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

All cancers result from the accumulation of mutations of proto-oncogenes and tumor suppressor genes. Sporadic and familial colorectal cancers result from the accumulation of the following genes, in a relatively stereotyped chronological order: the tumor suppressor gene apc whose mutations are responsible for the familial adenomatous polyposis; the proto-oncogene K-ras which is mutated in 50% of large adenomas (> 1 cm) and adenocarcinomas; the tumor suppressor gene dcc; and the tumor suppressor gene p53 whose inactivation in a factor of bad prognosis. While some of them are induced by mutagens, others result from an instability of the genome. Two types of instability are observed in both sporadic and familial colorectal cancer. The first type, which is found in 25-50% of cases, appears as cytogenetic abnormalities with aneuploidy and allelic losses. The second type of instability is induced by mutations of the hMSH2 or hMLH1 genes which code for proteins involved in the mechanism of DNA repair.
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PMID:[Genes, heredity and colorectal cancer]. 787 58

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

Desmoid tumors, which are locally invasive with recurrence but without metastasis, are frequently observed in patients with familial adenomatous polyposis after abdominal surgery or during pregnancy. This study analyzed mutation of the adenomatous polyposis coli gene in 8 desmoid tumors from 7 familial adenomatous polyposis patients using polymerase chain reaction-single-strand conformation polymorphism and the direct sequencing method. Seven somatic mutations, 1 somatic allele loss, and 6 germ-line mutations were detected. The majority of adenomatous polyposis coli gene mutations were deletions of 1 to 19 base pairs in exon 15, and all mutations led to the formation of stop codons. A somatic mutation with repetition of 82 base pairs from codon 1399 to 1426 was also observed in a desmoid, which was most likely caused by an error during replication or repair replication. No mutation was detected in exons 1 to 2 of H-ras, K-ras, and N-ras genes and in exons 5 to 8 of p53 gene, in these tumors. The simultaneous existence of somatic and germ-line alterations of adenomatous polyposis coli gene observed in all 8 tumors strongly suggests that inactivation of both alleles of adenomatous polyposis coli gene is involved in the development of desmoid tumors.
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PMID:Coexistence of somatic and germ-line mutations of APC gene in desmoid tumors from patients with familial adenomatous polyposis. 822 38

Colorectal carcinogenesis is a complex multistage process and occurs through the accumulation of gene mutations in both oncogenes and tumour suppressor genes. Frequent genetic abnormalities include mutation of the familial adenomatous polyposis (APC) and/or the mutated in colorectal cancer (MCC) genes on chromosome 5q21, activation of K-ras and loss of the tumour suppressor genes p53 and DCC (deleted in colorectal cancer). In our laboratory we have developed human in vitro colonic cell culture model systems, to determine the biological consequences of these well characterised genetic changes, and how such changes can uncouple proliferation from differentiation and ultimately lead to the malignant phenotype.
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PMID:Biological consequences of the genetic changes which occur during human colorectal carcinogenesis. 831 91

The DiFi human colorectal cancer cell line was recently established from a familial adenomatous polyposis patient with extracolonic features characteristic of the Gardner syndrome. These cells have now been propagated for 150 passages in standard culture media and vessels without feeder layers or collagen coatings. They retain features of colonic epithelial cells such as surface microvilli, secretory vesicles, and desmosomes. Cytosol of DiFi cells contains a high level (502 U/mg protein) of the mucin CA 19-9. In addition, DiFi cells produce carcinoembryonic antigen, and induce tumors in athymic mice. Cytoskeleton analysis of DiFi cells by fluorescence microscopy showed a pronounced disorganization of actin cable structure. The isozyme genetic signature of DiFi cells is unique (0.01 probability of finding the same genetic signature in a different cell line), differs from that of HeLa cells, and has expressional features seen in other colorectal cell lines. The DiFi cell karyotype is tetraploid, contains many marker chromosomes, and shows numerous episomal particles. Two copies of chromosome 18 were absent, and only a single normal chromosome 17 was found. This parallels detection of allelic losses from DiFi cell DNA at loci on chromosomes 17p and 18 using molecular (cDNA) probes. DiFi cells clearly express transcripts for the c-myc proto-oncogene, the c-myb proto-oncogene, and the p53 tumor suppressor gene. Transforming growth factor beta inhibits DiFi cell growth in soft agar and suppresses c-myc expression in these cells. The value of this cell line in the study of genetic alterations in colorectal cancer is discussed.
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PMID:Characterization of the DiFi rectal carcinoma cell line derived from a familial adenomatous polyposis patient. 838 96

