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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 gene has been elucidated as a tumor suppressor gene, and inactivation of this gene caused by deletion or point mutations may play a crucial role in the development of human malignancies. In colorectal carcinomas with an allelic deletion of the p53 gene, the remaining p53 gene was mutated with considerable frequency. It is most difficult to detect point mutations or small deletions of the gene because the mutations occur in diverse regions, although four hot spots have been observed [J.M. Nigro et al., Nature (Lond.), 342: 705-708, 1989]. The polymerase chain reaction and denaturing gradient gel electrophoresis facilitate detection of mutations in the hot spots of the p53 gene. Using these methods, we detected mutations in three adenomatous polyps and one carcinoma from familial polyposis coli patients and three carcinomas of sporadic cases. The DNA sequence analysis confirmed mutations of the p53 gene in 2 adenomas (13 base-pair deletions in one and a point mutation in the other) and 1 carcinoma (point mutation) from familial polyposis coli patients. These results suggest that the p53 gene mutations may be involved in the formation not only of carcinomas but also of adenomas which occur in familial polyposis coli patients.
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PMID:p53 gene mutations in colorectal tumors from patients with familial polyposis coli. 185 62

Two features of colorectal cancer have greatly aided the recent progress in understanding its genetics: firstly the majority of colorectal cancers arise from premalignant adenomatous polyps allowing the analysis of somatic genetic changes during tumorigenesis, and secondly there are several well defined inherited syndromes that predispose to colorectal cancer in an autosomal dominant manner. The familial polyposis gene has been mapped to chromosome 5q and loss of material on chromosome 5 shown in a large proportion of sporadic (non-familial) adenomas and carcinomas. Allele loss has also been found in a high proportion of colorectal cancers on chromosomes 17 and 18 and the respective genes involved identified as that coding for the oncoprotein p53 on 17p and the DCC ('deleted in colorectal carcinomas') gene on 18q. In addition activation of k-ras is found frequently in colorectal adenomas and carcinomas. The development of colorectal neoplasia is associated with the accumulation of genetic changes. Family studies of apparently sporadic colorectal cancer probands have shown an increased incidence of adenomas and carcinomas in first degree relatives. More recently pedigree studies have suggested that an inherited predisposition may be responsible for the majority of colorectal tumours.
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PMID:The genetics of colorectal cancer. 210 25

Remarkable advances in the understanding of specific inherited and acquired genetic events that are important in colonic carcinogenesis have occurred in the last several years. Studies of the population genetics of colon cancer have determined that the gene responsible for familial adenomatous polyposis (FAP), and Gardner's syndrome has been localized on the long arm of chromosome 5 and have more clearly defined the importance of genetic influences in 'sporadic' colon cancer. Studies of the molecular genetics of colon cancer have identified acquired alterations in oncogenes such as the K-ras gene and in putative tumor suppressor genes such as the FAP gene on chromosome 5, the p53 gene on chromosome 17, and the DCC gene on chromosome 18, which appear to mediate important steps in the adenoma-dysplasia-carcinoma sequence. Some of these research advances (FAP gene carriage) are already being used clinically to identify individuals at risk for colon cancer, and they offer great promise for the future of both prevention and therapeutic programs.
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PMID:Lessons from the genetics of colon cancer. 217 30

Coordinate loss of one copy of the p53 gene and mutation of the remaining copy occur in colorectal carcinomas and in many other human malignancies. However, the prevalence of p53 gene mutations in carcinomas which maintain both parental copies of p53 has not previously been evaluated. Moreover, it is not known whether p53 gene mutations are limited to malignant tumors or whether they can also occur in benign neoplasms. To answer these questions, a total of 58 colorectal tumors have been examined; in each tumor, allelic losses were assessed using restriction fragment length polymorphisms and p53 gene mutations were assessed by sequencing cloned polymerase chain reaction products. The following conclusions emerged: (a) p53 gene mutations occurred but were relatively rare in adenomas, regardless of size and whether the adenomas were derived from patients with familial adenomatous polyposis; (b) In carcinomas as well as in adenomas, p53 gene mutations were infrequently observed in tumors which contain both copies of chromosome 17p (17% of 30 tumors), while tumors which lost one copy of chromosome 17p usually had a mutation in the remaining p53 allele (86% of 28 tumors); (c) p53 gene mutations were found at similar frequencies in primary tumor samples and in cell lines derived from tumors. These and other data suggest that the rate limiting step in p53 inactivation is point mutation and that once a mutation occurs, loss of the remaining wild-type allele rapidly follows. Both mutations and allelic losses generally occur near the transition from benign to malignant growth, and the p53 gene may play a causal role in this progression.
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PMID:p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. 225 15

