Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A high frequency of point mutations at codon 12 of the Ki-ras gene has previously been reported for rat kidney mesenchymal tumors induced by methylating N-nitroso compounds. In this study, we analyzed renal tumors with divergent histogenesis, i.e., mesenchymal tumors (sarcomas), cortical epithelial tumors (carcinomas), and embryonal tumors (nephroblastomas). Renal mesenchymal tumors and carcinomas were induced in juvenile or young adult Wistar rats by a single dose of N-nitrosodimethylamine (NDMA) while nephroblastomas were induced in Nb hooded rats by a single transplacental dose of N-nitrosoethylurea (NEU). Nephroblastomas developing spontaneously in WAB/Not rats were also examined. Amplification of Ki-ras sequences from formalin-fixed, paraffin-embedded tissue by the polymerase chain reaction was followed by direct DNA sequencing. GGT----GAT point mutations at codon 12 of the Ki-ras gene were found in 9 of 12 (75%) renal mesenchymal tumors and in 9 of 12 (75%) cortical epithelial tumors induced by NDMA. Even higher incidences were observed in nephroblastomas (8/8; 100%) induced by NEU and in spontaneous nephroblastomas (10/11; 91%). These results indicate that Ki-ras mutations are frequent events during the development of kidney tumors irrespective of their histogenesis and suggest that they may play an important role in renal carcinogenesis in rats. These data further indicate that mutational activation of Ki-ras proto-oncogenes in carcinogen-induced rat kidney tumors occurs in a tissue-specific, rather than cell-specific, manner.
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PMID:Ki-ras mutations in spontaneous and chemically induced renal tumors of the rat. 179 84

Utilizing the polymerase chain reaction (PCR), we studied the presence and pattern of mutations in the Kirsten (Ki)-ras oncogene, using paraffin-embedded sections of pancreatic carcinoma tissue from 53 patients. Mutations in the Ki-ras oncogene were evident in 46 of the 53 patients (87%) in codon 12. The predominant mutation was from glycine (GGT) to aspartic acid (GAT). Among the 46, one had an additional mutation in Ki-ras codon 13, and no mutation was found in codon 61. These oncogenetic mutations were observed even in early stage pancreatic carcinoma, and there was no statistically significant difference in the rate or positivity of mutations among the stages of the disease. With regard to patient survival, statistical analysis comparing 37 patients with mutations in the Ki-ras oncogene and four patients without mutations revealed no significant difference. These results suggest that mutations in the Ki-ras oncogene may be related to the initiation of carcinogenesis, but are not linked to malignant potential or promotion of human pancreatic cancer.
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PMID:Mutations in the Kirsten-ras oncogene are common but lack correlation with prognosis and tumor stage in human pancreatic carcinoma. 196 23

The role of ras activation in the formation of spontaneous and chemically induced tumors was evaluated in the C3H mouse, a strain that has a low incidence of spontaneous lung tumors. Lung tumors were induced in C3H mice by treatment with 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 50 mg/kg, or nitrosodimethylamine (NDMA), 3 mg/kg for 7 weeks (3 times/week, i.p.). Eleven tumors from each treatment group were evaluated for activated ras genes by direct sequencing and oligonucleotide hybridization to slot blots of amplified DNA from these tumors. An activated K-ras gene was detected in 100% of NDMA- and NNK-induced lung tumors, and the activating mutation detected in all samples was a GC to AT transition (GGT to GAT) in codon 12. In contrast, only 40% of the seven spontaneous lung tumors analyzed contained an activated K-ras gene and the mutations identified were not localized to either a specific base or codon. Both NNK and NDMA can be activated via alpha-hydroxylation to methylating agents. The GC to AT mutation observed in codon 12 in the nitrosamine-induced tumors is consistent with the formation of an O6-methylguanine (O6MG) adduct. Similar concentrations (13-15 pmoles/mumol deoxyguanosine) of this promutagenic adduct were detected in lungs during treatment with either NNK or NDMA. Thus, both these nitrosamines appear to activate the K-ras gene in lung through a direct genotoxic mechanism involving the formation of the O6MG adduct. The frequency of K-ras activation was similar in chemically induced lung tumors from the sensitive A/J strain and the C3H mouse, indicating that susceptibility for neoplasia in these stains is not related to the ability to activate this gene. Although tumors were induced in lung from 100% of C3H mice following chronic carcinogen exposure, both the size and the multiplicity was significantly less, while latency was longer than that observed in the A/J mouse. These differences could not be attributed to an altered propensity for DNA damage, but rather suggest that genetic loci which regulate clonal expansion and growth of initiated cells play a major role in the susceptibility of pulmonary neoplasia.
Carcinogenesis 1991 Feb
PMID:Role of ras protooncogene activation in the formation of spontaneous and nitrosamine-induced lung tumors in the resistant C3H mouse. 199 95

