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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Carcinogenesis 1992 Nov
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

Two new human epithelial cell lines from sporadic colorectal adenomas designated S/RR and S/BR are reported. Both cell lines have extended growth capacities in vitro, reaching passages 38 and 40 respectively and show no sign of senescence. S/RR and S/BR cell lines have retained the ability to differentiate in vitro, as shown by mucin production from goblet-like cells. S/BR was derived from a large colonic tubular villous adenoma (3 to 4 cm), whereas S/RR was derived from a small rectal adenoma (< 1 cm), and may represent a relatively early-stage adenoma. The parent S/RR cell line has given rise to a clonogenic variant, designated S/RR/Cl, which also has shown no sign of senescence and has currently reached passage 43. Both the S/BR and the S/RR cell lines had mutations in codon 12 of the K-ras gene, while retaining one normal allele. The presence of this mutation, particularly in the cell line S/RR derived from a small adenoma, is consistent with ras mutation being a relatively early event in colorectal carcinogenesis and is perhaps involved in the ability of the adenoma cells to progress and to give rise to an immortal cell line in vitro. The clonal derivatives of the S/RR cells have an isochromosome 1q and abnormalities of chromosome 13 which include an isochromosome 13q. The S/BR cells have a deletion on the short arm of chromosome 1 and trisomy 7. The common abnormality for S/RR and S/BR cells involves chromosome 1. The involvement of different chromosomes in the 2 cell lines also suggests different pathways for malignant progression of the premalignant adenoma cells.
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PMID:Specific cytogenetic abnormalities and k-ras mutation in two new human colorectal-adenoma-derived cell lines. 142 33

In human lung cancers, alterations of both a dominant oncogene (ras) and a tumor suppressor gene (p53) have been identified. Polymerase chain reaction (PCR) analysis of mRNA was used to amplify the c-Ki-ras-2 and p53 genes from Syrian golden hamsters. The PCR products were confirmed by predicted-size analysis, probing with nonradioactive (biotin-labeled) oligonucleotides, and direct sequencing. Lung tumors were produced in hamsters by repeated injections of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Of six tumors examined, three (50%) had mutations in codon 12 of Ki-ras. Examination of the conserved regions of p53 revealed no mutations. We conclude that NNK-induced carcinogenesis in the hamster results in characteristic alterations of Ki-ras but may not necessarily involve the p53 gene.
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PMID:Mutational analysis of a dominant oncogene (c-Ki-ras-2) and a tumor suppressor gene (p53) in hamster lung tumorigenesis. 144 20

Multistage carcinogenesis involves genotoxic as well as non-genotoxic mechanisms. The importance of genotoxic events in human carcinogenesis is apparent from the analysis of tumours: for example, five to six genetic alterations can be found in most malignant colorectal tumours. While such measurable "footprints" (e.g. ras, p53 mutations) can be left in tumours by genotoxic events, non-genotoxic events cannot directly generate them. Thus, the lack of specific indicators of non-genotoxic events in carcinogenesis makes the identification of non-genotoxic carcinogens difficult. It is also important to emphasize that apparent "genotoxic" endpoints (mutations, chromosome aberrations) could be induced by "non-genotoxic" agents through indirect mechanisms (e.g. induced cell proliferation and/or genomic instability, oxidative damage, deamination of 5-methyl cytosine). This emphasizes the need for differentiating "events" from the actual "activities" of chemicals and the difficulty of classification of carcinogens into genotoxic and non-genotoxic. One of the best models for the study of interaction of genotoxic and non-genotoxic mechanisms during carcinogenesis is a two-stage carcinogenesis system using mouse skin, rat liver or cultured cells. Molecular analysis of tumours produced on mouse skin by the classical initiation-promotion protocol indicates that the mutation spectra of oncogenes, e.g. Ha-ras, are determined by initiating (genotoxic) and not by promoting (non-genotoxic) agents. However, since usually no tumours appear without the application of tumour-promoting agents, the manifestation of genotoxic events (Ha-ras mutation) is dependent on the action of non-genotoxic agents. Using a BALB c 3T3 two-stage cell transformation system, we have now succeeded in confirming this and have quantitated the initiation and promotion events. These studies may help us not only in understanding mechanisms of carcinogenesis but also in developing molecular quantitative risk assessment in terms of multistage carcinogenesis.
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PMID:Interaction and distinction of genotoxic and non-genotoxic events in carcinogenesis. 147 Dec 13

