Higher Risk Of Colon Cancer Research Articles

Hereditary and Familial Colon Cancer

Between 2% to 5% of all colon cancers arise in the setting of well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, and certain hamartomatous polyposis conditions. Each is associated with a high risk of colon cancer. In addition to the syndromes, up to one-third of colon cancers exhibit increased familial risk, likely related to inheritance. A number of less penetrant, but possibly more frequent susceptibility genes have been identified for this level of inheritance. Clarification of predisposing genes allows for accurate risk assessment and more precise screening approaches. This review examines the colon cancer syndromes, their genetics and management, and also the common familial colon cancers with current genetic advances and screening guidelines.

Abstract 4715: Genetic susceptibility to radiation-associated colon and rectum cancers among atomic-bomb survivors with special reference to the CD14 gene

Abstract Past epidemiology studies reported that atomic-bomb (A-bomb) radiation exposure enhanced risk of colon cancer, but not rectum cancer, among the survivors. The reason for this different sensitivity to radiation remains to be elucidated. Colorectal cancer is a multi-factorial disease, the onset of which is attributed to both environmental and genetic factors, with animal experiments showing that intestinal bacterial toxins accelerate carcinogenesis. It was recently reported that single nucleotide polymorphisms (SNPs) identified in the promoter region of CD14, encoding a receptor for the lipopolysaccharide component of the outer membrane of Gram-negative bacteria, regulate CD14 gene expression and thereby affect susceptibility to inflammatory diseases such as atopic dermatitis, coronary artery disease, and hepatic diseases. This study investigated relationship between a novel CD14 gene polymorphism and the development of radiation-associated colon and rectum cancers among an A-bomb survivor cohort, in terms of a case-cohort study. On the basis of this T/G polymorphism, we determined CD14 genotypes with 210 colorectal cancer cases and with a subcohort of 2,160 individuals who were randomly selected from the cohort. Our results showed that the individuals exposed to A-bomb radiation (≥5 mGy) were at an increased risk of colon cancer, but not rectum cancer, with relative risk (RR) of 1.19/Gy (95%CI: 1.04-1.36). When we divided the study subjects into three groups for radiation dose and into two groups for CD14 genotypes, significantly high risk of colon cancer was found with RR of 2.40 (95%CI: 1.37-4.23) for the combined category of CD14-T/T homozygote and the highest dose (≥0.7Gy), compared with the baseline category (CD14-T/G or G/G and no dose). These results suggest that CD14-related inflammatory response might be involved in the development of radiation-associated colon cancer, not rectum cancer, among A-bomb survivors, and that the CD14 genotyping might be involved in individual risk of colon cancer together with radiation dose. To find a functional significance of this polymorphism, we are currently working on ELISA-based assay to measure serum levels of soluble CD14 among healthy individuals in relation to the CD14 genotyping. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4715.

Resveratrol Suppresses Colitis and Colon Cancer Associated with Colitis

Resveratrol is a naturally occurring polyphenol that exhibits pleiotropic health beneficial effects, including anti-inflammatory, cardio-protective, and cancer-protective activities. It is recognized as one of the more promising natural molecules in the prevention and treatment of chronic inflammatory and autoimmune disorders. Ulcerative colitis is an idiopathic, chronic inflammatory disease of the colon associated with a high colon cancer risk. Here, we used a dextran sulfate sodium (DSS) mouse model of colitis, which resembles human ulcerative colitis pathology. Resveratrol mixed in food ameliorates DSS-induced colitis in mice in a dose-dependent manner. Resveratrol significantly improves inflammation score, downregulates the percentage of neutrophils in the mesenteric lymph nodes and lamina propria, and modulates CD3(+) T cells that express tumor necrosis factor-alpha and IFN-gamma. Markers of inflammation and inflammatory stress (p53 and p53-phospho-Ser(15)) are also downregulated by resveratrol. Because chronic colitis drives colon cancer risk, we carried out experiments to determine the chemopreventive properties of resveratrol. Tumor incidence is reduced from 80% in mice treated with azoxymethane (AOM) + DSS to 20% in mice treated with AOM + DSS + resveratrol (300 ppm). Tumor multiplicity also decreased with resveratrol treatment. AOM + DSS-treated mice had 2.4 +/- 0.7 tumors per animal compared with AOM + DSS + 300 ppm resveratrol, which had 0.2 +/- 0.13 tumors per animal. The current study indicates that resveratrol is a useful, nontoxic complementary and alternative strategy to abate colitis and potentially colon cancer associated with colitis.

