Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have identified a gene on chromosome 5q, designated MCC (mutated in colorectal cancers), as a candidate for the putative colorectal tumor suppressor gene that is located at 5q21. We examined loss of heterozygosity (LOH) at the MCC locus and its vicinity in sporadic colorectal carcinomas, using 12 RFLP (restriction fragment length polymorphism) markers. One clone, L5.71, had been used to identify the MCC gene; all 12 markers also had tight linkage to the gene responsible for adenomatous polyposis coli. All 40 cases studied were informative with at least one marker, and 22 of them (55%) showed LOH at one or more loci. LOH in the tumors was more frequent in the immediate vicinity of L5.71 than in distant parts of the chromosome, and a common region of deletion was detected between markers L5.62 and 15A6. In one case, alleles were retained at L5.71 and at loci proximal to L5.71, but alleles were lost at loci distal to L5.71. In another case, both alleles were retained at L5.71 but alleles were lost at loci proximal and distal to L5.71. These results support the conclusion that a tumor suppressor gene for colorectal carcinoma is located within or around locus L5.71.
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PMID:Frequent loss of heterozygosity at the MCC locus on chromosome 5q21-22 in sporadic colorectal carcinomas. 168 92

Recent studies have suggested the existence of a tumor suppressor gene located at chromosome region 5q21. DNA probes from this region were used to study a panel of sporadic colorectal carcinomas. One of these probes, cosmid 5.71, detected a somatically rearranged restriction fragment in the DNA from a single tumor. Further analysis of the 5.71 cosmid revealed two regions that were highly conserved in rodent DNA. These sequences were used to identify a gene, MCC (mutated in colorectal cancer), which encodes an 829-amino acid protein with a short region of similarity to the G protein-coupled m3 muscarinic acetylcholine receptor. The rearrangement in the tumor disrupted the coding region of the MCC gene. Moreover, two colorectal tumors were found with somatically acquired point mutations in MCC that resulted in amino acid substitutions. MCC is thus a candidate for the putative colorectal tumor suppressor gene located at 5q21. Further studies will be required to determine whether the gene is mutated in other sporadic tumors or in the germ line of patients with an inherited predisposition to colonic tumorigenesis.
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PMID:Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. 184 68

Our study was undertaken to determine the prognostic significance of several common genetic alterations observed in colorectal carcinomas. We have previously analysed loss of heterozygosity of the MCC, APC, p53 and DCC tumour suppressor gene loci as well as p53 gene mutations and protein over-expression in a series of 100 Dukes' stage B and C colorectal tumours obtained at surgery. To extend our observations of alterations that may occur in these tumours, mutations to the c-Ki-ras oncogene and APC tumour suppressor gene were detected by PCR single-strand conformation polymorphism analysis. Short-term follow-up revealed no significant association between overall patient survival and any single, or combination of, genetic alteration(s). Surprisingly, patients whose tumours showed evidence of p53 protein over-expression/accumulation by immunocytochemistry (ICC) had a significantly better prognosis (p = 0.039) than those whose tumours had no p53 ICC reactivity.
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PMID:The common molecular genetic alterations in Dukes' B and C colorectal carcinomas are not short-term prognostic indicators of survival. 798 12

We used Southern blot analysis and polymerase chain reaction-based techniques to examine deletions of tumour suppressor gene loci in 91 primary colorectal tumours. The tumour suppressor genes studied were MCC and APC on chromosome 5q, p53 on chromosome 17p, DCC on chromosome 18q, and the putative suppressor gene nm23-H1 on chromosome 17q. The most frequent allelic loss observed was in chromosome 17p with 76% (68/89) of informative tumours showing loss of heterozygosity at this locus, followed by 34% (19/55) for DCC, 31% (12/39) for MCC, 17% (9/53) for APC and 16% (3/19) for nm23. No significant differences in the frequency of these suppressor gene allelic losses were observed between Dukes B and C stage adenocarcinomas.
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PMID:Loss of heterozygosity of tumour suppressor gene loci in human colorectal carcinoma. 808 Jun 84

Thirty-four primary, untreated sporadic breast cancers were examined for loss of heterozygosity (LOH) at tumour suppressor loci involved in colorectal cancer: APC/MCC at 5q21 and DCC at 18q21. LOH was identified in 28% informative patients at 5q21 and 31% at 18q21. LOH at 5q21 and 18q21 was compared with allele loss at 17p13 and concurrent LOH at two or more of the loci was noted in 24% of tumours. Expression of a 12 kb DCC mRNA was demonstrated in 14/34 (42%) of the cancers and in all five tumours with LOH at the DCC locus there was an additional 11 kb DCC mRNA. Abnormalities of three loci involved in colorectal cancer (5q21, 17p13 and 18q21) therefore also occur in sporadic breast cancer. The accumulation of such genetic abnormalities may confer a growth advantage important in the development of breast cancer.
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PMID:Allele loss from 5q21 (APC/MCC) and 18q21 (DCC) and DCC mRNA expression in breast cancer. 831 22

