to be cost-effective and provides a higher sensitivity in dysplasia detection, then widespread education and implementation will be well worth the efforts. To do so, future studies will need to prove its benefits in preventing or reducing colon cancer morbidity and mortality in this high-risk patient population.

Does a diagnosis of GIST predict a second primary cancer?

10537 Background: There have been reports of a high frequency of metachronous cancers in patients diagnosed with GIST. The purpose of this study was to identify and describe patients with GIST who develop second primary cancers, and to calculate standardized incidence ratios (SIRs) to quantify the risk of additional malignancy. Methods: This was a retrospective, population-based cohort study using SEER data. Individuals diagnosed with GIST from 2001-2009 were identified as having a malignant primary tumor in the digestive tract, and included the following sites: C15.0-C26.9; C48.0-48.8; C49.4-49.5; C80.9 and a recorded histology code of 8935 and 8936. This restricted timeframe was imposed to account for changes in the recording of GIST incidence. Individuals with a previous cancer diagnosis or diagnosed post mortem only were excluded. Multiple primary SIRs and 95% confidence intervals (CI) were calculated using SEER*Stat software (V.7.1.0) and compared to general population rates. The SIR was interpreted as an estimate of relative risk (RR). Comparison of characteristics between single and multiple cancer GIST patients was performed using chi-square tests, p-values of &lt;0.05 were considered significant. Results: We identified n=1397 cases of GIST, of which 1291 analyzed. We observed a statistically significant increased incidence of second tumours in patients with a primary GIST (n=78, RR 1.36, 95% CI:1.1-1.7). Older age (p&lt;0.001) and tumor grade (p=0.014) were associated with second primaries, with grade being the only significant variable remaining after logistic regression. In both sexes we observed a significantly increased incidence of kidney cancer (RR 4.3, 95% CI: 1.7-8.9). In females there was a 3 fold higher incidence of colon cancer (RR 2.96 95% CI: 1.2-6.1). Conclusions: Patients with a diagnosis of GIST have a higher incidence of second cancers when compared with standardized incidence in the general population. High grade GISTs were associated with an additional malignancy. Both sexes were observed to have increased incidence of kidney cancer, with females at an increased risk of developing colon cancer. As part of GIST surveillance, screening for colon cancer in females and kidney cancer in both sexes may be considered.

Differences in colon cancer incidence rates by latitude.

e14627 Background: There is significant decrease in the ultraviolet B photons reaching the earth’s surface during November to February (Holick MF Am J Clin Nutr. 2004 Dec; 80(6 Suppl):1678S-88S). This results in little if any vitamin D3 production in the skin during this period. This study was conducted to evaluate difference in colon cancer age adjusted incidence rates in the northern (latitude ≥37o N) and the southern (latitude &lt; 37oN) regions in the contiguous United States during 1973-2008. Methods: Patients, aged 20 years and older, who had been diagnosed with colong cancer during January 1973 and December 2008, were selected from the Surveillance, Epidemiology, and End Results (SEER) 13 database. Based on the counties’ centroid, northern (latitude ≥37o N) and southern (latitude &lt; 37oN) regions were determined. We compared age adjusted incidence rates (AAIR) of colon cancer in the southern and northern regions among cohorts of patients categorized by age (≥20, 20-64, ≥65 years), gender (Men, Women) and Race (Caucasians, Blacks, Others). The AAIR was calculated per 100,000 population. We used SEER*Stat software to calculate age adjusted incidence rate, incidence ratio, confidence interval (CI, 95%) and P value. Results: There were 314,975 cases of colon cancer diagnosed among 608,245,557 US population during 1973-2008. The overall colon cancer AAIR was 57.1 per 100,000 population studied. The incidence rates were 49.1 in the south and 58.7 in the north of 37oN latitude, (95% CI 1.18-1.20, p&lt;0.05). The AAIRs for patients in the age group 20-64 years were 17.9 and 18.8 in the southern and northern regions, (CI 95%, 1.0346-1.0697), p&lt;0.0005 respectively. The incidence rates for patients aged ≥65 years were 194.3 and 243.9 in the southern and northern regions, (CI 95%, 1.0346-1.0697) p&lt;0.0005. Similarly, the AAIRs were significantly higher in the northern region compared to southern region for both sexes and all ethnic groups. Conclusions: Colon cancer age-adjusted incidence rate is significantly higher in the Northern compared to the Southern region of the US. The higher incidence of colon cancer in the North may be related to lack of sunlight exposure and relative vitamin D deficiency.

