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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retinoblastoma (RB) and the familial adenomatous polyposis/colorectal cancer (FAP/CRC) complex provide well-characterised examples of multistage carcinogenesis and inheritance of a predisposition to cancer. Retinoblastoma appears to conform to the simple two-step model first proposed by Knudson. The gene responsible for RB, now called Rb1, has been located in chromosome region 13q14. The Rb1 gene has been cloned and subjected to extensive analysis. It is probable that the Rb1 gene product has a role in the regulation of transcription. The familial form of RB occurs as the result of a germline mutation of one of the copies of the Rb1 gene. Colorectal cancer, in contrast, appears to be the result of four or five steps involving both activation of oncogenes and inactivation of antioncogenes. The FAP gene has been located in chromosome region 5q21 by genetic linkage, and a candidate gene, MCC (mutated in colon cancer), has been cloned. Other mutations in previously-identified genes that have been identified as important in the genesis of CRC include the activation of p53 and of Ki-ras. A gene lying in chromosome region 18q which is deleted in colorectal cancer, and hence named DCC has been cloned. Its protein product has sequence homology to neural cell adhesion molecules and other related cell-surface glycoproteins. Delineation of the genes involved in the development of tumours such as RB and CRC provides insight into the mechanisms by which sequential mutations result in carcinogenesis.
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PMID:Multistage carcinogenesis in paediatric and adult cancers. 131 30

We have studied three patients, one with extensive polyposis of the colon, who have constitutional interstitial deletions of the long arm of chromosome 5. High-resolution banding studies indicated that the deletion in the patient with polyposis spans the region 5q21-q22, which includes APC, a gene involved in familial adenomatous polyposis and sporadic colon cancer. Molecular analysis with probes for sequences flanking APC confirmed this conclusion. The deletions in the other two patients, who are too young to have developed polyposis, had breakpoints within this region, precluding the use of cytogenetic analysis alone in making definitive predictions about their risks. Molecular studies resolved the uncertainty; in situ and quantitative Southern hybridizations of four probes for polymorphic segments revealed that one of the patients has a deletion of MCC, a gene which is approximately 150 kb proximal to APC, and two flanking markers. He is at increased risk for polyposis, while the other patient is not. The physical descriptions of these patients, in conjunction with cases in the literature, begin to allow delineation of two distinct 5q-syndromes. These studies also provide precise physical mapping data for D5S71, D5S81, D5S84, and MCC on 5q.
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PMID:Phenotypic, cytogenetic, and molecular studies of three patients with constitutional deletions of chromosome 5 in the region of the gene for familial adenomatous polyposis. 832 66

Tumorigenesis is thought to be a multistep process in which genetic alterations accumulate to bring about the neoplastic phenotype. Colorectal tumors appear to arise as a result of the mutational activation of oncogenes coupled with the inactivation of several tumor suppressor genes. We have found frequent allelic deletions of specific portions of chromosomes 5, 17, and 18 which presumably harbor suppressor genes. The target of allelic loss events on chromosome 17 has been shown to be the p53 gene, which is frequently mutated not only in colon cancer but in several other tumor types as well. Candidate suppressor genes have also recently been identified on chromosomes 18 and 5. The DCC gene on chromosome 18q encodes a protein with significant sequence similarity to neural cell adhesion molecules and other related cell surface glycoproteins. Alterations of this gene may interfere with normal cell growth and differentiation by disrupting cell-cell or cell-substrate interactions. Two genes (MCC and APC) on chromosome 5q have also recently been identified and partially cloned. These genes are located in a region tightly linked to familial adenomatous polyposis (FAP). While MCC mutations have been found only in sporadic colon tumors, APC mutations have been identified in sporadic tumors as well as the germline of patients with FAP. Studies are currently in progress to increase our understanding of how alterations of these genes affect colorectal tumor cell growth.
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PMID:Suppressor gene alterations in the colorectal adenoma-carcinoma sequence. 146 93