To examine early genetic events during colorectal carcinogenesis, we searched for genetic alterations in 75 adenomas from seven patients with familial polyposis coli (FAP) and in 64 sporadic colorectal tumors (63 carcinomas and one adenoma). We investigated germ-line and somatic mutations in the APC gene, somatic mutations in the K-ras and p53 genes, and loss of heterozygosity (LOH) on chromosome 8p21-22. Thirty-two FAP adenomas carried detectable somatic mutations in the APC gene. The frequency of somatic APC mutations among adenomas was the same regardless of differences in size or histopathological classification. On the other hand, K-ras mutation was very rare in small adenomas where dysplasia was mild or moderate but frequent in large adenomas with severe dysplasia. Mutation of the p53 gene was observed in only two adenomas and LOH on 8p22 was detected in none. These results imply that a second 'hit' in the APC gene, but not necessarily mutation in K-ras or p53, is an important and critical event for formation of a colorectal adenoma.
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PMID:Detailed analysis of genetic alterations in colorectal tumors from patients with and without familial adenomatous polyposis (FAP). 839 78

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

Molecular genetics is a tool that can be learned as a language to assist clinicians in the management of colorectal cancer patients. Following a brief review of the genetic controls of colorectal cancer, the author focuses on the models of the Registry for Familial Adenomatous Polyposis and the Registry for Hereditary Nonpolyposis Colon Cancer to demonstrate most vividly the impact molecular genetics is currently having on the practical management of colon cancer. Recent discoveries of K-ras oncogene mutations in stool cultures and the prognostic implications of mutations of the TP53 and DCC genes are discussed in the context of future applications to the management of patients.
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PMID:Contributions of molecular genetics to the clinical management of colorectal cancer. 855 21

Recent advances in molecular genetics have revealed that multiple genetic alterations including activation of oncogenes and inactivation of tumor suppressor genes are required for tumor development and progression. Tumorigenesis of colorectal cancer, in which most cancers are considered to arise from preceding benign adenomas, has been well documented at the molecular level. Familial adenomatous polyposis (FAP), which is characterized by the development of hundreds to thousands of adenomatous polyps in the colon and rectum, one or more of which can progress to cancer if left without surgical treatment, is a good model for elucidation of genetic alterations involved in colorectal tumorigenesis. The adenomatous polyposis coli (APC) gene responsible for FAP was isolated in 1991, and germinal and somatic mutations of the APC gene have been identified. Moreover, activation of K-ras oncogene and inactivation of several tumor suppressor genes such as MCC, p53, and DCC are supposed to play important roles at specific stages of colorectal tumorigenesis. More recently, two genes, MSH2 and MLH1, responsible for hereditary non-polyposis colorectal cancer (HNPCC) have been identified. Thus the molecular mechanism of colorectal tumorigenesis now seems to be more complicated than has been supposed.
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PMID:Multistep carcinogenesis in colorectal cancers. 862 5

Genetic alterations in a tubular adenoma with severe dysplasia arising in a Brooke ileostomy of a familial adenomatous polyposis patient were analyzed. Clinical and morphological characteristics suggest that ileal mucosa progressed to colonic metaplasia and then to dysplastic adenoma. Such changes at ileostomy sites are rare, and little is known about the associated genetic alterations. To determine whether metaplastic epithelium progression to adenoma in the ileum is subject to the same mutations identified in colon carcinogenesis, we evaluated somatic genetic alterations associated with sporadic colorectal cancer development. Sequences examined included mutation cluster regions of the p53 tumor suppressor gene and the k-ras oncogene. Using polymerase chain reaction and DNA sequencing, we identified a point mutation at codon 12 of the K-ras oncogene. To our knowledge, this is the first report of a ras mutation occurring in a tumor originating from ileal mucosa.
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PMID:K-ras mutation in a tubular adenoma originating at an ileostomy in a familial adenomatous polyposis patient. 863 16


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