Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A database (http://perso.curie.fr/tsoussi ) is described, in which over 1000 mutations in the human APC gene of tumors (colon cancer predominantly) are compiled from the literature. It includes both molecular information about the mutations and clinical data about the patients. Software has been designed to analyse all this information in the database.
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PMID:APC gene: database of germline and somatic mutations in human tumors and cell lines. 939 50

An increased incidence of colorectal cancer has been observed in breast and breast-ovarian cancer syndrome families, including those of Ashkenazi origin. Recently, a germ-line missense mutation in the APC gene, I1307K, was identified that may indirectly cause colorectal cancer in Ashkenazi Jews. To determine whether the excess of colon cancer in some breast-ovarian cancer families is related to the I1307K mutation, we evaluated 264 Ashkenazi Jews from 158 families. Most of these individuals had either a personal or a family history of breast and/or ovarian cancer, and 19.3% (51 of 264) carried one of the recurrent BRCA1 (185delAG or 5382 insC) or BRCA2 (6174delT) mutations. We detected the APC I1307K mutation in 7% (11 of 158) of the Ashkenazi Jewish families and in 4.5% (12 of 264) of the individuals participating in these studies. Of the families studied, 26.6% (42 of 158) had at least one case of colorectal cancer in a first-, second-, or third-degree relative of the proband. Significantly, of the 12 individuals who possessed the I1307K mutation, none was diagnosed with colorectal cancer and none had a known first-, second-, or third-degree relative diagnosed with colon cancer. The results suggest that factors other than the I1307K mutation contribute to the increased incidence of colon cancer in Ashkenazi breast-ovarian cancer families. Our results emphasize that only a subset of Ashkenazi Jewish individuals with a family history of colorectal cancer should be viewed as candidates for genetic susceptibility testing for the I1307K APC mutation.
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PMID:The I1307K APC mutation does not predispose to colorectal cancer in Jewish Ashkenazi breast and breast-ovarian cancer kindreds. 940 54

Turcot syndrome is characterized by an association of malignant brain tumors and colon cancer developing in the patient's teens. Since the mechanism of carcinogenesis in Turcot syndrome is still unclear, we analysed genetic changes in tumors from a Turcot patient with no family history of the condition. All tumors, including one astrocytoma, three colon carcinomas, and two colon adenomas, exhibited severe replication error (RER), and all colon tumors showed somatic mutations at repeated regions of TGFbetaRII, E2F-4, hMSH3, and/or hMSH6 genes. Somatic APC mutations were detected in three of three colon carcinomas, and somatic p53 mutations were detected in the astrocytoma and two of three colon carcinomas, both of which showed two mutations without allele loss. We also found that normal colon mucosa, normal skin fibroblasts and normal brain tissue from this patient showed respective high frequencies of RER, in contrast to usual HNPCC patients in which RER was very rare in normal tissues. These results suggest that extreme DNA instability in normal tissues causes the early development of multiple cancer in Turcot syndrome. A missense mutation (GAG to AAG) at codon 705 of hPMS2 gene was detected in one allele of this patient, which was inherited from his mother without tumors. Additional unknown germline mutation may contribute to the genetic instability in normal tissues.
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PMID:Drastic genetic instability of tumors and normal tissues in Turcot syndrome. 941 79

A rat model for human ulcerative colitis (UC) has been developed by using 1-hydroxyanthraquinone (1-HA) to cause severe inflammation of colonic mucosa. 1-HA also has synergistic effects on the carcinogenicity of methylazoxymethanol (MAM) acetate in the rat colon. In this study, four adenomas and 16 adenocarcinomas induced in male F344 rats by 1-HA and MAM acetate were examined for mutations in the entire coding regions and introns flanking coding exons of the APC gene by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and PCR-restriction-SSCP analyses. No mutations were found. These results, together with our previous observations of a relative lack of Ki-ras gene mutations in the same tumors, are similar to those found in human UC-associated colon cancer, suggest a common pathway in these two systems, although they are different in their implication of p53 mutations. Therefore, this model may have some relevance and application to the study of colon cancer in human inflammatory bowel disease, which is not associated with APC mutations or with Ki-ras or p53 mutations.
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PMID:No involvement of APC gene mutations in ulcerative colitis-associated rat colon carcinogenesis induced by 1-hydroxyanthraquinone and methylazoxymethanol acetate. 943 83