Previously, we demonstrated point mutations of the H-ras gene in N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT)-induced rat urinary bladder carcinomas. In this study, ras oncogene activation was examined in urinary bladder carcinomas induced by N-(4-hydroxybutyl)nitrosamine (BBN) or N-methyl-N-nitrosourea (MNU) administration followed by uracil treatment. In the first experiment, MNU (20 mg/kg body wt) was i.p. injected into 11 male F344 rats twice a week for 4 weeks, followed by feeding 3% uracil for 20 weeks (MNU/uracil group). Ten rats were given only 3% uracil without MNU pretreatment. In the second experiment, 20 male F344 rats were given 0.05% BBN in the drinking water for 4 weeks, then fed 3% uracil for 20 weeks (BBN/uracil group). Another 20 rats were fed 3% uracil without the BBN pretreatment. Transitional cell carcinomas were induced in the urinary bladder of all rats in the MNU/uracil and BBN/uracil groups. Papillomas and hyperplasias were present in the rats given uracil without prior BBN or MNU. DNA and protein were extracted from the tumors (MNU/uracil or BBN/uracil groups) or from the scraped bladder epithelium (uracil alone groups). Sequences around codons 12, 13 and 61 of H-, K- and N-ras genes were examined by direct sequencing after polymerase chain reaction, and p21 was examined by Western blotting. No mutation was found within the examined sequences and p21 showed no changes in mobility. There was no difference in the level of p21 expression between rats treated with MNU/uracil or BBN/uracil compared to corresponding uracil alone groups. These results indicate that the ras oncogene was not activated in urinary bladder carcinomas induced by BBN or MNU in combination with uracil treatment, in contrast to previous findings with FANFT.
Carcinogenesis 1992 Dec
PMID:Absence of ras oncogene activation in rat urinary bladder carcinomas induced by N-methyl-N-nitrosourea or N-butyl-N-(4-hydroxybutyl)nitrosamine. 147 35

Molecular epidemiology is increasingly being applied in studies of cancer risks derived from exposure to environmental carcinogens of both endogenous and exogenous origins. Analytical methods have been developed that are capable of detecting and quantifying levels of covalent adducts of several important classes of carcinogens with cellular DNA and blood proteins. Methods of sufficient sensitivity and specificity to detect ambient levels of exposure are in current use. These are being used in studies related to tobacco use (polycyclic aromatic hydrocarbons, aromatic amines, tobacco-specific nitrosamines); dietary exposures (aflatoxins, N-nitrosamines, heterocyclic amines); medicinal exposures (cisplatin, alkylating agents, 8-methoxypsoralen, ultraviolet photoproducts); occupational exposures (aromatic amines, polycyclic aromatic hydrocarbons, oxides of ethylene and styrene, and vinyl chloride); and oxidative damage (8-hydroxyguanine, thymine glycol). Methodologic improvements together with their expanded use in feasibility studies continue to produce results that support the validity of this approach for detecting and quantifying exposure to carcinogens. Genetic markers are also being used to detect early biological responses in efforts to link carcinogen exposure to initiating events in the carcinogenesis process. These include, in addition to traditional cytogenetic markers (e.g., chromosomal aberrations, sister chromatid exchange, micronuclei), other alterations in chromosomal structure such as restriction fragment length polymorphisms, loss of heterozygosity, and translocation markers. Specific genetic changes have recently been identified as critical molecular events in the initiation and development of many cancers. Important among these are activation of oncogenes, especially those of the ras family, and inactivation of tumor-suppressor genes (e.g., p53 and Rb) by point mutations and/or chromosomal deletions and other structural changes. Although some of these changes are known to occur in chemically induced tumors of experimental animals, the possible role of chemical carcinogens in the induction of genetic abnormalities in human cancers has yet to be determined. Continuing investigations employing the methods of molecular epidemiology promise to provide further evidence concerning these relationships. Future investigations employing newly developed molecular biological methods, in particular those based on polymerase chain reaction amplification of DNA, to identify alterations in DNA and chromosomal structure, combined with methods for characterizing exposure to carcinogens and early effects, have great potential for further elucidating the role of genotoxic agents in the etiology of human cancers and also for the development of strategies for their prevention.
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PMID:Molecular epidemiology in cancer risk assessment and prevention: recent progress and avenues for future research. 148 46

We studied the prevalence of point mutations in ras oncogenes (K-ras and N-ras) in DNA from white blood cells and tumor tissue from 36 untreated patients with non-small-cell lung cancer, all of whom were smokers or ex-smokers. We observed somatic K-ras mutations in one-third of the lung carcinomas studied but no N-ras mutation. K-ras codon 12 mutations were found more frequently in adenocarcinomas than in the other histopathological subtypes studied. More than 60% (10/16) of the lung adenocarcinomas had a codon 12 mutation, most of which were G to T transversions. No mutations was found in white blood cell DNA. Two polymerase chain reaction screening methods, oligonucleotide hybridization and denaturing gradient gel electrophoresis (DGGE), were used to detect the mutations. The oligonucleotide method appears to be more sensitive than DGGE, but DGGE proved to be a reliable nonradioactive method for rapid screening of point mutations in genes relevant to carcinogenesis.
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PMID:Detection of ras gene mutations in human lung cancer: comparison of two screening assays based on the polymerase chain reaction. 148 47