Heritable and genetic factors pertinent to colon cancer can be divided into three categories: inherited syndromes, genetic epidemiology, and molecular genetics. Familial adenomatous polyposis (FAP) and Gardner syndrome (GS) are rare dominantly inherited syndromes characterized by hundreds to thousands of colonic adenomatous polyps. Colon cancer occurs at a young age in both diseases unless the colon is removed. Peutz-Jeghers syndrome and familial juvenile polyposis are inherited hamartomatous polyposis conditions with a less dramatic, but definite, increased risk for colon cancer. These four polyposis syndromes together account for less than 1% of cases of colon malignancy. Hereditary nonpolyposis colorectal cancer is a dominantly inherited form of colon cancer characterized by an early age of onset and a predilection for proximal colonic tumours. Multiple primary malignancies are frequently observed and one or several adenomatous polyps are often present in affected individuals; 4-6% of colon cancer cases occur in relationship to this syndrome. Genetic epidemiological studies have consistently shown that first-degree relatives of persons with colon cancer have a twofold to threefold increased risk of having colon malignancy. More recent studies have found a similar risk among relatives of those with adenomatous polyps. Studies of colon cancer and adenomatous polyps in pedigrees have further demonstrated that this familial clustering probably occurs on the basis of partially penetrant inherited susceptibilities. These inherited susceptibilities probably interact with environmental factors to give rise to polyp growth and finally colon cancer. Molecular studies have begun to elucidate the genetic mechanisms of colon cancer at the DNA level. The germinal mutation of FAP and GS has been localized to the long arm of chromosome 5. Tissue samples from "random" adenomatous polyps and colon cancers have shown frequent and specific acquired DNA sequence deletions on chromosomes 5, 17, and 18. Mutations and over-expression of the ras oncogene likewise have been observed in such tissues. The chromosome 5 defect in polyp and cancer tissues is probably at the same locus as the germinal mutation of FAP. There is evidence that this locus normally regulates expression of the c-myc oncogene, which in turn probably has a regulatory function in DNA replication. The chromosome 17 deletion is a mutation of the gene for the transformation-associated protein, p53. Appropriate screening starting at a relatively young age is necessary to prevent cancer in the inherited syndromes. Screening is also indicated in close relatives of those with nonsyndromic or common colon cancer in view of the moderately increased risk for colon cancer in this group.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Risk and surveillance of individuals with heritable factors for colorectal cancer. WHO Collaborating Centre for the Prevention of Colorectal Cancer. 228 1

Adenomatous polyposis, mainly of the colon, (APC) is a rare dominantly inherited susceptibility to colon cancer in which individuals develop hundreds of polyps mainly in their large bowel. The APC gene has been localised to chromosome 5q21 by following up a case report of an individual with an interstitial deletion on chromosome 5q who had multiple developmental abnormalities together with adenomatous polyposis. A DNA marker (D5S71) was found to be closely linked to APC in family studies and localised to 5q21 by in situ annealing. Material from further patients with deletions in this region of chromosome 5 has been used, by a combination of somatic cell hybrid and long-range DNA analysis, to identify new DNA markers close to the APC gene. These and other markers now provide the basis for genetic counselling of nearly all families with APC. These studies are being extended, together with other approaches for analysing DNA clones around the APC gene, in the search for the gene itself. Allele loss in tumour as compared to normal tissue from sporadic cases of colorectal carcinomas has clearly implicated the APC gene in at least 25 to 40% of all cases of colorectal carcinomas. Similar studies by Vogelstein and others as well as ourselves have further implicated recessive changes on chromosomes 17 and 18 in the development of colorectal carcinomas. Following the demonstration by Vogelstein of the role of p53 mutations in connection with the chromosome 17 changes, we have now shown, using monoclonal antibodies to the mutant p53 products and by other approaches, that changes in the p53 gene may occur in up to 50% or more of colorectal carcinomas. Frequent mutations of the K-ras dominant oncogene, as well as changes in the expression of human leucocyte antigen (HLA)-A, B, C determinants, are further genetic changes that appear commonly to be involved in the progression of colorectal carcinomas. The latter have important implications for T cell immune response to tumours and its manipulation for treatment and even prevention of colorectal cancer. We may soon be approaching a situation when it will become possible to identify all the genetic steps and their sequence during tumour progression, as well as their functional significance largely through the induction of inappropriate growth and the suppression of differentiation.
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PMID:Genetic analysis of colorectal cancer. 256 87

The development of effective screening tests for colorectal tumors is essential given the high frequency of these cancers in the general population, and more especially in various groups at risk. Sporadic and hereditary colorectal cancers result from the accumulation of mutations in oncogenes, such as ras, myc, neu/HER2, and in tumor suppressor genes such as apc, dcc, p53. The detection of ras or p53 mutations in DNA extracted from stool has been shown to be feasible and might be useful for the development of new screening tests. Many mutations in these genes can also be used as new prognostic factors. Identification of mutation in the apc gene responsible for familial polyposis, or its indirect detection through the study of polymorphism in such families, is completely changing the previously recommended medical attitude for the screening of this disease, and therefore may decrease or even avoid major medical follow-up. These changes are also true for the nonpolyposis hereditary colorectal tumors, also called Lynch syndrome, since the responsible hMSH2, hMLH1, hPMS1 and hPMS2 genes have recently been cloned. Mutations in these genes do not seem to be limited to families with Lynch syndrome, and could account for a predisposition of some patients to develop colorectal or other tumors.
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PMID:Contribution of molecular oncology in the detection of colorectal carcinomas. 749 39