While evidence in both sporadic and inherited human colorectal cancer and MIN mice implicate the tumor suppressor gene, APC, in the causation of colorectal carcinogenesis, this gene has not been confirmed to be involved in rodent chemically-induced colon cancer models (RCCM). These experimental models are widely used to elucidate mechanisms involved in colon carcinogenesis (initiation, promotion and progression) as well as studies on chemoprevention (dietary and other) and intervention. To validate the RCCM as relevant models for sporadic human colorectal cancer, and to facilitate research on the role of the APC gene in colon carcinogenesis, we investigated the role of APC in azoxymethane (AOM)-induced colorectal tumors in mice. Using an antibody that recognizes the carboxy terminus of APC, we have characterized the pattern of staining observed in normal mouse intestinal tissue, in MIN mouse intestinal adenomas and in AOM-induced mouse colon tumors. The APC protein was localized in the cytoplasm of normal colonic epithelial cells. In the small intestine there was APC immunoreactivity along the villous and staining of the Paneth cells at the base of the glands. In the proximal and distal colonic crypts there appeared to be a gradient of staining which increased towards the luminal surface. This gradient was not as apparent in the small intestinal villi. Nuclei and mucus in the goblet cells showed no immunoreactivity. MIN mouse small bowel and colonic adenomas, known to have lost APC, stained negatively for APC. AOM-induced adenomas and carcinomas also consistently stained negatively using this antibody. This study demonstrates for the first time the loss of wild-type APC protein in AOM-induced mouse colon tumors and suggests that alterations in expression of this tumor suppressor gene, which is so commonly mutated in human colon cancer, is also involved in this animal model of colon cancer.
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PMID:AOM-induced mouse colon tumors do not express full-length APC protein. 945 Apr 92

Irinotecan (CPT-11) is a water-soluble analogue of camptothecin showing activity in colon cancer. Recently, we identified a major metabolite of CPT-11 in patients' plasma, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC), which is produced by the oxidation of the distal piperidine ring (P. Rivory et al, Cancer Res., 56: 3689-3694, 1996). As with all active camptothecin derivatives, CPT-11 is subject to spontaneous interconversion between a lactone and a carboxylate form in aqueous media. The kinetics of biotransformation of the two forms of CPT-11 into APC was studied using pooled human liver microsomes. The formation of APC was characterized by the following parameters: Km = 18.4 +/- 1.4 and 39.7 +/- 11.6 microM; and Vmax = 26.0 +/- 0.6 and 13.4 +/- 1.7 pmol/min/mg protein for the lactone and carboxylate forms of CPT-11, respectively. This reaction was found to be catalyzed principally by cytochrome P-450 (CYP) 3A because of three key results: (a) the CYP 3A-selective inhibitors ketoconazole (1 microM) and troleandomycin (100 microM) inhibited APC formation by 98 and 100%, respectively, mostly in a competitive way; (b) using microsomes from transfected lymphoblastoid cells expressing specific CYPs, we found that only those from CYP 3A4 cDNA-transfected cells transformed CPT-11 into APC; and (c) using 15 individual preparations of human liver microsomes, we observed highly significant correlations between the activity of CPT-11 metabolism into APC and both immunoreactivity with anti-CYP 3A antibodies and testosterone 6beta hydroxylation, an activity specifically mediated by CYP 3A. The effect on this metabolism of 11 drugs used at 100 microM was studied with CPT-11 lactone at 25 microM. Amikacin, Bactrim, ciprofloxacin, rocephine, 5-fluorouracil, metoclopramide, morphine, and paracetamol had no effect, but ondansetron, loperamide, and racecadotril inhibited this pathway by 25, 50, and 50%, respectively. These concentrations exceed those expected in vivo. APC formation in patients may thus be influenced by coadministered ketoconazole therapy and may decline after administration of CPT-11 because of the lactonolysis of the latter.
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PMID:Metabolism of irinotecan (CPT-11) by human hepatic microsomes: participation of cytochrome P-450 3A and drug interactions. 945 91