Relationship of non‐alcoholic fatty liver disease to colorectal adenomatous polyps

Metabolic syndrome and insulin resistance are associated with a higher risk of colon cancer. Non-alcoholic fatty liver disease (NAFLD) is regarded as a manifestation of metabolic syndrome in the liver. This investigation was initiated to determine whether NAFLD has a relationship to colorectal adenomatous polyps. We examined the 2917 participants who underwent a routine colonoscopy at Kangbuk Samsung Hospital in 2007. We divided the 2917 subjects into the adenomatous polyp group (n = 556) and the normal group (n = 2361). Anthropometric measurements, biochemical tests for liver and metabolic function, and abdominal ultrasonographs were assessed. The prevalence of NAFLD was 41.5% in the adenomatous polyp group and 30.2% in the control group. By multiple logistic regression analysis, NAFLD was found to be associated with an increased risk of colorectal adenomatous polyps (odds ratio, 1.28; 95% confidence interval, 1.03-1.60). An increased risk for NAFLD was more evident in patients with a greater number of adenomatous polyps. NAFLD was associated with colorectal adenomatous polyps. Further studies are needed to confirm whether NAFLD is a predictor for the development of colorectal adenomatous polyps and cancer.

Abstract B112: Metabolic syndrome and risk of colon adenomas

Abstract Background: The metabolic syndrome (MetSyn) is characterized by central obesity, impaired glucose tolerance, hypertension, hypertriglyceridemia and low-density lipoprotein cholesterol, that may lead to cardiovascular disease and type 2 diabetes mellitus. This syndrome has also been associated with risk of colorectal neoplasia. Even though colon adenomas are the main precursor lesions for colorectal cancer, few studies have examined the relationship between MetSyn and adenomatous polyps. Thus, we aimed to determine the association between the MetSyn and adenomatous polyps in a population of adults in the United States. Methods: In an ongoing screening colonoscopy-based study, we have prospectively collected data (lifestyle risk factors and fasting blood samples) from 323 incident polyp cases (26.2%) and 910 (73.8%) controls at the University Hospitals of Cleveland; as part of the Case Transdisciplinary Research in Cancer and Energetics (TREC) Colon Polyps Study. Information on relevant covariates was collected through a computer-assisted interview. Height, weight, waist and hip measurements, as well as blood collection was obtained just prior to their colonoscopy by a research nurse. The MetSyn was determined by the use of both the criteria of the American Heart Association/National Heart, Lung, and Blood institute (AHA/NHLBI) revised definition of the NCEP-ATP III report and the criteria of the International Diabetes Federation (IDF). Descriptive statistics and unconditional logistic regression models were used to assess the association between the MetSyn and likelihood of being diagnosed with adenomatous polyps, with each of the two MetSyn definitions. Results: Our study population included 469 women (38%) and 764 men (62%). The mean age of participants was 55.4±8.9 years, 473 (38%) of participants classified themselves as African American and 760 (62%) as Caucasian. For both criteria used, the prevalence of the MetSyn was higher in cases (NCEP-ATPIII=48.3%, IDF=58.4%) than controls (NCEP-ATPIII=41.2%, IDF=49.9%) (p<0.05). After adjusting for age, race, cigarette consumption, NSAID use and family history of colorectal cancer, persons with MetSyn according to the IDF criteria, were 41% more likely to have polyps (OR=1.41, 95% CI= 1.07–1.86, p=0.0140) as compared to those without the MetSyn. Analysis using the ATP-III criteria showed that persons with MetSyn were 24% more likely to have polyps (OR=1.24, 95% CI=0.95–1.63), although this association was not statistically significant (p=0.1149). Conclusions: The MetSyn appears to be an independent risk factor of polyps; particularly when the IDF criteria are used. These results suggest that patients with the MetSyn are potentially at increased risk for colorectal cancer. Thus, colorectal cancer screening should be emphasized in patients with the MetSyn, and individuals at high risk of colon cancer should be encouraged to reduce their MetSyn factors. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B112.

