Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This is the first report of chromosome 18 allele loss in colorectal carcinomas from FAP patients and concurrent allele losses on chromosomes 5 and 18 in sporadic colorectal cancer. This is based on our investigation of twenty-two colorectal carcinomas from sporadic cases and FAP patients which revealed tumor-specific allele loss of at least 44% at the D18S6 locus on chromosome 18 in informative cases. These results coupled with the tentative assignment of an HNPCC gene to chromosome 18 suggests that a gene on chromosome 18 may be involved in the etiology of some colon cancers. Possible mechanisms involving genetic changes on chromosome 18 in colon cancer are discussed in relation to tumor- or growth-suppressor genes.
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PMID:Chromosome 18 allele loss at the D18S6 locus in human colorectal carcinomas. 341 2

The lectin GS I-A4 binds to terminal alpha-N-acetylgalactosaminyl (GalNAc) groups (which include the Tn antigen), but not to the closely related tumor-associated epitope, sialylated Tn antigen. The lectin also precipitates asialo OSM, but not its native sialylated form. Lectin histochemistry with human colonic tissues showed that GS I-A4 specifically stained specimens of colon cancer and colonic tissues from individuals with FAP; however, normal colonic tissues from patients without colonic disease were rarely stained with this lectin. Glycoconjugates bound by GS I-A4 were observed on the surface membranes of 2 human colon cancer cell lines, LS174t and SW1116, when fluorescein isothiocyanate (FITC)-conjugated GS I-A4 was used. GS I-A4 was toxic to these 2 human colon cancer cell lines in monolayer culture. A dose-response study conducted using 10-160 micrograms/ml, of GS I-A4 demonstrated significant dose-related toxicity against LS174t and SW1116 cells. At concentrations > 80 micrograms/ml, > 99% of LS174t and > 90% of SW1116 cells were killed. Four mM GalNAc specifically inhibited the cytotoxic effect of GS I-A4 (p < 0.001), whereas 4mM N-acetylglucosamine (GlcNAc) had no effect. Two other lectins that recognize terminal alpha-GalNAc residues, DBA and LBL, were significantly less cytotoxic to the colon cancer cells than GS I-A4. In the light of these findings, we speculate that GS I-A4 may have potential use as a diagnostic agent against colorectal cancer.
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PMID:The lectin Griffonia simplicifolia I-A4 (GS I-A4) specifically recognizes terminal alpha-linked N-acetylgalactosaminyl groups and is cytotoxic to the human colon cancer cell lines LS174t and SW1116. 751 54

Dissection of germline mutations in a sensitive and specific manner presents a continuing challenge. In dominantly inherited diseases, mutations occur in only one allele and are often masked by the normal allele. Here we report the development of a sensitive and specific diagnostic strategy based on somatic cell hybridization termed MAMA (monoallelic mutation analysis). We have demonstrated the utility of this strategy in two different hereditary colorectal cancer syndromes, one caused by a defective tumour suppressor gene on chromosome 5 (familial adenomatous polyposis, FAP) and the other caused by a defective mismatch repair gene on chromosome 2 (hereditary non-polyposis colorectal cancer, HNPCC).
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PMID:Monoallelic mutation analysis (MAMA) for identifying germline mutations. 755 Mar 26

Colorectal cancer is the second leading cause of death from malignancies in Western Countries. In spite of advances in treatment, little change in survival has been accomplished in last decades and this mandates greater importance to prevention and early detection. Although dietary factors have received primary attention familial clustering suggests that susceptibility to KCR is inherited. Hereditary colorectal cancer can arise on Familial Adenomatous Polyposis (HCC) or not on polyposis (HNPCC) and members of these families are at high risk of such neoplasias. Anyway, even in "sporadic" forms of KCR first-degree relatives have a 2 to 3-fold increased risk of the same cancer. The most desirable screening protocol would be a simple procedure involving only a blood test to identify gene defect by molecular biology techniques. Unfortunately, this is not practically possible, for lack of specific genetic alterations, out of FAP, and only the study of family history can enable targeted surveillance and cost-effective management strategies.
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PMID:[Heredity and colorectal cancer]. 765 49

