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)

Almost 20% of colon cancers are characterized by genomic instability at simple repeated sequences. This instability is the result of a deficient DNA mismatch repair system. Sporadic, as well as hereditary carcinomas of the proximal colon display this effect. In this study, we examined colorectal adenocarcinoma cell lines, with or without wild-type adenomatous polyposis coli (APC) protein, for the presence of microsatellite instability. The three cell lines that maintained full-length APC protein also displayed the highest level of instability, suggesting a negative correlation between APC mutations and microsatellite instability. This data, in addition to other studies that show a negative correlation between microsatellite instability and mutations in p53 and K-ras, support the idea of a second pathway for colorectal cancer development.
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PMID:Microsatellite instability in colorectal adenocarcinoma cell lines that have full-length adenomatous polyposis coli protein. 758 8

Familial adenomatous polyposis (FAP) is an inherited predisposition to colorectal cancer caused by germline mutations in the adenomatous polyposis coli (APC) gene located on chromosome segment 5q21-q22. We detected a germline rearrangement of the APC gene in a Dutch FAP family by screening genomic DNA samples with APC cDNA probes. Subsequent molecular and cytogenetic studies revealed a constitutional reciprocal translocation t(5;10)(q22;q25) that resulted in the disruption of the APC gene. Southern blot and polymorphic marker analysis indicated that part of the APC gene had been deleted. Analysis of the APC protein product indicated that the translocation breakpoint did not lead to the formation of a detectable truncated APC protein but apparently resulted in a null allele. Evaluation of the clinical phenotypes in the patients suggested that they exhibited features of an unusual form of FAP characterized by a slightly delayed age of onset of colorectal cancer and a reduced number of colorectal polyps. The latter were mainly sessile and were located predominantly in the proximal colon. To our knowledge, this is the first description of FAP caused by a reciprocal translocation disrupting the APC gene.
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PMID:Molecular, cytogenetic, and phenotypic studies of a constitutional reciprocal translocation t(5;10)(q22;q25) responsible for familial adenomatous polyposis in a Dutch pedigree. 766 39

Genetic predispositions to colorectal cancer can schematically be divided in two categories depending on the presence or absence of a diffuse polyposis i.e.: a large number of adenomatous polyps in the colon and rectum of affected patients. These syndromes are referred as familial adenomatous polyposis coli and hereditary non polyposis colon cancer (HNPCC) respectively. The gene which when altered causes familial adenomatous polyposis coli is called APC and has been identified in 1991 but the function of its product remained elusive. Recent experimental data indicate that the APC protein can interact with catenins and tubulins, two groups of proteins known to be components of adherens junctions and cytoskeleton. Thus the APC protein may play a role in cell adhesion and in transduction of signal regulating the cell cycle. Of more immediate clinical interest is the observation that specific APC mutations appear to participate in the severity of the disease and determine the development of hypertrophy of the retinal pigment epithelium, a diagnostically important manifestation of the APC disease found in 70% of the patients. HNPCC syndromes have been recognized as being frequently associated with a defect in the DNA mismatch repair pathway. Furthermore, human genes, demonstrating homology with the bacterial DNA repair genes MutS and MutL, have been identified and shown to be altered in several HNPCC families. There are now indications that genotyping of tumor DNA at particular loci, termed microsatellite, may contribute in the identification of patients genetically predisposed to tumor development.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Genetic predispositions to colorectal cancer. 767 42

The APC tumor-suppressor protein associates with beta-catenin, a cell adhesion protein that is upregulated by the WNT1 oncogene. We examined the effects of exogenous APC expression on the distribution and amount of beta-catenin in a colorectal cancer cell containing only mutant APC. Expression of wild-type APC caused a pronounced reduction in total beta-catenin levels by eliminating an excessive supply of cytoplasmic beta-catenin indigenous to the SW480 colorectal cancer cell line. This reduction was due to an enhanced rate of beta-catenin protein degradation. Truncated mutant APC proteins, characteristic of those associated with cancer, lacked this activity. Mutational analysis revealed that the central region of the APC protein, which is typically deleted or severely truncated in tumors, was responsible for the down-regulation of beta-catenin. These results suggest that the tumor-suppressor activity of mutant APC may be compromised due to a defect in its ability to regulate beta-catenin.
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PMID:Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. 770 72

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

Germ-line mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis (FAP). Genotype-phenotype correlation studies in patients with FAP have demonstrated associations of certain variants of the disease with mutations at specific sites within the APC gene. In a large FAP family, we identified a frameshift mutation located in the alternatively spliced region of exon 9. Phenotypic studies of affected family members showed that the clinical course of FAP was delayed, with gastrointestinal symptoms and death from colorectal carcinoma occurring on average 25 and 20 years later than usual, respectively. The numbers of colorectal adenomas differed markedly among affected individuals and the location of colorectal cancer lay frequently in the proximal colon. Our findings suggest that the exon 9 mutation identified in the pedigree is associated with late onset of FAP. The atypical phenotype may be explained by the site of the mutation in the APC gene. Analysis of the APC protein product indicated that the exon 9 mutation did not result in a detectable truncated APC protein. Given the location of the mutation within an alternatively spliced exon of APC, it is conceivable that normal APC proteins are produced from the mutant allele by alternative splicing.
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PMID:APC mutation in the alternatively spliced region of exon 9 associated with late onset familial adenomatous polyposis. 852 31