An animal model of carcinogenesis has been exploited to analyze the various events involved in carcinogen-induced T cell lymphomagenesis. Two carcinogenic agents, the alkylating agent N-methylnitrosourea (NMU) and ionizing gamma-radiation, induce tumors in C57BL/6J mice that are phenotypically and histologically identical. Are the genetic events similar or different in the T cell tumors produced by these two carcinogenic agents? NMU treatment produced a different spectrum of activated oncogenes from gamma-irradiation. The K-ras oncogene was preferentially activated in all of the NMU-induced tumors, most frequently by a GGT to GAT transition in codon 12. Ionizing gamma-radiation produced two different transforming activities. Approximately half of the radiation-induced tumors contained activated N-ras genes and half contained a novel non-ras transforming activity. Analysis of NMU- and gamma-irradiated treated animals for chromosomal abnormalities showed anomalies early in the disease. Although both agents produce tumors containing trisomy of chromosome 15, the timing of this event appears to be different occurring early in NMU-induced tumors and later in gamma-radiation induced tumors. In addition, a unique marker chromosome consisting of a translocation between chromosomes one and five appears to be involved in the early stages of radiation-induced disease and may be associated with the novel transforming activity detected in these same tumors. Expression of receptors for the T cell growth factor (IL-2R) is similar in both NMU- and gamma-irradiation induced tumors. Changes in the expression of IL-2R on different T cell populations with disease progression may account for thymus dependent and thymus independent phases of malignant T cell growth.
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PMID:Multistage carcinogenesis in murine thymocytes: involvement of oncogenes, chromosomal imbalances and T cell growth factor receptor. 268 36

The authors previously reported a significant frequency of activating point mutations in codon 12 and 13 of the K-ras gene in endometrial carcinoma and endometrial atypical hyperplasia from Osaka, Japan. They also showed that alterations of the p53 gene are found frequently in those tumors. This study was designed to reveal possible demographic differences in the prevalence of K-ras and p53 mutations in endometrial carcinoma. Tumor-enriched areas of paraffin-embedded histologic sections obtained through the Colorado Central Cancer Registry were isolated and extracted for DNA. Fragments amplified by polymerase chain reaction (PCR) were screened for transforming mutations in codon 12, 13, or 59-63 of K-ras by direct sequencing. Of 38 endometrial adenocarcinomas that were analyzed, K-ras activation was detected in 4 cases (11%), three in codon 12 (a single case with a GGT-->AGT transition, a single case with a GGT-->GAT transition, and a single case with a GGT-->TGT transversion) and one in codon 13 (a GGC-->GAC mutation). The prevalence of K-ras mutations was significantly lower in endometrial carcinomas from Colorado (4 of 38, 11%) than in those from Osaka, Japan (17 of 57, 31%; P = .02). Mutations in exons 5-8 of p53 were screened by PCR-SSCP analysis, and subsequently confirmed by direct sequencing. Mutations in the p53 gene were detected in 5 of 38 endometrial carcinomas from Colorado (13%), including a single base substitution mutation in 3 cases (60%) and a deletion mutation in 2 cases (40%). Mutations in the p53 gene were significantly more frequently found in G3 cancers (3 of 7, 43%) than G1-G2 cancers combined (2 of 31, 6%; P = .025). Although the prevalence of p53 mutations in endometrial carcinomas from Colorado was not significantly different compared to that from Osaka, Japan (9 of 40, 23%), a G:C-->A:T transition at a CpG site, which was the most common base substitution mutation among Japanese, was not included in any tumors from Colorado. A rare polymorphism in codon 213 (CGA-->CGG) was observed in three cases. These observations may indicate that genetic or environmental factors may significantly influence the pathway of endometrial carcinogenesis.
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PMID:Alteration of the p53 tumor suppressor gene and activation of c-K-ras-2 protooncogene in endometrial adenocarcinoma from Colorado. 785 67