We present a restriction fragment length polymorphism (RFLP) analysis of 29 benign and 30 malignant prostatic tumors, using polymorphic DNA probes to the putative tumor suppressor genes DCC (Deleted in Colorectal Carcinoma; chromosome 18q21.3), nm23-H1 (17q21.3), APC (Adenomatous Polyposis Coli; 5q21) and p53 (17p13). Six of 23 evaluable cancers (26%) showed loss of heterozygosity (LOH) at DCC; 5 were advanced stage and one was clinically localized (p < 0.05). Mapping 18q deletions, another (advanced) cancer showed LOH at a locus distal to DCC (18q22), but no LOH at DCC. Three of 15 evaluable cancers (20%), all advanced, showed LOH at APC. Three of eight (38%) cancers, of which 2 were advanced, showed LOH at p53. One high grade/stage cancer of 21 (5%) showed LOH at nm23-H1 (and also at DCC). Combining data, allelic losses at either DCC, APC, or p53 genes were seen in 13% of localized cancers, but in 71% of advanced cancers (p < 0.002). Allelic loss involving nm23-H1 is rare in prostatic carcinoma. We suggest that loss of tumor suppressor genes DCC and/or an unidentified gene located distally on chromosome 18q, APC, or p53 may influence progression in prostatic carcinoma.
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PMID:Somatic allelic loss at the DCC, APC, nm23-H1 and p53 tumor suppressor gene loci in human prostatic carcinoma. 751 Mar 45

We analyzed somatic mutations of the adenomatous polyposis coli (APC), p53, and K-ras genes in gastroduodenal polyps and normal gastroduodenal mucosa from 21 familial adenomatous polyposis patients, using PCR-single-strand conformation polymorphism and direct sequencing methods. Seventy-five polyps were obtained from these patients endoscopically or surgically, and they were histopathologically diagnosed as mild adenoma, moderate adenoma, severe adenoma, adenocarcinoma, and fundic gland polyp. Examining the APC-coding region where somatic mutations in colorectal tumors are known to be clustered, we detected 47 somatic mutations. The frequency of mutation detected was 6 of 9 (67%) in ampullary adenomas, 1 of 2 (50%) in ampullary adenocarcinoma, 11 of 24 (46%) in non-ampullary adenomas, 26 of 29 (90%) in gastric adenomas, and 3 of 11 (27%) in gastric fundic gland polyps. These mutations frequently occurred at codons 1450, 1462-1465, and 1554-1556, the third being a newly found hot spot. All mutations formed stop codons that resulted in truncated APC proteins. K-ras mutation was detected only in an ampullary adenocarcinoma, and p53 mutation was not detected in any of the tumors analyzed. There was no somatic mutation detected in samples of flat mucosa that were diagnosed as normal mucosa both endoscopically and histopathologically. Frequent APC mutations in mild and small adenomas, similar to the findings in severe and large adenomas, suggested that the genetic change in the APC gene occurs in an early stage of forming gastroduodenal adenomas. Moreover, the presence of somatic APC mutations in fundic gland polyps suggests that inactivation of the APC gene plays a role not only in forming adenomas but also in forming hyperplastic polyps in fundic gland mucosa, and there may be some additional steps to the adenoma-carcinoma sequence.
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PMID:Somatic mutations of the adenomatous polyposis coli gene in gastroduodenal tumors from patients with familial adenomatous polyposis. 760 37

Fascinating progress has been made in the past 2 years in our understanding of the genetic alterations associated with colorectal cancer predisposition and development. First, the genotype-phenotype relationship of the cancer susceptibility syndrome associated with familial adenomatous polyposis has been shown to depend on mutation type. Second, hereditary nonpolyposis colorectal cancer syndromes have been recognized as being frequently associated with a defect in the DNA mismatch-repair pathway. A gene on chromosome 2 called hMSH2, which demonstrates homology with the bacterial repair gene MutS, has been shown to be altered in some families with hereditary nonpolyposis colorectal cancer. A defect on chromosome 3 may act by impairing the same pathway. Genotyping of particular loci, termed microsatellite, provides an easy identification of tumors deficient in mismatch repair. Third, the mechanisms by which the inactivation of tumor-suppressor genes such as p53 and APC may contribute to the tumorigenic process have begun to be elucidated. These different discoveries will have important impacts in the prevention and management of colorectal carcinoma, one of the most frequent human cancers.
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PMID:Advances in the genetics and molecular biology of colorectal tumors. 780 42


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