Abnormalities affecting tumour suppressor genes on chromosome 5q21 are increasingly recognised as important in the pathogenesis of a variety of human cancers, particularly of the gastrointestinal tract. We have examined a series of gastric and pancreatic cancers from European patients for loss of heterozygosity (LOH) of markers within and around the APC and MCC genes on chromosome 5q21 using restriction fragment length polymorphism and polymerase chain reaction techniques. We find that LOH of the APC and MCC genes is particularly frequent in gastric cancers of diffuse type, but very infrequent in pancreatic cancers. We have also used single-strand conformational polymorphism to screen for abnormalities of the sequence of the APC and MCC genes in a panel of pancreatic cancer cell lines. Our results suggest that there are distinct differences in the molecular pathogenesis of gastric and pancreatic cancer and that abnormalities of APC and MCC may be involved particularly in the diffuse type of gastric cancer.
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PMID:Abnormalities affecting the APC and MCC tumour suppressor gene loci on chromosome 5q occur frequently in gastric cancer but not in pancreatic cancer. 840 87

Two distinct gene classes have been implicated in colorectal carcinogenesis. Tumour promoter genes (oncogenes, dominant oncogenes) produce an excessive positive stimulus to cell proliferation. The ras family of oncogenes are an example. Acquired mutations of the c-k-ras gene are commonly found in colonic adenomas and carcinomas. Tumour suppressor genes (anti-oncogenes, recessive oncogenes) normally constrain or regulate cell proliferation. Loss of this function through gene deletion or mutation is oncogenic. Inherited tumour suppressor gene mutations have now been identified in several of the familial cancer syndromes. Acquired tumour suppressor gene mutations are found in both sporadic and hereditary cancers. Together with the tumour promoter genes they provide the genetic basis for the cellular changes occurring during carcinogenesis. The retinoblastoma gene was the first human tumour suppressor gene to be characterized and exemplifies the class. More recently, linkage studies in the hereditary cancer syndromes and the detection of specific deletions in sporadic tumours have helped to identify several new tumour suppressor genes. At least four of these (MCC, APC, p53 and DCC) apparently contribute to sporadic colorectal carcinogenesis. Germ line APC mutations produce the inherited colorectal cancer syndrome familial adenomatous polyposis (FAP). Detection of these mutations using linked markers has already found clinical application in the screening of families with this disease. In the future, genetic diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) and the recognition of those genetically susceptible to sporadic colorectal cancer may become possible. At the same time, as our understanding of the genes involved improves, new avenues for treatment and prevention of colorectal cancer may emerge.
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PMID:Tumour suppressor genes and colorectal neoplasia. 847 56

A characteristic feature of colorectal cancer genesis is its stepwise progression, which offers unique possibilities for studying its development. There are two principal kinds of mutation leading to uncontrolled cell proliferation and cancer. The first renders a stimulatory gene hyperactive--generation of an oncogene--and the second is the inactivation of a tumour suppressor gene. Current knowledge suggest that the change from normal mucosa to a small adenoma may be mediated by mutations of the APC gene and MCC gene on chromosome 5, by chromosome 5 deletion, by c-myc activation, and by DNA hypomethylation. The development to a large adenoma may be caused by Ki-ras mutation and further change to a dysplastic adenoma by deletion of the DCC gene on chromosome 18. The ability to become an invasive carcinoma may then be mediated by p53 mutations and deletion of chromosome 17p. Identification of genetic markers for metastatic disease is under progress.
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PMID:Genetic aspects of colorectal cancer: the surgeon's view. 889 51

Four genetic polymorphisms in the APC and MCC genes at chromosome 5q21 were analysed for loss of heterozygosity (LOH) in 97 primary squamous carcinomas and adenocarcinomas of the lung. LOH was identified in at least two polymorphic loci in 41 percent of informative cases. There was no significant difference in the frequency of LOH between squamous carcinomas and adenocarcinomas. Within the adenocarcinoma group, however, LOH appeared to be more common in tumours having a bronchial origin (5/9; 56 per cent) than in parenchymal adenocarcinoma (6/21; 29 per cent). All 32 tumours showing LOH at one or more polymorphic sites were examined for mutations in the mutation cluster region (MCR) of APC by single-strand conformational polymorphism (SSCP) analysis. Mutations were not detected in any of these cases. We therefore propose that it is likely that a tumour suppressor gene on 5q other than APC is involved in the pathogenesis of lung cancer.
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PMID:Loss of heterozygosity at 5q21 in non-small cell lung cancer: a frequent event but without evidence of apc mutation. 894 12

Von Hippel-Lindau (VHL) disease is an inherited autosomal dominant neoplastic disorder causing central nervous system haemangioblastomas. The VHL gene (3p25-3p26) is known to be a tumour suppressor gene, with its inactivation being responsible for a predisposition to tumour development. As far as we know, the present report of VHL disease manifestation in identical twins is unique. Genetic inquiry into the family background did not reveal this disease among their progenitors. For presymptomatic diagnosis of 17 presently unaffected family members, constitutional DNA of the twins was screened for VHL germline mutations, using loss of heterozygosity studies and exon-specific DNA sequencing. To determine the influence of somatic mutations of the VHL gene in tumourigenesis, DNA of five surgically removed intracerebral haemangioblastomas of the identical twins was analyzed in comparison with their constitutional DNA by DNA sequencing of the complete VHL coding region. However, no allelic losses were found for the VHL gene or for various other tumour suppressor genes (p53, BRCA1, BRCA2, DCC, and MCC). Furthermore, no mutations were found in the constitutional DNA of either twin sister or in the DNA of all five tumour lesions. Based on our observations, we conclude that in certain VHL families, presymptomatic molecular diagnosis of the disease is not feasible and requires close clinical surveillance of all individuals at risk.
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PMID:Multiple intracerebral haemangioblastomas in identical twins with von Hippel-Lindau disease--a clinical and molecular study. 963 66


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