The Dysfunction of NK Cells in Patients with Type 2 Diabetes and Colon Cancer

Glucose metabolism disorders influence anticarcinogenic function of natural killer (NK) cells. The aim of this study was to evaluate the number and cytotoxic activity of NK cells in type 2 diabetic (T2D) patients with negative family history of cancer, type 2 diabetic subjects with newly diagnosed untreated colon cancer (T2DCC) and patients without type 2 diabetes with newly diagnosed, untreated colon cancer (CC). Incubation tests were performed in 18 T2D patients, treated with diet and oral antidiabetic agents, 16 T2DCC; cT1-4N0M0 (c-clinical diagnosis based on computed tomography, colonoscopy and histopathology) treated with diet and oral antidiabetic agents and 16 normoglycemic CC; cT1-4N0M0. Control group included 18 metabolically healthy (with normal fasting glucose and normal glucose tolerance) subjects (HS) with negative family history of cancer, matched by age, BMI and waist circumference. Peripheral blood mononuclear cells were isolated by means of gradient centrifugation. The K562 human erythroleukemia cell line served as the standard target for human NK cytotoxicity assay. The T2D revealed an increased number of NK cells (13.56 ± 5.9 vs 9.50 ± 4.8 %; p < 0.05) when compared with HS, yet these cells had a decreased activity (3.3 ± 2.5 vs 9.4 ± 3.6 %; p < 0.01). The CC demonstrated a decreased activity (2.9 ± 1.8 %; p < 0.01) but a similar number (8.82 ± 3.7 %; not significant) of NK cells when compared to HS. The T2DCC NK cells were characterized by trace cytotoxic activity (1.1 ± 0.7 %; p < 0.01) and nearly three times greater amount (21.24 ± 7.5 %; p < 0.01) when compared to T2D. Type 2 diabetes and CC are associated with disadvantageous alterations of NK cells, leading to impairment in their cytotoxic activity. The impaired activity of NK cells in T2D can be involved in the increased carcinogenic risk and can promote a higher incidence of CC.

High Density Lipoprotein (HDL): Another Cog in the Colon Cancer Wheel?

Purpose: Epidemiologic studies have suggested that low HDL levels may be associated with higher incidence of colon cancer (CRC). Dyslipidemia is a pathological alteration of lipid and lipoprotein concentrations and a key component of the metabolic syndrome. HDL and HDL-related molecules have been associated with multiple protective functions including anti-inflammatory, antioxidant and anti-microbial activity and a possible role in innate immunity. This retrospective study looks at the relationship between HDL levels and the occurrence of CRC and adenomas. Methods: Retrospective case-control study looked at the association between biopsy-diagnosed CRC and adenomas and HDL levels. Data was collected for a two year period and included demographics, HDL level, endoscopy and biopsy findings, site of lesions and time period between endoscopy and HDL levels. A cut-off value of <=40mg/dl was used to define low HDL level. T-test was used to compare HDL levels between the CRC group and adenoma group. The association between colon cancer and low HDL levels was examined using chi-square and odds ratio was calculated. Results: 183 patients met inclusion criteria (66.3 ± 4.9 years, 36% males,). CRC was present in 53% of subjects. The CRC group was older (71 ± 12 years old) than the adenoma group (66 ± 5 years old, P <0.001). The time period between HDL measurement and diagnosis was not statistically different between the CRC and adenoma groups (242 ± 725 days and 267 ± 252 days, respectively, P = 0.76). The CRC group had a higher incidence of low HDL as compared to the adenoma group (55.7% versus 33.7%) with an odds ratio of 2.5 (95% CI 1.35-4.49, P = 0.003). Multivariate logistic regression analysis adjusting for HDL and age revealed older age and low HDL level were independent predictors of CRC. Conclusion: This small study in a community teaching hospital confirmed the association seen before between lower HDL levels and CRC risk. Interestingly, the CRC group was 2.5 times more likely to have lower HDL levels. In our study, older age and lower HDL levels were independent predictors of CRC risk. The final word on the causative role of HDL in CRC is still unclear and this data may represent another cog in the wheel of colon cancer causation.