Aggressive gastric cancer in a patient with an APC mutation and a monoallelic MYH mutation

Familial Adenomatous Polyposis Syndrome (FAP) is an autosomal dominant inherited hereditary colorectal cancer syndrome that is characterized by hundreds to thousands of adenomatous colonic polyps and, without treatment and close surveillance, confers a high lifetime risk of colon cancer. Polyps usually develop in adolescence and virtually all will develop polyps by age 30. It is caused by a mutation in the Adenomatous Polyposis coli (APC) gene which is responsible for tumor suppression and controls apoptosis. While benign fundic gland polyps are common, gastric cancer is rare in the Western population. MYH Associated Polyposis Syndrome (MAP) is an autosomal recessive disease caused by biallelic mutations in the MYH gene which is part of the base excision repair system. Patients with MAP exhibit an attenuated form of polyposis with 10's to 100's of adenomatous polyps and have a later age of onset, typically 10 years later than FAP. Currently to be diagnosed with MAP patients must carry biallelic mutations though recent studies have described similar colon cancer risks for monoallelic carriers. We report on a case of a 65 year old woman with an APC mutation positive FAP (de novo) who also carries a monoallelic mutation in the MYH gene G382D that developed metastatic gastric cancer within a year of a clear CT scan. She had undergone a colectomy with IRA in her 20's and had been followed by yearly endoscopic surveillance that demonstrated polyps in the remaining rectum as well as adenomatous duodenal polyps and gastric polyps with no evidence of malignancy. At 61 she was converted to a I-Pouch and continued with appropriate surveillance. At age 64 Spieglman Stage III duodenal adenomatosis was detected and EGDs were done every 3 months. In March 2008 she presented to the ER with epigastric pain, hematochezia and hemetemesis following an EGD and polypectomy earlier that day. A CT of the chest, abdomen and pelvis did not reveal any abnormalities. She continued to be monitored every 3 months and in March 2009 she had progressed to Spieglman Stage IV. Biopsies were obtained from the duodenal adenomas and were negative for high grade dysplasia. Two months later a CT scan revealed abnormal nodules in the liver. A diagnosis of metastatic gastric cancer was made following further studies.

Plasma enterolactone and risk of colon and rectal cancer in a case–cohort study of Danish men and women

This case-cohort study examined the association between plasma enterolactone concentration and incidence of colon and rectal cancer in the Diet, Cancer and Health cohort, which enrolled 57,053 participants aged 50-64. Information about diet and lifestyle was obtained by questionnaire, and data on prescriptions of antibiotics were obtained from the Danish Prescription Registry. Cases diagnosed during 5.9 years of follow-up and a randomly selected sample of the cohort had a plasma sample analyzed for enterolactone by time-resolved fluoro-immuno assay. Associations were analyzed by Cox proportional hazards model. A total of 244 colon cancer cases, 137 rectal cancer cases, and 370 sub-cohort members were included in the statistical analyses. For each doubling in enterolactone concentration, we found lower risk of colon cancer among women [IRR (95% CI) = 0.76 (0.60-0.96)] and a tendency toward lower risk of rectal cancer [IRR (95% CI) = 0.83 (0.60-1.14)]. Among men, a doubling in enterolactone tended to be associated with higher risk of colon cancer [IRR (95% CI) = 1.09 (0.89-1.34)] and was associated with statistically significantly higher risk of rectal cancer [IRR (95% CI) = 1.74 (1.25-2.44)]. Exclusion of antibiotics users strengthened the results slightly. In conclusion, with higher enterolactone levels, we found lower risk of colon cancer among women and higher risk of rectal cancer among men.

