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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A concise review of the literature that evaluates the risk of colorectal cancer among NSAID users has been presented. Animal studies document a protective effect of NSAIDs in preventing colorectal cancers in carcinogen-induced (AOM) models and in Min mice. NSAIDs are protective in the animal model, even if given 14 weeks after administration of the carcinogen, indicating that these agents must be acting early in the adenoma-to-carcinoma sequence. Treatment of FAP patients with NSAIDs causes regression of adenomas that were already present before initiation of therapy. Many epidemiologic studies have examined the relationship between aspirin use and colorectal cancer. Most show a marked decrease in the relative risk (40% to 50%) of this tumor among continuous aspirin users. The appropriate dose and duration of aspirin treatment needed for optimal results are still unknown. Future work, directed at the molecular basis for the chemoprotective effects of NSAIDs in humans, may reveal strategies for the development of better chemopreventive agents. One effect shared by all NSAIDs is inhibition of cyclooxygenase. Presently, whether inhibition of COX-1 or COX-2 is required for the protective effect of aspirin and other NSAIDs is unclear. The authors and others have demonstrated that COX-2 is up-regulated from 2 to 50 fold in 85% to 90% of colorectal adenocarcinomas, making the COX-2 enzyme a more likely target. The authors have also reported a dramatic increase in COX-2 expression in colon tumors that develop in rats after AOM treatment. Drugs are currently being developed that preferentially inhibit either COX-1 or COX-2. If COX-2 is found to be a relevant target in the prevention of colorectal cancer, these newly developed, selective NSAIDs may play a role in future chemoprevention strategies.
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PMID:Nonsteroidal anti-inflammatory drugs, eicosanoids, and colorectal cancer prevention. 896 Aug 92

The authors have presented a concise review of the studies which evaluate the risk of colorectal cancer among NSAID users. Animals studies have clearly documented a protective effect of NSAIDs in preventing colon cancers in a carcinogen-induced (AOM) model. NSAIDs are protective in the animal model, even if given 14 weeks after administration of the carcinogen, indicating that they must be playing a role very early in the adenoma-to-carcinoma sequence of events. Several studies have indicated that treatment of FAP patients with NSAIDs causes a regression of adenomas that were already present prior to initiation of NSAID therapy. Many epidemiological studies have examined the relationship between aspirin use and colorectal cancer. Most of these studies have shown a marked decrease in the relative risk (40-50%) of colorectal cancer among continuous aspirin users. The appropriate dose and duration of aspirin treatment for optimal effects are still unknown. Future work, directed at the molecular basis for the chemoprotective effects of NSAIDs in humans, may reveal strategies for the development of better chemopreventive agents. One effect shared by all NSAIDs is their ability to inhibit cyclooxygenase. Presently, it is not clear whether inhibition of cyclooxygenase-1 or -2 effects on other signaling pathways are required for the protective effect of aspirin and other NSAIDs. The authors and others have demonstrated that COX-2 is upregulated from 2- to 50-fold in 85-90% of colorectal adenocarcinomas, which makes the COX-2 enzyme a possible target. Drugs are currently under development at several pharmaceutical companies that preferentially inhibit either COX-2 or COX-2. If COX-2 is found to be a relevant target in the prevention of colorectal cancer, then these newly developed, more selective NSAIDs may play a role in future chemoprevention strategies.
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PMID:Colorectal cancer and nonsteroidal anti-inflammatory drugs. 916 Jan 11

151 members of 10 affected families with FAP have been registered at the authors' regional polyposis registry, among them 51 FAP patients were verified histologically. The disorder is autosomal dominant thus the chance for the inheritance of the mutated allele is fifty percent in the offspring of an affected patient. Because of the high risk the registration and regular control of family members is recommended. They can be divided into high risk and low risk group based on presymptomatic tests. The examination of retina pigmentepithel was the only possibility for presymptomatic diagnosis earlier. After localization and identification of APC gene responsible for the disease molecular genetic methods have been introduced for presymptomatic diagnosis. The authors performed presymptomatic tests based on ophthalmologic and molecular genetic methods among family members at risk. Ophthalmologic examination was done in 53 while molecular genetic investigation in 54 cases. All the results of endoscopic, ophthalmological and molecular genetic examinations were available in 35 persons, among them 19 FAP have been found. Ophthalmological examination were informative in 33 out 35 cases (unequivocal positive or negative) while results of molecular genetic methods and sigmoidoscopy were correlated in every case. Authors stress the significance of complex screening of affected families with FAP in the prevention of colorectal cancer and extracolonic malignant processes.
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PMID:[Complex screening of family members at risk for familial adenomatous polyposis]. 944 80