Familial adenomatous polyposis (FAP) is an autosomal, dominantly inherited disease that predisposes to colorectal cancer and is characterized by the presence of hundreds to thousands of adenomas covering the colon and rectum. Mapping of the FAP locus to 5q21-q22 by linkage studies in families ultimately allowed the identification of the APC (Adenomatous Polyposis Coli) gene itself. The APC gene comprises 15 exons with a 9 kilobase RNA transcript and a 312 kilodalton final protein product. This discovery transformed the diagnosis of FAP and offered direct identification of defective gene carriers by mutation screening. Currently used techniques have been successful in detecting mutations in 15 to 67 percent of patients. To date, at least 136 different mutations have been described in 301 unrelated FAP patients, most of which (98%) are translation terminating mutations leading to a truncated final protein product. Promising applications or development of novel procedures, like the protein truncation test (PTT), are under way for the remaining FAP patients. With the exception of the description of a critical boundary in exon 9 for the presence or absence of CHRPE, there are no clear genotype-phenotype relationships, but mutations located in the 5' half of exon 15 seem to lead to a more severe phenotype. Very little is know about the APC protein product function. The APC protein could be involved in cell-to-cell signalling and/or cell adhesion functions. The APC gene is a tumour suppressor gene involved in early stages of sporadic colorectal carcinogenesis. Further understanding of the APC gene function may define a rational approach for early detection, prevention strategies, assessment of prognosis and treatment of colorectal cancer. In this regard, animal models of FAP, like the MIN (Multiple Intestinal Neoplasia) mouse or the APC 1638 mouse, are promising and powerful tools.
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PMID:The genetic background of familial adenomatous polyposis. Linkage analysis, the APC gene identification and mutation screening. 877 1

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 (FAP) is an inherited predisposition to colorectal cancer characterized by the development of numerous adenomatous polyps predominantly in the colorectal region. Germline mutations in the adenomatous polyposis coli (APC) gene are responsible for most cases of FAP. Mutations at the 5' end of APC are known to be associated with a relatively mild form of the disease, called attenuated adenomatous polyposis coli (AAPC). We identified a frameshift mutation in the 3' part of exon 15, resulting in a stop codon at 1862, in a large Dutch kindred with AAPC. Western blot analysis of lymphoblastoid cell lines derived from affected family members from this kindred, as well as from a previously reported Swiss family carrying a frameshift mutation at codon 1987 and displaying a similar attenuated phenotype, showed only the wild-type APC protein. Our study indicates that chain-terminating mutations located in the 3' part of APC do not result in detectable truncated polypeptides and we hypothesize that this is likely to be the basis for the observed AAPC phenotype.
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PMID:Germline mutations in the 3' part of APC exon 15 do not result in truncated proteins and are associated with attenuated adenomatous polyposis coli. 893 9

Desmoid tumours are generally very rare but occur about 100 times more frequently in the colorectal cancer predisposition syndrome familial adenomatous polyposis (MIM 175100), being represented in about 10% of patients. In addition to desmoid disease occurring in familial adenomatous polyposis (FAP) there exist familial infiltrative fibromatosis (MIM 135290) kindreds where there is no evidence of FAP. Previously we have described a kindred with familial infiltrative fibromatosis (FIF) in which desmoid tumours were associated with nonpolyposis colorectal cancer. FAP is caused by mutations in the APC gene and various genotype-phenotype relationships have been defined including reports that colorectal polyposis is less severe with mutations 5' to codon 157 and that the risk of desmoid tumours is high in FAP patients with APC gene mutations between codons 1444 and 1598. There is relatively little information on the phenotype of APC gene mutations 3' to codon 1598; however, one large family has been reported with a mutation at codon 1987 which presents with a highly variable phenotype which includes desmoid disease. We screened our original FIF kindred and three further families with a similar phenotype for mutations in the APC gene. A 4 bp frameshift deletion in codon 1962 was identified in the original FIF kindred and two further apparently unrelated families. Haplotype analysis suggests a common origin for the APC mutation in all three families. Affected individuals had no evidence of congenital hypertrophy of the retinal pigment epithelium. Colorectal polyposis was variable, and most affected patients had either none or a few late onset polyps. These findings demonstrate (i) that FAP and FIF are allelic, and (ii) that APC gene mutations which truncate the APC protein distal to the beta-catenin binding domain are associated with desmoid tumours, absent CHRPE and variable but attenuated polyposis expression.
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PMID:Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3' APC gene mutation. 896 44


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