Mucin‐depleted foci show strong activation of inflammatory markers in 1,2‐dimethylhydrazine‐induced carcinogenesis and are promoted by the inflammatory agent sodium dextran sulfate

Mucin-depleted foci (MDF), formed by dysplastic crypts devoid of mucins, have been identified in the colon of carcinogen-treated rodents and in humans at high risk for colon cancer. The lack of the protective layer of mucus may cause inflammation which has been linked to colon carcinogenesis, therefore, the expression of markers such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (i-NOS) and macrophage infiltration was studied with immunohistochemistry (IH) in MDF harvested from F344 rats treated with the colon carcinogen 1,2-dimethylhydrazine (DMH). The same determinations were performed in aberrant crypt foci (ACF) and, at a later time point, in tumours. A dramatic increase in COX-2, i-NOS and macrophage infiltration was observed in MDF but ACF showed a moderate increase compared with the paired normal mucosa. Tumours were positive for all the markers. RT-PCR experiments demonstrated that i-NOS RNA expression was increased in a set of MDF confirming the results obtained with immunohistochemistry. In an inflammation-cancer experimental model [mice treated with azoxymethane (AOM) and dextran sodium sulphate (DSS)], we observed that DSS-induced inflammation promoted MDF in a dose-dependent manner, whereas ACF were not affected. In conclusion, we report here for the first time a strong activation of the inflammatory process in MDF, which may contribute to the further progression of MDF to tumours.

T1984 The Nutritional Role of the Microbiota in Populations with a High and Low Risk of Colon Cancer

T1984 The Nutritional Role of the Microbiota in Populations with a High and Low Risk of Colon Cancer

The Legume Inflammation Feeding Experiment (LIFE): Weight Loss Effects

The LIFE study was a randomized controlled crossover feeding experiment intended to assess the effects of a low‐glycemic legume‐rich diet on biomarkers of inflammation and insulin resistance (IR). Sixty‐four male participants (35‐75 yrs) were recruited from Central Pennsylvania and divided into 4 possible groups: IR (Y or N) and history of adenomatous polyps (Y or N). All participants consumed a legume diet (LG; 1 1/2 cup cooked dry beans) and an average American diet (AA), each for four weeks split by a 3‐week washout interlude. A total of 44 of the subjects completed the required two dietary periods and then completed an optional 4‐week weight‐loss period. During the weight loss period we tested whether the legume rich diet would facilitate weight loss. Subjects were asked to consume the bean‐containing foods but were able to eliminate other foods. For the weight loss period, incipient mean BMI (±S.D.) was 29.04 (3.39). Initial results indicate a mean change in BMI of 1.36 (1.01) accounting for a 5.09% decrease in BMI with a significant difference over the dietary period (P=0.0001). Mean change in BMI was calculated for each of the classifications and proved to be significantly different from across strata (P= 0.0033). Those participants experiencing the most weight loss (> 5.2kg) also experienced a significant decrease in serum total cholesterol (TC) and LDL cholesterol (LDL‐C) (P=0.0345 and 0.001, respectively). Results indicate that the legume‐rich diet may have favorable effects on weight‐loss among individuals at high risk for colon cancer. Supported by the National Cancer Institute; partial support provided by the GCRC, PSU.

Protein Kinase Cβ Is an Effective Target for Chemoprevention of Colon Cancer

Colon cancer develops over a period of 10 to 15 years, providing a window of opportunity for chemoprevention and early intervention. However, few molecular targets for effective colon cancer chemoprevention have been characterized and validated. Protein kinase CbetaII (PKCbetaII) plays a requisite role in the initiation of colon carcinogenesis in a preclinical mouse model by promoting proliferation and increased beta-catenin accumulation. In this study, we test the hypothesis that PKCbetaII is an effective target for colon cancer chemoprevention using enzastaurin (LY317615), a PKCbeta-selective inhibitor, in a mouse model of colon carcinogenesis. We find that enzastaurin potently reduces azoxymethane-induced colon tumor initiation and progression by inhibiting PKCbetaII-mediated tumor cell proliferation and beta-catenin accumulation. Biochemically, enzastaurin reduces expression of the PKCbetaII- and beta-catenin/T-cell factor-regulated genes PKCbetaII, cyclooxygenase II, and vascular endothelial growth factor, three genes implicated in colon carcinogenesis. Our results show that enzastaurin is an effective chemopreventive agent in a mouse model of sporadic colon cancer that significantly reduces both tumor initiation and progression by inhibiting expression of proproliferative genes. Thus, PKCbetaII is an important target for colon cancer chemoprevention and the PKCbeta-selective inhibitor enzastaurin may represent an effective chemopreventive agent in patients at high risk for colon cancer.