The tumor suppressor gene APC was recently identified, and the cDNA was cloned from chromosome 5q21. Point mutations affecting APC are seen in the hereditary syndrome familial adenomatous polyposis, and point mutations in APC and a closely linked gene, MCC, as well as loss of heterozygosity involving chromosome 5q have been reported in sporadic colon cancer. To our knowledge, loss of heterozygosity involving APC or MCC or both has not yet been described in any other human cancer besides lung cancer. We used the polymerase chain reaction and DNA content flow cytometric nuclear sorting to examine 30 primary human esophageal cancers for loss of heterozygosity of APC or MCC or both. Loss of one allele was detected in 77% of 26 informative cases. These data suggest that loss of heterozygosity of regions on 5q including the APC and MCC genetic loci is involved in the development and/or progression of most human esophageal cancers. They imply that inactivation of APC, MCC, and/or a linked gene on chromosome 5q plays a role in the pathogenesis of some cancers of the upper gastrointestinal tract, as well as in colon cancer and familial adenomatous polyposis.
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PMID:Loss of heterozygosity involving the APC and MCC genetic loci occurs in the majority of human esophageal cancers. 156 31

Hereditary nonpolyposis colorectal carcinoma (HNPCC) is the most common form of hereditary colon cancer. Autosomal dominant inheritance is evident from pedigrees but the genetic basis of the disorder is otherwise unknown. Recently, two genes in 5q21 involved in colon carcinogenesis, APC and MCC, were identified, and APC was shown to be the gene predisposing to familial adenomatous polyposis. To determine if these genes also confer susceptibility to HNPCC we performed linkage analyses in nine affected families. The MCC-APC region could be formally excluded as the locus for HNPCC in seven families. In one family the results were suggestive of exclusion, although they were not conclusive. The remaining family was uninformative. We used two alternative definitions of affected status. Based on haplotypes for MCC and APC the added pairwise logarithm-of-odds score for all nine families was -22.57 at the recombination fraction of 0.00 using more stringent criteria for the HNPCC phenotype and -22.67 for less stringent criteria. In addition to blood DNA samples from living family members, DNA from formaldehyde-fixed archival pathology specimens from decreased individuals contributed to these linkage results.
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PMID:Evidence that the MCC-APC gene region in 5q21 is not the site for susceptibility to hereditary nonpolyposis colorectal carcinoma. 164 45

Genetic and environmental aspects play an important role in the development of colorectal cancer. However, the common molecular alteration in both hereditary and sporadic colon cancer is localized in the APC gene. the APC gene maps in the long arm of chromosome 5 and was discovered in patients with familial adenomatous polyposis (FAP). The search for the APC gene led to the identification of restriction fragment length polymorphisms (RFLPs) in FAP patients. Using these RFLPs in relatives of FAP patients it is possible to make the presymptomatic and prenatal diagnosis. The FAP syndrome is an interesting model of carcinogenesis in vivo. Thus the different stages involved in the FAP syndrome which include hyperproliferative epithelium, adenoma, adenocarcinoma and metastases, have allowed the analysis of molecular alterations in oncogenes and tumor suppressor genes. The APC gene alteration if not inherited, occurs as the earliest molecular alteration in the development of colorectal cancer whereas structural alterations of the genes myc, ras, p53, MCC and DCC are considered to be late events. All these investigations have lead to 1) a better understanding of the ethiology of cancer and 2) early diagnosis of colorectal cancer in both the hereditary and sporadic forms of the disease.
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PMID:[Molecular genetics of colorectal cancer and carcinogenesis]. 813 31

To test the reliability of linkage-disequilibrium analysis for gene mapping, we compared physical distance and linkage disequilibrium among seven polymorphisms in the adenomatous polyposis coli (APC) region on chromosome 5. Three of them lie within the APC gene, and two lie within the nearby MCC (mutated in colon cancer) gene. One polymorphism lies between the two genes, and one is likely to be 5' of MCC. Five of these polymorphisms are newly reported. All polymorphisms were typed in the CEPH kindreds, yielding 179-205 unrelated two-locus haplotypes. Linkage disequilibrium between each pair of polymorphisms is highly correlated with physical distance in this 550-kb region (correlation coefficient -.80, P < .006). This result is replicated in both the Utah and non-Utah CEPH kindreds. There is a tendency for greater disequilibrium among pairs of polymorphisms located within the same gene than among other pairs of polymorphisms. Trigenic, quadrigenic, three-locus, and four-locus disequilibrium measures were also estimated, but these measures revealed much less disequilibrium than did the two-locus disequilibrium measures. A review of 19 published disequilibrium studies, including this one, shows that linkage disequilibrium nearly always correlates significantly with physical distance in genomic regions > 50-60 kb but that it does not do so in smaller genomic regions. We show that this agrees with theoretical predictions. This finding helps to resolve controversies regarding the use of disequilibrium for inferring gene order. Disequilibrium mapping is unlikely to predict gene order correctly in regions < 50-60 kb in size but can often be applied successfully in regions of 50-500 kb or so in size. It is convenient that this is the range in which other mapping techniques, including chromosome walking and linkage mapping, become difficult.
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PMID:Linkage disequilibrium predicts physical distance in the adenomatous polyposis coli region. 761 Dec 89