The colon carcinogenic process is believed to begin with both genetic and morphological alterations in a few individual crypts. These select crypts, called aberrant crypt foci (ACF), are widely agreed upon as precursors of colon cancer. The ACF assay involves testing potential chemopreventive agents by counting the number of ACF in a carcinogen-treated colon. This assay has the advantage of not only being less expensive and time-consuming than tumor-producing studies, but will also allow the elucidation of the colon carcinogenic process by letting the researcher explore the changes that occur at a pre-cancerous stage. The ACF assay has been used most frequently in rodent models. In the rodent colon, ACF are easy to distinguish due to their distinct morphological, histological, and biological characteristics. In addition, the ACF assay has been used to look at specific genetic alterations in the crypts such as K-ras, p53, and APC mutations. Our laboratory has consistently used the ACF assay to test many potential chemopreventive agents using rats induced by the colon carcinogen azoxymethane (AOM). Potential chemopreventive agents have been tested in both the initiation or the post-initiation period Research supports the notion that aberrant crypt foci represent a true neoplastic lesion for colon cancer. By studying these lesions both grossly and genetically it may be possible to learn more about the causes of colon carcinogenesis. In addition, by testing new compounds through the ACF assay, it is possible not only to discover potentially new chemopreventive compounds, but also to discover the mechanisms behind them. Because of this, the ACF assay is an invaluable method that will help reveal the process of colon carcinogenesis.
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PMID:Inhibition of aberrant crypt foci by chemopreventive agents. 962 97

The presence of inactivating mutations in the transforming growth factor-beta (TGF-beta) type II receptor (RII) gene in the colon cancer suggests that it may behave like a tumour suppressor gene. RII is mutated in the majority of colon tumours exhibiting widespread microsatellite instability, a characteristic generally referred to as the replication error phenotype (RER+). We investigated the association between RII mutations and various clinicopathological variables and genetic alterations in a large series of sporadic adenocarcinomas arising in the proximal colon. RII mutations were found in 17 per cent (36/210) of right-sided tumours and in 86 per cent (32/37) of those displaying RER+. They were associated with the absence of lymph node invasion (P = 0.04), poor histological differentiation (P = 0.006), and with a trend for improved patient survival. Tumours with an RII mutation also showed non-significant trends for a lower incidence of p53 protein overexpression and of p53, K-ras, and APC gene mutation compared with tumours with normal RII. These results indicate that right-sided colorectal tumours containing RII mutations resemble those with the RER+ phenotype in terms of their clinicopathological features and genetic alterations.
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PMID:Mutation of the transforming growth factor-beta type II receptor gene in right-sided colorectal cancer: relationship to clinicopathological features and genetic alterations. 966 4

Familial adenomatous polyposis is a dominantly inherited colon cancer syndrome associated with germ-line mutations in the APC tumor suppressor gene. An APC gene sequence alteration, the I1307K allele, occurs in 6% of the Ashkenazi Jewish population and is reported to double the risk for colorectal cancer. We screened a population of 190 Ashkenazi women who were diagnosed with epithelial ovarian carcinoma for the I1307K variant and measured the effect of this allele on the risk for cancer development in their first-degree relatives. We identified the I1307K allele in 7.9% (15 of 190) of our ovarian cancer cases. The average age of ovarian cancer diagnosis in carriers of the I1307K allele (57.5 years) was not statistically different than the age for noncarriers (56.4 years; P = 0.70). Among the 1087 first-degree relatives, there were 23 cases of colorectal cancer; 3 of 100 relatives of probands with the I1307K allele (3.0%) had a history of colorectal cancer versus 20 of 987 relatives of probands without the I1307K allele (2.1%; relative risk, 1.48; 95% confidence interval, 0.45-4.88; P = 0.462). Relatives of the I1307K carriers had a risk of 38.0% for developing any cancer to age 80, similar to the risk for relatives of noncarriers of the I1307K allele (42.1%; P = 0.86). The average age of diagnosis of cancer of any type was not different between relatives of carriers (59.0 years) and noncarriers (60.4 years). In the Ashkenazi Jewish population, the I1307K allele is unlikely to increase the risk of ovarian cancer or of cancer in general.
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PMID:No association of the I1307K APC allele with ovarian cancer risk in Ashkenazi Jews. 967 45