The diagnosis and treatment of colorectal cancer remains a formidable health care problem. Colorectal cancer is the second most frequently diagnosed cancer in both men and women in Western countries and accounts for over 55,000 deaths annually in the United States alone. Cancer of the colon and rectum is eminently curable by surgical resection if identified early; however, despite our best efforts, patient survival from this disease has changed little over the past 50 years. With the advent of molecular and genetic techniques, a number of novel discoveries have been made in the last decade which have greatly expanded our understanding of the etiology and cellular mechanisms contributing to the development and subsequent progression of colorectal cancer. This review summarizes the recent molecular advances in the understanding of both familial (HNPCC and FAP) and sporadic colorectal cancers. The numerous scientific advances described in this review offer the promise of the development of novel chemotherapeutic agents, more accurate prognostic indicators and better screening techniques.
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PMID:Molecular advances in the etiology and treatment of colorectal cancer. 957 30

As a signaling protein in the Wnt pathway beta-catenin plays a crucial role in the regulation of cellular proliferation. Recently, oncogenic beta-catenin mutations were described in human colorectal cancer and melanoma cell lines. Since activating mutations in the beta-catenin gene have similar effects on the biochemical level as inactivating mutations in the tumor suppressor gene APC, it is speculated that beta-catenin mutations may substitute APC gene inactivation in carcinogenesis. To address this question we analyzed twenty-three sporadic colorectal tumors of different progression states for mutations in the beta-catenin gene. Eighteen of these tumors showed the wildtype APC gene sequence. In only one of the tumors with wildtype APC a beta-catenin gene mutation was found. This tumor was of the RER (replication error) phenotype which may explain the finding that the mutation occurred in a sequential repeat motif of the beta-catenin gene. The second aim of this study was to investigate whether differences in the phenotypic variability in FAP (familial adenomatous polyposis coli) might be due to inherited alterations in the beta-catenin gene. For this we analyzed DNA from fourteen FAP patients from eight different families for germline mutations in the beta-catenin gene. We did not find any beta-catenin gene alteration in these samples. Our results indicate that somatic beta-catenin activating mutations contribute only to a minor part of human colorectal tumors and that germline beta-catenin mutations do not play a role in the variability of symptoms in FAP.
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PMID:A beta-catenin mutation in a sporadic colorectal tumor of the RER phenotype and absence of beta-catenin germline mutations in FAP patients. 959 32

Recent advancement of molecular biology disclose responsible genes of FAP(familial adenomatous polyposis) and HNPCC(hereditary non polyposis colorectal cancer). Gardner Syndrome is now categorized as subtype of FAP. Turcot Syndrome is now known as a heterogeneous disease. Turcot Syndrome caused by APC gene develops medulloblastoma and Turcot Syndrome caused by mismatch repair gene develops glioblastoma. Because of the discovery of APC gene, the presymptomatic diagnosis of asymptomatic gene carriers are now available and preventive surgery can be planned. FAP patients with mutated APC gene between codon 1250 and 1464 shows severe phenotype. It is known that FAP patient whose APC gene mutation locates at codon 1309 develops cancer 10 years earlier in comparison to the rest of the cases. Consequently risky rectal mucosa should be removed in this group of patients. As for HNPCC, presymptomatic diagnosis is still not possible because the penetrance rate has not been estimated yet and some additional responsible genes are expected to be discovered. Replication error, mutator phenotype of mismatch repair gene is useful indicator to predict second primary cancers. When the patient in a HNPCC family develops adenoma with microsatellite mistability, preventive colectomy might be one of the surgical option with the informed consent of the patient.
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PMID:[Molecular biological background of FAP and HNPCC, and treatment strategies of both diseases depend upon genetic information]. 969 69