Family communication, genetic testing and colonoscopy screening in hereditary non‐polyposis colon cancer: a qualitative study

Genetic testing and colonoscopy is recommended for people with a strong history of colorectal cancer (CRC). However, families must communicate so that all members are aware of the risk. The study aimed to explore the factors influencing family communication about genetic risk and colonoscopy among people with a strong family history of CRC who attended a genetic clinic with a view to having a genetic test for hereditary non-polyposis colon cancer (HNPCC). Interviews were held with 30 people with a high familial risk of colon cancer. The transcripts were transcribed verbatim and analysed using Interpretative Phenomenological Analysis. The family context, family history and perceptions about family duties and responsibilities were important motivators for communication about risk, genetic testing and colonoscopy and influenced participation in genetic testing and screening programmes. Participants reported usually communicating openly with their relatives about genetic risk and colonoscopy. Individuals felt a duty towards affected relatives and to their own children. The influence of the spouse and other relatives, particularly those affected by CRC, was also important. Colonoscopy was perceived to be embarrassing, unpleasant and sometimes painful. While there was sometimes anxiety about the result of the colonoscopy the results were usually reassuring. The family context and the experience of the family history can have an impact on communication, genetic testing and screening in HNPCC and this should be explored during counselling. Some individuals might benefit from support in communicating with relatives about genetic risk. Ways of improving the individual's experience of colonoscopy should also be examined.

Identification of Mucin Depleted Foci in the Human Colon

Aberrant crypt foci (ACF) originally described in rodents treated with colon-specific carcinogens have been identified also in humans at high risk of colon cancer (CRC) and are extensively used as cancer biomarkers. However, studies documenting the heterogeneity of ACF have questioned their precancerous nature. Recently, we described dysplastic foci depleted of mucins (MDF) in the colon of rats treated with colon-specific carcinogens. Like colon tumors, MDFs show activation of Wnt signaling driven by mutations in the beta-catenin gene and Apc, a key gene in colorectal carcinogenesis. Because MDFs have been identified thus far only in rodents, we wanted to search for similar lesions in humans. Familial adenomatous polyposis (FAP) subjects, carrying germ-line mutations in the APC gene, are at high risk of CRC. Therefore, we first searched for MDF-like lesions in unsectioned colon samples from FAP patients and then in patients with sporadic CRC. MDFs were present in the colon of FAP patients (average of 0.0577 lesions/cm(2)) and at a much lower density in CRC patients (average of 0.0006 lesions/cm(2)). ACFs were also observed in all patients. Histologic preparations of all the MDFs identified in FAP and CRC consisted of microadenomas at variable grades of dysplasia. The occurrence of MDF-like lesions in high-risk patients provides evidence that these lesions have a counterpart in human pathology and, as observed in rodents, may represent the very early stages of CRC.

American ginseng suppresses inflammation and DNA damage associated with mouse colitis