Alterations in glucose-6-phosphate dehydrogenase and mitochondria oxygen consumption in rats fed with cycads, Nigerian- like and western -like folic acid supplemented diets

Alterations in mitochondria oxygen consumption and glucose-6-phosphate dehydrogenase was studied in 96 Wister albino rats exposed to cycads and fed on Nigerian like and western like diets supplemented with folic acid. The animals were divided into three diet classes of 32 animals each. First group was fed with a wholly compounded Nigerian like diet (NLD) which was low in protein and high in carbohydrate and fiber. Another group was fed with a western like diet (WLD) which was high in protein and fat while the third group of animals was fed with a normal diet (ND) which served as the control class. The animals of each class were further distributed into four subgroups of eight rats each. In each subclass, first group received the diet alone; second group received the diet and cycads, third group received the diet and folic acid while the fourth group received the diet, cycads and folic acid. Exposing the colon of rats to NLD decreased glucose-6-phosphate dehydrogenase activity and increased mitochondria oxygen consumption. WLD increased glucose-6-phosphate dehydrogenase activity and decreased mitochondria oxygen consumption while folic acid decreased glucose-6-phosphate dehydrogenase activity but increased mitochondria oxygen consumption at the initial stage of colon carcinogenesis. These results suggest that NLD and folic acid may protect rats against colon cancer and the WLD may enhance colon carcinogenesis. Therefore, a nutritional shift from NLD to WLD is likely to cause a higher incidence of colon cancer. Key words: Cycads, glucose-6-phosphate dehydrogenase, mitochondria oxygen consumption, Nigerian-like diet (NLD), Western-like diet (WLD).

The melatonin action on stromal stem cells within pericryptal area in colon cancer model under constant light

Constant light (LL) is associated with high incidence of colon cancer. MLT supplementation was related to the significant control of preneoplastic patterns. We sought to analyze preneoplastic patterns in colon tissue from animals exposed to LL environment (14 days; 300 lx), MLT-supplementation (10 mg/kg/day) and DMH-treatment (1,2 dimethylhydrazine; 125 mg/kg). Rodents were sacrificed and MLT serum levels were measured by radioimmunoassay. Our results indicated that LL induced ACF development ( p < 0.001) with a great potential to increase the number of CD133(+) and CD68(+) cells ( p < 0.05 and p < 0.001). LL also increased the proliferative process (PCNA-Li; p < 0.001) as well as decreased caspase-3 protein ( p < 0.001), related to higher COX-2 protein expression ( p < 0.001) within pericryptal colonic stroma (PCCS). However, MLT-supplementation controlled the development of dysplastic ACF ( p < 0.001) diminishing preneoplastic patterns into PCCS as CD133 and CD68 ( p < 0.05 and p < 0.001). These events were relative to decreased PCNA-Li index and higher expression of caspase-3 protein. Thus, MLT showed a great potential to control the preneoplastic patterns induced by LL.

Abstract B48: Do the gut flora play a role in the high incidence of colon cancer in African Americans?

Abstract Colonic adenomatous polyps are common tumors occurring in 50% of Western populations with 10% risk of malignant progression. To date, the environmental exposures proposed to promote the development of colorectal cancer (CRC) have been primarily dietary agents. However, the local environment to which the colonic mucosa is exposed is created by the bacterial microbiota of the colon and their metabolic products that include toxins. African Americans are known to have a higher incidence of colon cancer than other groups. We analyzed the gut flora from African Americans patients by both 16S rDNA sequencing and HIT (Human Intestinal Tract) Chip. Our findings reflected a high prevalence of Bacteroidetes and Clostridia groups with the Bacteroidetes slightly more represented in patients with colon polyps than healthy ones. While Bifidobacteria were not detected at all in all samples, Lactobacilliwere present at a very low frequency. Both bacteria are referred to as “good bacteria” and are generally associated with healthy colon. Helicobacter bacteria, associated with gastric cancer, were also detected in all analysed samples. Bacteroides fragilis and relatives were present in all samples at a high frequency. It is noteworthy that an enterotoxigenic Bacteroides fragilis have been found to trigger colon polyps formation in Min mice through a pSTAT3 pathway. A tissue microarray immunohistochemistry experiment on colon adenoma and matched normals revealed a strong expression of pSTAT3 both in colonic epithelial cells and in colonic immune cells in adenoma samples but not as much in normal ones. These findings highlight the presence of a possible ETBF-like induction mechanism in the analysed samples. Enzyme immunoassay for the detection of antibodies against ETBF toxin would confirm such findings and a metagenomic analysis of the analysed samples would shed light on predominant bacterial functions in adenoma patients that might play a role in colon oncogenic transformation in this population. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B48.

