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

The three ras genes code for proteins with a putative role in cellular signal transduction. They belong to a larger family of small guanosine-triphosphate (GTP)-binding proteins. The ras proteins acquire transforming activity when amino acids are substituted at one of a few specific sites, as a result of a point mutation in the gene. In about one third of adenocarcinomas of the lung, a K-ras mutation is present in codon 12 of the gene. Patients with early stages of K-ras mutation-positive tumors have a very unfavorable prognosis, even if apparently radical resection of the tumor has taken place. K-ras mutations are very rare among nonsmokers, and it is reasonable to assume that carcinogens in tobacco smoke directly cause the mutation. The types of ras mutations found in lung cancer are different from those in gastrointestinal malignancies. Colon cancer is mainly associated with mutations leading to substitution of the normal glycine at amino acid position 12 of K-ras by either valine or aspartic acid, and mutations in N-ras are not exceptional. In contrast, the predominant mutation in lung cancer leads to substitution of cysteine in codon 12. Several other members of the ras gene superfamily are also expressed in human lung cancer, but a possible relationship with lung tumorigenesis remains to be established.
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PMID:The ras gene family in human non-small-cell lung cancer. 132 34

The main objective of the present investigation was to understand the molecular events involved in the genesis of aberrant crypt foci. Aberrant crypt foci were induced in Sprague-Dawley rats with a single injection of azoxymethane. Aberrant crypts have been identified topographically in the colon and are hypothesized to represent preneoplastic lesions. In order to understand the molecular events involved in the early stages of colon cancer, PCR-amplified DNA from aberrant crypts was hybridized with oligonucleotide probes specific for the detection of point mutations in codon 12 of K-ras. The mutation identified was a G to A transition resulting in the substitution of the amino acid aspartic acid (asp) for glycine (gly). This mutation was present in 6/19 (32%) of aberrant crypts examined. The identical mutation was also identified in adenomacarcinoma tissue while no mutation could be detected in normal intestinal mucosa. For further confirmation of these results, the presence of the mutated ras protein (rasAsp-12) was detected in aberrant crypts by immunohistochemistry. This investigation provides the first identification of a ras point mutation in aberrant crypt foci.
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PMID:Evidence for a ras gene mutation in azoxymethane-induced colonic aberrant crypts in Sprague-Dawley rats: earliest recognizable precursor lesions of experimental colon cancer. 142 79

Tumorigenesis is a multistep process involving mutations of dominantly acting proto-oncogenes and mutations and loss-of-function mutations of tumor suppressor genes. Some of these mutations may be inherited, but most of them are acquired. Models for the sequential steps of the genetic changes involved in tumor development have been proposed for certain cancers, such as colon cancer. In the case of ovarian cancer, relatively little is known about the genetic events associated with the initiation or subsequent progression and metastases of the tumor. Cytogenetic analysis has revealed a high incidence of both structural and numerical chromosome changes, and the extent of these changes seems to increase with tumor progression. Oncogene activations of the proto-oncogenes K-ras, c-myc and c-erbB-2 have been found more frequently in aggressive ovarian tumors and may be associated with poor survival. Tumor-specific allele loss involving putative tumor suppressor genes has been observed for loci at chromosomes 11p, 17p, and 17q,--loci commonly deleted in other cancers too. A relatively high incidence of allelic loss on chromosome 6q appears to be specific to ovarian carcinoma. Familial breast/ovarian cancer has been suggested to map to chromosome 8q. Recently we have found a germ-line mutation in the tumor suppressor gene p53 in a family with breast- and ovarian cancers, indicating that this is the predisposing gene in this family. Genetic changes important for the etiology of ovarian cancers seem to involve both somatic mutations of oncogenes and somatic or germ-line inactivation of tumor suppressor genes.
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PMID:Oncogenesis in ovarian cancer. 150 89

We have been studying a rat model of colon cancer in which tumors are induced by direct application of N-methyl-N-nitrosourea (MNU) to discrete areas of the colonic mucosa for a limited period of time. Activation of the ras genes by point mutation has been observed in many experimental tumors, including tumors induced by MNU. To detect potential activating point mutations in the H-ras and K-ras oncogenes in MNU-induced rat colon tumors, DNA samples from 40 adenomas, nine carcinomas, and 14 histologically normal tissue samples from 14 rats--as well as from 16 foci induced on NIH3T3 cells by tumor DNAs--were amplified by the polymerase chain reaction and hybridized with allele-specific oligonucleotide probes. No H-ras point mutations were observed in any of these samples. We did detect K-ras point mutations, however, in four primary tumours--one adenoma (2.5%) and three carcinomas (33%); these mutations were all G----A transitions at the second nucleotide of codons 12 and 13. The absence of detectable ras mutations from the majority of tumors suggests that, in contrast to other animal models utilizing MNU, tumorigenesis in MNU-induced rat colon tumors may predominantly involve activation of genes other than ras.
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PMID:K-ras oncogene mutations in rat colon tumors induced by N-methyl-N-nitrosourea. 173 72