We have extended the algebraic models for cancer initiation and progression developed by Nordling, Armitage-Doll and Knudson-Moolgavkar to include the effect of cell turnover rate in normal tissue, stochastic growth of preneoplastic adenomas, and the general case wherein a subfraction of the population is at risk. We have also gathered the mortality data available for the United States from 1900 to 1991 and categorically organized them by birth year cohorts and age specific death rates for ages 0 to 104 in 5-year groupings. Using these data, we first explored the quantitative nature of the biases of underreporting or misdiagnosis as historical age-dependent functions. Then we used the extended algebraic model to calculate the parameters of subpopulation fraction at risk, mutation rates and adenoma growth rates. We observe that death rates for all cancers are low in childhood and early adulthood, rise in middle age in an approximately linear manner, reach a maximum in old age, and even after correction for reporting bias, decrease markedly in extreme old age. We represent this behavior as the natural result of a continuous process of cell division, death and mutation within a subpopulation at risk. This population at risk within any birth cohort is defined by the product of a constant inherited risk factor multiplied by a historically valuable environmental risk factor. Our formulation permits explicit calculation of the fraction at risk of death from any cancer as a historical function. With regard to the algebraic description of the process of carcinogenesis, we use Nordling's concept that n genetic events in a cell population of constant cell number are required to initiate a colony capable of net cell growth or 'adenoma.' We adopt and extend Moolgavkar's use of the 'Gambler's Ruin' stochastic process to describe the probability of adenoma survival and the canonical expectation that a surviving adenoma will soon contain many initiated cells by virtue of stochastic distribution of surviving cells. We consider that within the growing adenoma, it is necessary for a cell to acquire m additional mutations in order to attain the carcinoma phenotype of cell growth rapid enough to kill in a short time. This would be irrespective of the need for any additional genetic events that may define the subsequent phenotypes of large lethal tumors, as these would be automatically acquired and be physiologically selected in any rapidly growing cell mass. It is evident that the steps of initiation and progression are dependent on both the rates of genetic change per cell division and the cell kinetic rates of division and death. We have chosen to first examine colon cancer because the rates of cell division in normal colonic epithelium, dysplastic adenomas and small carcinomas have been directly observed as reported herein. For colon cancer, we calculate that about 65% of the US population is at risk for both males and females, and that this fraction has been constant for the earliest recorded birth cohorts of the mid-19th century to the beginning of the 20th century. The changes that have been observed in colon cancer mortality rates appear to arise from historical changes in death rates by unknown 'other causes of death', which share both genetic and environmental risk factors with colon cancer and explicitly include undiagnosed deaths by colon cancer. Considering all possible values of n and m, we find the case of n=2 and m=1 to give the best concordance with present knowledge of mutations in the colon by the loss of two alleles of the APC gene and the observation that for m=1, a rate of genetic change approximately equal to that calculated for initiation mutation rates is obtained. Our estimates for the rate of initiation and progression mutation rates show no significant historical shifts and are approximately 1-2x10-7 events per cell division. (ABSTRACT TRUNCATED)
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PMID:Mutation, cell kinetics, and subpopulations at risk for colon cancer in the United States. 968 10


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