T2012 Cytokine Gene Polymorphisms, Cytokine Levels and Risk of Colorectal Neoplasia in the Screened Population of Northeast Scotland

Introduction Chronic inflammation plays a key role in the pathogenesis of many cancers but its role in colorectal neoplasia (CRN) is not clear. Our aim was to investigate the effect of cytokine gene polymorphisms and circulating cytokine levels on risk of CRN in North East Scotland, which has a high incidence of colon cancer. Methods Subjects underwent a complete bowel cancer screening colonoscopy and were free of IBD. Blood-derived DNA was used to genotype polymorphisms in the IL1B, IL1-RN, IL6, IL8, IL10, PTGS2 and TNFA genes using 5′ nuclease taqman assays. Serum high-sensitivity C-reactive protein (Hs-CRP) and plasma levels of six cytokines (IL-1β, IL-4, IL-6, IL-8, IL-10 and TNF-α) were measured. Subjects with adenomas with or without cancer (cases) were compared against subjects with no evidence of adenoma or cancer (controls). For Hs-CRP and plasma cytokines, levels were divided into tertiles and compared against each other. χ 2 test was used for comparing cases and controls. Logistic regression analysis adjusting for gender was used and odds ratios (OR) with 95% CI were calculated. Results For the genetic study, a total of 295 cases were compared with 398 controls. Mean age of the cases was 64.4 years compared to 62.3 years in controls (p Conclusion Proinflammatory cytokine gene polymorphisms in IL-1B increase the risk of developing adenomas while those in the IL-8 increase the risk of progression to advanced lesions. Hs-CRP and IL-8 levels predict presence and severity of CRN. Along with the NSAID findings, our data point to inflammation as an underlying pathogenetic mechanism in this cancer.

PP-012 Cytokine gene polymorphisms, cytokine levels and risk of colorectal neoplasia in the screened population of northeast Scotland

<h3>Introduction</h3> Chronic inflammation plays a key role in the pathogenesis of many cancers but its role in colorectal neoplasia (CRN) is not clear. Our aim was to investigate the effect of cytokine gene polymorphisms and circulating cytokine levels on risk of CRN in North East Scotland, which has a high incidence of colon cancer. <h3>Methods</h3> Subjects underwent a complete bowel cancer screening colonoscopy and were free of IBD. Blood-derived DNA was used to genotype polymorphisms in the IL1B, IL1-RN, IL6, IL8, IL10, PTGS2 and TNFA genes using 5′ nuclease taqman assays. Serum high-sensitivity C-reactive protein (Hs-CRP) and plasma levels of six cytokines (IL-1β, IL-4, IL-6, IL-8, IL-10 and TNF-α) were measured. Subjects with adenomas with or without cancer (cases) were compared against subjects with no evidence of adenoma or cancer (controls). For Hs-CRP and plasma cytokines, levels were divided into tertiles and compared against each other. χ² test was used for comparing cases and controls. Logistic regression analysis adjusting for gender was used and odds ratios (OR) with 95% CI were calculated. <h3>Results</h3> For the genetic study, a total of 295 cases were compared with 398 controls. Mean age of the cases was 64.4 years compared to 62.3 years in controls (p&lt;0.01) and males were overrepresented in the cases (66.1% vs 53.3% in controls, p&lt;0.001). Regular use of NSAID was more common among controls compared to cases (p&lt;0.0001). The pro-inflammatory IL-1B-31 C*C genotype increased the risk of having an adenoma by 1.9-fold compared to the IL-1B-31 T*T genotype (95% CI 1.2 to 3.0). Among subjects with adenoma, the pro-inflammatory IL8-251-A*A genotype increased the risk of having a high-risk lesion (cancer, large adenoma, or multiple adenomas) compared to the IL-8-251 T*T + T*A genotypes (OR 3.4, 95% CI 1.7 to 7.0). None of the other polymorphisms showed any significant associations. Having a Hs-CRP level in the highest tertile compared to the lowest two tertiles increased the risk of having an adenoma by 1.6-fold (95% CI 1.0 to 2.6) and cancer by 2.1-fold (95% CI 0.9 to 5.0). Among subjects with adenomas, having an IL-8 plasma level in the highest tertile compared to the lowest two tertiles doubled the risk of having a high-risk lesion. <h3>Conclusion</h3> Proinflammatory cytokine gene polymorphisms in IL-1B increase the risk of developing adenomas while those in the IL-8 increase the risk of progression to advanced lesions. Hs-CRP and IL-8 levels predict presence and severity of CRN. Along with the NSAID findings, our data point to inflammation as an underlying pathogenetic mechanism in this cancer.