First, and most importantly, the standard of care for treating adenomatous polyps is polypectomy and not therapy with NSAIDs. The initial clinical observation by Waddell and Loughry in 1983 that sulindac treatment influenced rectal polyps in patients with FAP has led to a considerable amount of research, commentary, and discussion during the past decade. These original observations have been validated by controlled clinical trials. Work presented in this issue by Ladenheim et al. indicates that sulindac may not be effective therapy for sporadic polyps that are present before initiation of treatment (secondary prevention). Even though their study may have failed to show a small effect of NSAIDs on polyps, further investigation of the ability of NSAIDs to cause regression of established polyps is probably not warranted. A more clinically relevant question, whether or not these agents can be used in a primary prevention strategy to prevent the development of adenomas in a colon devoid of these lesions, is currently being addressed in a large trial with sufficient statistical power to render firm conclusions (personal communication, January 1995). The multiple reports that sulindac treatment causes regression of adenomas in patients with FAP has stimulated research directed at understanding the molecular basis for these effects. If we are able to understand the molecular mechanism by which NSAIDs decrease the risk of colorectal cancer, we might be able to design more effective drugs or other approaches that would be clinically useful in humans for colorectal cancer chemoprevention.
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PMID:Nonsteroidal anti-inflammatory drug use and sporadic colorectal adenomas. 769 75

Sulindac is useful in regression of adenomatous polyps. In addition to orally administered sulindac, rectal preparations also appear to be efficacious [32]. However, further studies are necessary to determine whether regression of adenomas, the precursor of colorectal cancer, will cause decrease in colorectal cancer risk in both FAP and non FAP patients. Moreover, clinical studies are needed to test the application of this potential chemopreventative drug in several other patient populations. Several interesting observations have been made concerning the use of sulindac. Indomethacin, a related NSAID to sulindac, did not cause polyp regression. Also, upper gastrointestinal tract polyps in the stomach and duodenum appear not to be affected by sulindac therapy. These observations might be explained by the metabolism of sulindac in which the pharmacologically active sulfide metabolite is generated and distributed in the large intestine. Also, investigators noted that after discontinuation of sulindac adenomas recurred. Sulindac treatment was well tolerated at the usual clinical doses. Although some investigators have speculated on the effect of prostaglandin inhibition sulindac on cAMP-dependent mechanisms which control cellular proliferation [33], the cause of adenoma regression is unknown. There is evidence that colorectal endogenous prostaglandin levels decrease with sulindac. Evaluation of colorectal mucosal cellular proliferation in patients treated with sulindac has revealed a decrease in labelling index by bromodeoxyuridine labeling in one study [28] but no change in labelling index by [3H]thymidine incorporation in another investigation [34]. Also, ki 67 labelling index, another measure of cellular proliferation, was not affected in the colorectal mucosa of patients taking sulindac.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sulindac and polyp regression. 771 90

Heterogeneity among and within FAP pedigrees for the age of symptom onset and the age at death from colorectal cancer was studied in a sample of 583 patients of the Italian Polyposis Registry. The among pedigree variation was largely explained by clustering of families in two groups, 'early FAP' (most colorectal cancer deaths below 45 years of age) and 'late FAP' families (most deaths above age 45). The within-family variation was explained by a marked phenomenon of anticipation (15 years per generation, on the average), possibly not due to ascertainment bias. We then considered the pedigrees with identified mutation in the APC gene. Six families shared a common deletion at codon 1309 and showed the early FAP phenotype. Two families shared a mutation at codon 1061 and revealed the late FAP phenotype. Another two families (codons 453 and 302) clustered with the late FAP group, whereas a family with mutation at codon 835 clustered with the early FAP group. We suggest that there are at least two classes of mutations in the APC gene with different consequences at the phenotypic level. It seems that there are several critical points within the APC protein sequence at which truncation causes a more aggressive disease than truncation at other points.
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PMID:Age of onset in familial adenomatous polyposis: heterogeneity within families and among APC mutations. 786 89