Ulcerative colitis (UC) is a dynamic, idiopathic, chronic inflammatory condition associated with a high colon cancer risk. American ginseng has antioxidant properties and targets many of the players in inflammation. The aim of this study was to test whether American ginseng extract prevents and treats colitis. Colitis in mice was induced by the presence of 1% dextran sulfate sodium (DSS) in the drinking water or by 1% oxazolone rectally. American ginseng extract was mixed in the chow at levels consistent with that currently consumed by humans as a supplement (75 p.p.m., equivalent to 58 mg daily). To test prevention of colitis, American ginseng extract was given prior to colitis induction. To test treatment of colitis, American ginseng extract was given after the onset of colitis. In vitro studies were performed to examine mechanisms. Results indicate that American ginseng extract not only prevents but it also treats colitis. Inducible nitric oxide synthase and cyclooxygenase-2 (markers of inflammation) and p53 (induced by inflammatory stress) are also downregulated by American ginseng. Mucosal and DNA damage associated with colitis is at least in part a result of an oxidative burst from overactive leukocytes. We therefore tested the hypothesis that American ginseng extract can inhibit leukocyte activation and subsequent epithelial cell DNA damage in vitro and in vivo. Results are consistent with this hypothesis. The use of American ginseng extract represents a novel therapeutic approach for the prevention and treatment of UC.

The Genetic Information Nondiscrimination Act — A Half-Step toward Risk Sharing

Consider three Americans — one with an increased genetic risk for colon cancer, one with a family history of colon cancer, and one with a colonoscopic finding of several large adenomatous polyps. Under the Genetic Information Nondiscrimination Act (GINA), which was recently signed into law by President George W. Bush, health insurance companies may not refuse to cover and may not raise premiums for the first two people, whose genetic information or family history puts them at higher risk for colon cancer.1 Insurers could, however, refuse to sell the third person an individual policy or could quadruple his or her . . .

Colorectal Care Benefits Eldest Patients

Colorectal Care Benefits Eldest Patients

Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps

Several dietary factors have been considered to be involved in the increasing incidence of colorectal cancer in industrialised countries. Experimental and epidemiological evidence has been suggestive but not conclusive for a protective role for high dietary calcium intake. Intervention studies with colorectal cancer as an endpoint are difficult to perform owing to the large number of patients and the long follow-up required; studies using the appearance of colorectal adenomatous polyps as a surrogate endpoint are therefore considered in reviewing the existing evidence. This systematic review aims to assess the effect of supplementary dietary calcium on the incidence of colorectal cancer and the incidence or recurrence of adenomatous polyps. We searched the Cochrane Controlled Trials Register, the Cochrane Colorectal Cancer Group specialised register, MEDLINE, Cancerlit , and Embase, to July 2007. The reference lists of identified studies were inspected for further studies, and the review literature was scrutinized. Randomised controlled trials of the effects of dietary calcium on the development of colonic cancer and adenomatous polyps in humans are reviewed. Studies of healthy adults and studies of adults at higher risk of colon cancer due to family history, previous adenomatous polyps, or inflammatory bowel disease were considered; data from subjects with familial polyposis coli are excluded. The primary outcomes were the occurrence of colon cancer, and occurrence or recurrence of any new adenomas of the colon. Secondary outcomes were any adverse event that required discontinuation of calcium supplementation, and drop-outs before the end of the study. Two reviewers independently extracted data, assessed trial quality and resolved discrepancies by consensus. The outcomes were reported as odds ratios (OR) with 95% confidence intervals (CI). The data were combined with the fixed effects model. Two studies with 1346 subjects met the inclusion criteria. Both trials were well designed, double - blind, placebo controlled trials, included participants with previous adenomas. The doses of supplementary elemental calcium used were 1200 mg daily for a mean duration of 4 years, and 2000 mg/day for three years. The rates of loss to follow -up were 14 % and 11%. For the development of recurrent colorectal adenoma, a reduction was found (OR 0.74, CI 0.58,0.95) when the results from both trials were combined. Although the evidence from two RCTs suggests that calcium supplementation might contribute to a moderate degree to the prevention of colorectal adenomatous polyps, this does not constitute sufficient evidence to recommend the general use of calcium supplements to prevent colorectal cancer.