The growth of three non-tumorigenic human colonic adenoma cell lines, designated AA/C1, RG/C2 and RR/C1, was inhibited by low concentrations of transforming growth factor beta (TGF-beta) (0.05-0.5 ng ml-1). However, the growth of five human colon cancer cell lines under identical conditions was resistant to high concentrations of TGF-beta (2-10 ng ml-1). This is the first report of well-characterized premalignant human colonic cells showing sensitivity to TGF-beta. The TGF-beta-sensitive adenoma cell line AA/C1 was derived from a relatively large adenoma with a K-ras gene mutation and represents a relatively late-stage adenoma, indicating that loss of response to TGF-beta occurs at a relatively late stage in colorectal carcinogenesis and that the presence of a ras gene mutation does not necessarily confer resistance to TGF-beta. Of further interest, the RG/CZ cell line has a p53 mutation showing that p53 mutations do not necessarily lead to TGF-B insensitivity. Furthermore, in this paper we show that the conversion of the AA/C1 adenoma cell line to a tumorigenic phenotype [Williams et al., (1990) Cancer Res., 50, 4724] is accompanied by a reduced response to the growth-inhibitory effects of TGF-beta up to 10 ng ml-1. Reduced responsiveness to the inhibitory effects of TGF-beta may be an important event in the loss of growth control in colorectal carcinogenesis.
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PMID:Differential sensitivity of human colonic adenoma and carcinoma cells to transforming growth factor beta (TGF-beta): conversion of an adenoma cell line to a tumorigenic phenotype is accompanied by a reduced response to the inhibitory effects of TGF-beta. 188 18

To study the possible role of ras oncogene activation in the dissemination of colon cancer, we determined point mutations in codons 12, 13 and 61 in K- and N-ras in 3 groups of tumors: (A) primary tumors of patients who had undergone surgery for Dukes' B (early-stage) colon cancer, (B) primary tumors and metastases from patients undergoing resection of isolated lung metastases and (C) primary tumors and metastases from patients undergoing resection of isolated liver metastases. In 129 samples from 93 patients, 54 (42%) were positive for point mutations in either K- or N-ras. Most mutations (89%) were found in the K-ras gene. In group A (n = 50) ras point mutations were detected in 16 cases (32%) (15 in K-ras and 1 in N-ras). Thirteen out of 23 cases in group B (57%) were positive for a ras point mutation: 10 in K-ras and 3 in N-ras. In group C (n = 20), point mutations in codon 12 of K-ras, but none in H- or N-ras, were found in 10 cases (50%). In 31 cases the primary tumors from the metastases in groups B and C were available for analysis and 15 contained a ras point mutation (48%). Not all mutations were present in both the primary tumor and the metastasis. In 3 instances, a mutation was detected in the metastasis but not in the primary tumor, whereas in 1 case a mutation was found in the primary tumor.
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PMID:Differential activation of ras genes by point mutation in human colon cancer with metastases to either lung or liver. 195 91

We have studied the expression of oncogene-encoded mRNAs in a rat model of colon cancer. In this model, rats are intrarectally administered several low doses of the direct-acting carcinogen, N-methyl-N-nitrosourea (MNU). Tumors, predominantly adenomas, develop 5-7 months following administration of the carcinogen, and many of these progress to carcinomas. Upon assaying the steady-state levels of oncogene-encoded transcripts in normal rat colon, we found that fos and N-myc are highly expressed; H-ras, K-ras, myc, myb, and neu messages are present at lower levels; and N-ras, abl, and raf mRNAs are absent. When we compared transcript levels in rat tumors to those in normal colons from the same animal, we observed a 2-4 fold increase in both myc- and H-ras-encoded mRNAs and a 2-7 fold increase in myb message, but no change in expression of any of the 7 other genes. To test whether this increased expression is related to tumor production or is simply a result of the more rapid cellular turnover observed in tumor tissue, the level of oncogene-encoded transcripts was assayed in colonic mucosae of rats given two treatments known to enhance cell turnover and DNA synthesis in the colon. Neither acute application of MNU nor a diet containing 1% cholic acid caused any change in the level of oncogene-encoded mRNAs in rat colons, thus suggesting that the increased abundance of myc, myb, and H-ras messages in tumors is associated with tumor formation. The enhancement of expression of these genes in adenomas, as well as in carcinomas, further suggests that these alterations occur relatively early during the tumorigenic process.
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PMID:Enhanced expression of oncogene-encoded mRNA in a rat model of colon cancer. 201 8

In this report, point mutations of the K-ras gene at codon 146 were analyzed in 25 cases of colon cancer, 4 cases of lung cancer, and 41 cases of lymphoid malignancy. A codon 146 mutation substituting threonine (ACA) for alanine (GCA) was detected in the tumor tissue of a patient with colon cancer and was not detected in the normal tissue of the same patient. Any additional mutations of the ras gene family were not detected in this patient. These results suggest that the codon 146 mutation of the K-ras gene could be involved in the development of naturally occurring human malignancies.
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PMID:A novel point mutation at codon 146 of the K-ras gene in a human colorectal cancer identified by the polymerase chain reaction. 201 78

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

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


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