Conflicting data exist on the prognosis of hereditary colorectal cancer. HNPCC patients, in particular, are often reported to have a better survival. We examined 2,340 colorectal-cancer patients treated in our Institution: 144 HNPCC patients (Amsterdam Criteria), 161 FAP patients and 2,035 patients with sporadic cancer. Data on hereditary-cancer patients treated between 1980 and 1995 was collected in a registry. The 2,035 sporadic colorectal-cancer patients (controls) included all new cases treated in the Department of Gastrointestinal-Tract Surgery during the same period. Observed survival was estimated using the Kaplan-Meier method. Cumulative survival probability was estimated at 5 years within each group and stratified by various clinical and pathological variables. The age distribution at diagnosis of sporadic patients was significantly higher than that of FAP and HNPCC patients (median 60 years vs. 43 and 49 years; p < 0.0001). In the HNPCC group, 40% had a right cancer location, vs. 14% in the FAP group and 13% in the sporadic-cancer group. In the sporadic group, 51% were early-stage cancers (Dukes A or B) vs. 48.4% and 52.1% in the FAP and HNPCC groups respectively. In the HNPCC, FAP and sporadic-cancer groups, the 5-year cumulative survival rate was 56.9%, 54.4% and 50.6% respectively. Survival analysis by the Cox proportional-hazards method revealed no substantial survival advantage for HNPCC and FAP patients compared with the sporadic group, after adjustment for age, gender, stage and tumor location. The hazard ratio for HNPCC was 1.01 (95% CI 0.72-1.39) and 1.27 (95% CI 0.95-1.7) for FAP patients compared with the sporadic-colorectal-cancer group.
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PMID:Survival of patients with hereditary colorectal cancer: comparison of HNPCC and colorectal cancer in FAP patients with sporadic colorectal cancer. 993 97

The epidemiology and molecular biology of colorectal cancer are reviewed with a view to understanding their interrelationship. Risk factors for colorectal neoplasia include a positive family history, meat consumption, smoking, and alcohol consumption. Important inverse associations exist with vegetables, nonsteroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy, and physical activity. There are several molecular pathways to colorectal cancer, especially the APC (adenomatous polyposis coli)-beta-catenin-Tcf (T-cell factor; a transcriptional activator) pathway and the pathway involving abnormalities of DNA mismatch repair. These are important, both in inherited syndromes (familial adenomatous polyposis [FAP] and hereditary nonpolyposis colorectal cancer [HNPCC], respectively) and in sporadic cancers. Other less well defined pathways exist. Expression of key genes in any of these pathways may be lost by inherited or acquired mutation or by hypermethylation. The roles of several of the environmental exposures in the molecular pathways either are established (e.g., inhibition of cyclooxygenase-2 by NSAIDs) or are suggested (e.g., meat and tobacco smoke as sources of specific blood-borne carcinogens; vegetables as a source of folate, antioxidants, and inducers of detoxifying enzymes). The roles of other factors (e.g., physical activity) remain obscure even when the epidemiology is quite consistent. There is also evidence that some metabolic pathways, e.g., those involving folate and heterocyclic amines, may be modified by polymorphisms in relevant genes, e.g., MTHFR (methylenetetrahydrofolate reductase) and NAT1 (N-acetyltransferase 1) and NAT2. There is at least some evidence that the general host metabolic state can provide a milieu that enhances or reduces the likelihood of cancer progression. Understanding the roles of environmental exposures and host susceptibilities in molecular pathways has implications for screening, treatment, surveillance, and prevention.
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PMID:Colorectal cancer: molecules and populations. 1130 47

About 5% of colorectal cancer cases are due to an autosomal dominant genetic predisposition with high penetrance. In this condition, the patient is carrier of a pathogenic gene mutation present in all body cells which can be transmitted to descendants, a so-called germ line mutation. The mutation is usually present in a tumour suppressor gene. Three subgroups of hereditary colorectal cancer can be distinguished on the basis of the clinical characteristics: (a) syndromes without polyposis (mostly hereditary non-polyposis colorectal carcinoma; HNPCC), (b) syndromes with adenomatous polyposis (mostly familial adenomatous polyposis; FAP) and (c) syndromes with hamartomatous polyposis. Recently, the main gene defects which underlie these syndromes were identified. Consequently, it is possible in approximately half the families with HNPCC or FAP in patients with colorectal cancer to demonstrate the causative gene defect and subsequently, by blood testing of healthy relatives to determine who is and is not a carrier of this hereditary condition. Thus, preventive measures can be directed toward family members with a demonstrable high risk of large bowel cancer.
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PMID:[Genetics of colorectal cancer. I. Non-polyposis and polyposis forms of hereditary colorectal cancer]. 1038 34

Familial risk of colon cancer is a commonly encountered issue, involving both rare inherited syndromes of colon cancer and common familial clustering of cases. The genes that give rise to the rare syndromes of FAP and HNPCC are now known and current research is addressing the cellular mechanisms of these genes and the proper application of genetic testing in families with one of the syndromes. Common familial clustering of cases appears to arise from an interaction of mildly to moderately severe inherited susceptibility factors with certain environmental factors to give rise to adenomatous polyps and then finally colorectal cancer. Research in this area involves identification of these purportedly more common susceptibility genes, and determination of how each interacts with environmental factors to give rise to polyps and cancer. Optimal application of varying degrees of familial risk to screening strategies is also being determined.
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PMID:Familial association. 1070 79


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