Risk of Malignancy in Patients With Schizophrenia or Bipolar Disorder

There is conflicting evidence on whether people with schizophrenia have a different risk of cancer from that of the general population. To determine the risk of 6 common cancers in patients with schizophrenia or bipolar disorder. Population-based, nested, case-control study. A total of 454 practices contributing to the QRESEARCH general practice database. We analyzed 40,441 incident cases of 6 cancers (breast, colon, rectal, gastroesophageal, prostate, and respiratory) and up to 5 controls per case matched by single year of age, sex, general practice, and calendar time. Odds ratios (ORs) for cancer risk associated with schizophrenia and bipolar disorder, adjusting for smoking, body mass index, socioeconomic status, comorbidities, and prescribed medications, including antipsychotics. For breast cancer, we identified 10,535/50,074 cases/controls; colon cancer, 5108/24,458; rectal cancer, 3248/15,552; gastroesophageal cancer, 3854/18,477; prostate cancer, 10,190/48,748; and respiratory cancer, 7506/35,981. After adjustment, patients with schizophrenia had a 190% increased colon cancer risk (adjusted OR, 2.90; 95% confidence interval [CI], 1.85-4.57), a marginal increased breast cancer risk (adjusted OR, 1.52; 95% CI, 1.10-2.11), and a 47% decreased respiratory cancer risk (adjusted OR, 0.53, 95% CI, 0.34-0.85). Patients with schizophrenia taking antipsychotics had a 308% increased colon cancer risk (adjusted OR, 4.08; 95% CI, 2.43-6.84). Patients with bipolar disorder had cancer risks similar to patients with neither condition after adjustment. Patients with schizophrenia have a significantly higher risk of colon cancer and a lower risk of respiratory cancer compared with patients without schizophrenia after adjustment for confounders. In contrast, the risks of cancer in patients with and without bipolar disorder are similar, suggesting that residual confounding is unlikely to explain the findings. The increased risk of colon cancer is particularly marked in patients with schizophrenia who take antipsychotic medications.

Overview of Experimental Data on Reduction of Colorectal Cancer Risk by Inulin-Type Fructans

Colorectal cancer is related to diet, lifestyle, physical inactivity, and obesity. The responsible carcinogens cause mutations or enhance cell growth. Inulin-type fructans may counteract the effects via their gut flora-mediated fermentation products in vitro and in vivo. Important products formed by fermentation of inulin-type fructans with human gut flora are short-chain fatty acids. Of these, butyrate and propionate inhibit growth of colon tumor cells and histone deacetylases. Butyrate also causes apoptosis, reduces metastasis in colon cell lines, and protects from genotoxic carcinogens by enhancing expression of enzymes involved in detoxification. Fermentation supernatants of inulin have similar growth-inhibitory effects on colon adenoma and carcinoma cells and induce histone hyperacetylation by inhibiting histone deacetylases. In animal models inulin-type fructans prevent and retard colorectal carcinogenesis. Several studies reported the reduction of chemically induced preneoplastic lesions or tumors in the colon of rodents treated with inulin-type fructans. The human intervention study (SYNCAN project) sought to provide the experimental evidence for risk reduction by inulin-type fructans in humans. One group of polypectomized people at high risk for colon cancer and another of colon cancer volunteers after curative resection were given a synbiotic preparation. There were clear functional effects of the synbiotic because numerous different cancer risk markers were favorably altered. In conclusion, there is considerable experimental evidence that inulin modulates parameters of colon cancer risks in human colon cells, in animals, and in a human intervention trial. The involved mechanisms possibly include reduction of exposure to risk factors and suppression of tumor cell survival.

Nitric Oxide Inactivates the Retinoblastoma Pathway in Chronic Inflammation

Patients with chronic inflammatory bowel disease have a high risk of colon cancer. The molecules that initiate and promote colon cancer and the cancer pathways altered remain undefined. Here, using in vitro models and a mouse model of colitis, we show that nitric oxide (NO) species induce retinoblastoma protein (pRb) hyperphosphorylation and inactivation, resulting in increased proliferation through the pRb-E2F1 pathway. NO-driven pRb hyperphosphorylation occurs through soluble guanylyl cyclase/guanosine 3',5'-cyclic monophosphate signaling and is dependent on the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase MEK/ERK and phosphatidylinositol 3-kinase/AKT pathways. Our results reveal a link between NO and pRb inactivation and provide insight into molecules that can be targeted in the prevention of the inflammation-to-cancer sequence.