Activation of aminoimidazole carcinogens by nitrosation: Mutagenicity and nucleotide adducts

2-Amino-3-methylimidazo[4,5- f]quinoline (IQ) and 2-amino-3,8-dimethylimidazo[4,5- f]quinoxaline (MeIQx) are heterocyclic amines (HCAs) derived from high temperature cooking of meat and thought to cause colon cancer in humans. Reactive nitrogen oxygen species, which are mediators of the inflammatory response, can convert these amines to the corresponding N-nitrosamines, N-NO-IQ and N-NO-MeIQx. This study was designed to evaluate whether these N-nitrosamines are genotoxic and could be responsible, in part, for the high incidence of colon cancer in individuals with colitis. Such an association would counsel reduced intake of well-done red meat by colitis patients. Mutagenicity was evaluated by reversion of a lacZ frameshift allele in three different E. coli strains. Strains DJ701 and DJ702 express recombinant ( S. typhimurium) aromatic amine N-acetyltransferase (NAT); DJ702 also expresses recombinant human cytochrome P450 1A2 and NADPH-P450 reductase; and DJ2002 served as an N-acetyltransferase-negative control. In strain DJ701, N-NO-IQ and N-NO-MeIQx elicited dose-dependent mutagenicity, which was not further increased in DJ702. Neither nitrosamine was mutagenic in strain DJ2002. While both N-nitrosamines are stable for >4 h (pH 7.4, 37 °C), they react with DNA or 2′-deoxyguanosine 3′-monophosphate at lower pH (5.5) to form adducts. HOCl, a component of the inflammatory response, increased adduct formation, as measured by 32P-postlabeling. Following treatment with nuclease P1 and separation by two-dimensional thin-layer chromatography and then HPLC, N-NO-IQ and N-NO-MeIQx were shown to form the same adducts as those formed by N-OH-MeIQx or N-OH-IQ, namely N-(deoxyguanosin-8-yl) adducts. In summary, these N-nitrosamines are genotoxic and might be alternatives to their hydroxylamine analogues as activated intermediates leading to initiation of colon cancer in individuals with colitis.

Social inequality and incidence of and survival from cancers of the colon and rectum in a population-based study in Denmark, 1994–2003

We investigated the effects of socioeconomic indicators, demographic indicators and health-related indicators on the incidence of and survival from colon cancer and rectal cancer diagnosed in 1994–2003 with follow-up through 2006 in Denmark using information from nationwide registers. The analyses were based on data on 9958 patients with colon cancer and 7411 patients with rectal cancer in a cohort of 3.22 million people born between 1925 and 1973 and aged ⩾30 years. Higher incidences of colon and rectal cancers were associated with greater social disadvantage, predominantly amongst men, in regard to cohabiting status, housing tenure, dwelling size and affiliation to the work market. Comorbidity was associated with a higher incidence of colon cancer in both sexes. Short- and long-term relative survival from both colon and rectal cancers decreased with poorer education, disposable income, affiliation to the work market, housing tenure, dwelling size and cohabiting status.