The life-threatening event of early colorectal cancer in FAP patients may effectively be prevented by prophylactic colectomy. Desmoid tumors and periampullary carcinoma are now becoming the most frequent causes of death in FAP patients. Since the establishment of the Heidelberg polyposis registry in January 1991 we evaluated the frequency of desmoid tumors in 171 prospectively reexamined FAP patients. 29 patients (17%) with desmoid tumors were identified. In our series R0-resection with a wide security margin was performed in 12 cases, 3 of which developed a desmoid recurrence, 8 are free of desmoids and one treated for an intraabdominal desmoid states being well but refuses a radiological reevaluation. Tumor debulking was performed in 6 patients and led to an aggressive desmoid progression in 4 patients despite additional postoperative administration of tamoxifen and sulindac. Nonsurgical treatment with tamoxifen and sulindac seemed beneficial in 5 of 7 patients, 4 showed a stagnation of tumor growth, a reduction of an abdominal wall desmoid was documented in one female with a further intraabdominal desmoid. In life-threatening cases chemotherapy and radiation therapy may be considered. In two females radiation therapy resulted in a remarkable tumor reduction. The operative trauma of previous colectomy is considered the most relevant predisposing external factor inducing desmoid growth in FAP patients. 50% (11/22) of the desmoid tumors in our series were diagnosed within the first two years postoperatively, and 72% (18/22) of the desmoids developed within the first four years after colectomy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Desmoid tumors in patients with familial adenomatous polyposis (FAP). Clinical and therapeutic observations from the Heidelberg polyposis register]. 852 53

Germline mutations of the adenomatous polyposis coli gene are associated with the dominantly inherited syndrome of familial adenomatous polyposis. Somatic mutations in this gene are an early event in sporadic colorectal tumorigenesis. Here we report a family with genetic characteristics that do not conform exactly to either of these situations. The index case and three siblings presented with colorectal cancer, and another sibling had lung cancer. There was no evidence of colorectal cancer susceptibility in previous generations, although one case of gastric cancer was observed. Using restriction fragment length polymorphism, single-strand conformational polymorphism, and sequencing analysis, we screened each living family member for alterations in the mutation cluster region of exon 15 of the APC gene. A constitutional single base pair substitution at codon 1317 was observed in two of the siblings with colorectal cancer, but neither exhibited any colonic features typical of FAP nor an early onset of cancer. This constitutional change is a missense mutation and therefore does not result in the truncation of the APC protein, the most commonly observed result of mutation in this gene. We present evidence that this change is not a polymorphism and may be capable of conferring a growth advantage. This particular germline APC mutation does not completely cosegregate with cancer in this family; therefore, we conclude that another gene locus may be responsible for the increased cancer risk observed.
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PMID:Germline APC mutation (Gln1317) in a cancer-prone family that does not result in familial adenomatous polyposis. 883 76

Familial adenomatous polyposis is a genetically inherited disease with very high risk of colorectal cancer and with a large expression of multiple extracolonic malignancies. In recent years two surgical options are available for the treatment of FAP: total colectomy with ileorectal anastomosis and restorative proctocolectomy with ileoanal reservoir. The preservation of the rectum offers good quality of life and good functional results, but needs an accurate surveillance of the rectal stump and screening for the development of cancer. Restorative proctocolectomy is reserved for patients with large or confluent polyps of the rectum, for older patients and for those who had already had an ileorectal anastomosis and who develops subsequently large adenomas at increased risk for rectal cancer. Prophylactic procedures of surveillance, screening and surgery have reduced in patients at risk the incidence of colorectal cancer. But recently an increased number of malignant extracolonic tumors (gastric cancer, duodenal and periampullary cancer, small intestinal cancer, adrenal and thyroid cancer) and abdominal desmoid tumors, that causes a significant mortality, has been documented. The knowledge of the extracolonic features of FAP suggests a careful follow-up of the patients and the prevention and treatment of upper gastrointestinal cancers and desmoid disease.
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PMID:[Familial adenomatous polyposis. Problems encountered with rectum preservation in surgical treatment and life expectancy]. 894 6


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