The predisposition to colon cancer is multigenetically controlled in animals and probably also in humans. We have analyzed the multigenic control of susceptibility to 1,2-dimethylhydrazine-induced colon tumors in mice by using a set of 20 homozygous CcS/Dem recombinant congenic strains, each of which contains a different random subset of approximately 12.5% of genes from the susceptible strain STS/A and 87.5% of genes from the relatively resistant strain BALB/cHeA. Some CcS/Dem strains received the alleles from the susceptible strain STS/A at one or more of the multiple colon tumor susceptibility loci and are susceptible, whereas others are resistant. Linkage analysis shows that these susceptibility genes are different from the mouse homologs of the genes known to be somatically mutated in human colon cancer (KRAS2, TP53, DCC, MCC, APC, MSH2, and probably also MLH1). Different subsets of genes control tumor numbers and size. Two colon cancer susceptibility genes, Scc1 and Scc2, map to mouse chromosome 2. The Scc1 locus has been mapped to a narrow region of 2.4 centimorgans (90% confidence interval).
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PMID:Fine mapping of colon tumor susceptibility (Scc) genes in the mouse, different from the genes known to be somatically mutated in colon cancer. 857 18

The APC/MCC gene (Familial Adenomatous Polyposis) at 5q21 plays a role in colon cancer carcinogenesis. LOH at this locus has also been described in gastric cancer and preneoplastic lesions. The APC locus has been recently related to a cell surface adhesion molecule and its alteration may favour metastatic dissemination. LOH at 5q21 has been associated with poor prognosis in other tumors such as lung cancer. Thirty-six gastric cancers were evaluated for LOH at 5q21 with 2 polymorphic markers from microdissected paraffin-embedded material. All tumors were classified by stage, histologic type, degree of differentiation and survival rates. In 4 cases, intestinal metaplasia cells in the adjacent mucosae were also microdissected. Six cases of moderate-severe gastric dysplasia were also added to the study. LOH was determined in 84% of the informative cases of GC, affecting both early and advanced stages of disease. Genomic instability was assessed in 5 cases, 3 of them associated with LOH. The only case of gastric cancer that did not show LOH or instability at 5q21 was a stage II, poorly differentiated intestinal carcinoma without evidence of recurrence after a 36 month follow-up period (the mean survival rate in our series was 28.3% at 36 months). We also found LOH in 2/6 dysplastic lesions and 1/4 intestinal metaplasias. Our data show that LOH at 5q21 is frequent in gastric cancer and is also present in intestinal metaplasia and dysplastic lesions. LOH at this locus is not a prognostic factor in GC in our study, due to the high incidence of LOH that we found.
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PMID:LOH at the APC/MCC gene (5Q21) in gastric cancer and preneoplastic lesions. Prognostic implications. 918 90

We describe three unrelated kindreds, affected by familial adenomatous polyposis (FAP), with 5q submicroscopic deletions that encompass the entire adenomatous polyposis coli (APC) gene and the adjacent DP1 gene. In one family the deletion encompasses also the MCC (mutated in colon cancer) gene. Affected members of these families had dysplastic adenomatous polyps and congenital hypertrophy of the retinal pigment epithelium (CHRPE); no individual was affected by mental retardation or facial dysmorphism. The deletions were detected by linkage analysis with several intragenic and closely flanking polymorphic markers and confirmed by a quantitative PCR analysis. This procedure could have an impact on the detection of the molecular defect in FAP patients in whom mutational analysis fails to identify the specific mutation.
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PMID:Three submicroscopic deletions at the APC locus and their rapid detection by quantitative-PCR analysis. 1048 59


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