The presence of an activating mutation in the Ha-ras gene in hamster cheek pouch tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) complete carcinogenesis was investigated. The normal sequence of a fragment of genomic DNA encompassing codon 61 of the Ha-ras gene was amplified by the polymerase chain reaction using primers designed for a highly conserved region of the mouse Ha-ras-1 gene. The sequence of the amplified fragment was determined by a direct sequencing technique and exhibited 83.3% and 87.5% homology with the corresponding human and mouse sequences, respectively. At the amino acid level, the sequence was identical among the three species. Paraffin sections of 11 squamous cell carcinomas of the cheek pouch were used to detect mutated Ha-ras alleles. DNA sequencing of the tumors showed that six of 11 tumors presented an A----T transversion in the second position of codon 61, resulting in an amino acid change from glycine to leucine. As has been demonstrated in other systems, we have shown a specific mutation of the Ha-ras gene in chemically induced tumors of the hamster cheek pouch, further supporting the role of this oncogene in chemical carcinogenesis.
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PMID:Activating mutation of the Ha-ras gene in chemically induced tumors of the hamster cheek pouch. 149 2

The high incidence and profile of ras gene mutations reported in spontaneous and chemically induced liver tumours of the B6C3F1 mouse provides a potential means of determining in vivo genotoxicity and its relevance to carcinogenicity. We analysed spontaneous and chemically induced [with 4-amino-biphenyl (ABP), 2-acetylaminofluorene (AAF) and diethylnitrosamine (DEN)] hepatocellular tumours of the C57Bl/10J mouse for H-ras, K-ras and N-ras gene mutations to see if mutational analysis of the ras genes could be useful for such a determination in this strain. Regions of DNA spanning codons 12, 13 and 61 of the ras genes were amplified from formalin fixed liver tumour sections using the polymerase chain reaction. Mutations were detected using allele specific oligonucleotide probing and confirmed by sequencing. We have found that there are few ras mutations in either spontaneous or chemically induced liver tumours in the C57Bl/10J mouse. Out of 25 spontaneous tumours two contained an A to T transversion and one contained an A to G transition in base 2 of H-ras codon 61 and two contained a G to A transition in base 2 of K-ras codon 13 (the K-ras mutations were only faintly detectable and may be present in a subpopulation of the tumour cells). In the case of the 18 ABP induced tumours one contained a C to A transversion in base 1 of H-ras codon 61, and one contained an A to T transversion in base 2 of H-ras codon 61 and one contained a G to C transversion in base 1 of K-ras codon 13. One C to A transversion in base 1 of H-ras codon 61 was detected out of eight AAF induced tumours. Of the 25 DEN induced tumours, one contained an A to G transition and one contained an A to C transversion in base 2 of H-ras codon 61. The data indicate that at least in hepatocellular tumours of the C57Bl/10J strain and using chronic dosing regimes the ras genes do not represent markers for in vivo genotoxic activity.
Carcinogenesis 1992 Aug
PMID:Point mutation analysis of ras genes in spontaneous and chemically induced C57Bl/10J mouse liver tumours. 149 88

As part of an evaluation of the effectiveness of using ras mutation analysis for distinguishing carcinogen-induced from spontaneous tumors, we examined the profile of ras gene point mutations in spontaneous, 7,12-dimethylbenz[a]anthracene (DMBA)-induced, and N-nitrosodiethylamine (DEN)-induced lung tumors from Crl:CD-1(ICR)BR (CD-1) mice. Although all of the lung tumors were assayed for mutations in the Ha-ras, Ki-ras, and N-ras genes (codons 12, 13, and 61), only Ki-ras mutations were found, which is consistent with other studies that have noted a strong preference for Ki-ras gene activation in mouse, rat, and human lung tumors. We found that spontaneous CD-1 mouse lung tumors had a very high frequency of Ki-ras gene activation (17 of 20 tumors; 85%), distributed among codons 12 (5 of 20), 13 (1 of 20), and 61 (11 of 20). DMBA-induced lung tumors had a slightly higher frequency of Ki-ras gene mutations (16 of 16; 100%), again distributed among codons 12 (5 of 16), 13 (2 of 16), and 61 (9 of 16). However, seven of the DMBA tumors had mutations qualitatively different from those found in spontaneous tumors. In contrast to DMBA-induced tumors, DEN-induced tumors had a lower frequency of Ki-ras mutations (36%) when compared with spontaneous lung tumors, suggesting that DEN primarily induces lung carcinogenesis by a mechanism other than ras gene activation. Thus, although spontaneous and induced CD-1 mouse lung tumors have a strong tissue-specific preference for carrying an activated Ki-ras gene, the nature of the initiating carcinogen can influence the frequency or profile of Ki-ras mutations.
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PMID:Activation of the Ki-ras gene in spontaneous and chemically induced lung tumors in CD-1 mice. 150 45


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