Lung tumors were induced in A/J mice by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and the related compounds acetoxymethylmethylnitrosamine (AMMN) and 4-acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc). NNK both methylates and pyridyloxobutylates DNA while AMMN and NNKOAc only methylate or pyridyloxobutylate DNA, respectively. The lung tumors were analyzed for mutations in the Ki-ras oncogene by PCR amplification followed by either restriction fragment length polymorphism, hybridization, or sequencing procedures. NNK induced GGT to GAT mutations in codon 12 (26 of 28 samples analyzed). AMMN induced GGT to GAT mutations in 18 of 18 samples. In contrast, NNKOAc induced a variety of changes including GGT to GAT (8/21), GGT to TGT (5/21) and GGT to GTT (4/21) mutations. These results demonstrate that DNA methylation causes mainly G to A transitions in the Ki-ras gene of A/J mouse lung tumors, consistent with previous results and a role for O6-methyl-guanine, while DNA pyridyloxobutylation induces G to A transitions as well as G to T transversions, perhaps due to the steric bulk of the adducts which are formed. The results are discussed with respect to mutations observed in rodent and human lung tumors.
Carcinogenesis 1993 Nov
PMID:G to A transitions and G to T transversions in codon 12 of the Ki-ras oncogene isolated from mouse lung tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and related DNA methylating and pyridyloxobutylating agents. 790 20

Cyclopenta[cd]pyrene (CPP) is a ubiquitous cyclopenta-fused polycyclic aromatic hydrocarbon. CPP is highly genotoxic in bacterial and mammalian systems inducing gene mutations, sister chromatid exchanges and morphological transformation. CPP is a mouse skin carcinogen, a mouse skin tumor initiator and induces pulmonary tumors in newborn mice. We have examined the tumorigenic activity of CPP in strain A/J mice, have determined the formation and persistence of CPP-induced DNA adducts in lung tissue, and analyzed the mutational spectrum in the Ki-ras oncogene from CPP-induced tumors. CPP dissolved in tricaprylin was administered by i.p. injection to male A/J mice (20 mice/dose) at 0, 10, 50, 100 and 200 mg/kg. Animals were killed 8 months later and the lungs removed, fixed, and surface adenomas enumerated. CPP proved to be highly tumorigenic in A/J mice in terms of inducing lung adenomas. The observed tumor multiplicities (lung adenomas/mouse) were: 97.7 +/- 28.7 at 200 mg/kg, 32.8 +/- 15.4 at 100 mg/kg, 4.63 +/- 2.11 at 50 mg/kg and 0.58 +/- 0.82 at 10 mg/kg. Tricaprylin-treated controls produced 0.60 +/- 0.58 lung adenomas/mouse. Groups of mice treated under the same dosing conditions as those in the tumor studies were killed 1, 3, 7, 14 and 21 days after treatment. The lungs were removed, and the DNA was subjected to DNA adduct analysis by the 32P-postlabeling method. Total CPP-DNA adducts in mouse lung peaked at day 3 with 5870 amol CPP adducts/micrograms DNA after a single dose of 200 mg/kg. DNA adduct levels decreased to 1800 amol CPP adducts/micrograms DNA at day 21. Qualitative DNA adduct analysis revealed four major adducts and one minor adduct. Co-chromatography of the lung DNA from CPP-treated mice with calf thymus DNA treated with CPP-3,4-oxide indicated that all DNA adducts were oxide derived and comparison with CPP-3,4-oxide-treated polydeoxyguanylic acid suggests that almost all of these adducts are CPP-3,4-oxide-2'-deoxyguanosine adducts. Ki-ras codon 12 mutation analysis of the DNA from tumors taken from the 100 and 200 mg/kg CPP dose groups demonstrated the following patterns: GGT-->CGT (50%); GGT-->GTT (15%); GGT-->TGT (25%); GGT-->GAT (10%). We conclude that CPP is highly tumorigenic in the A/J mouse lung adenoma model, being five times more active than benzo[a]pyrene. This is unlike the result of CPP as a mouse skin tumorigen or tumor initiator in which CPP is considerably less potent than benzo[a]pyrene.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1994 Apr
PMID:Cyclopenta[cd]pyrene-induced tumorigenicity, Ki-ras codon 12 mutations and DNA adducts in strain A/J mouse lung. 814 68

Thirty-five patients with ovarian tumors operated on between December, 1989 and June, 1991 were studied to detect K-ras codon 12 point mutation (PM). (1) Five of 35 ovarian tumors (14.3%) disclosed K-ras PM at codon 12 and all the PM cases were in transition from GGT to GAT. On the other hand only one case (5.3%) with K-ras oncogene amplification was found and no C-myc or erbB-2 amplification was detected. (2) The incidence of PM according to clinical stages was seen in 3 of 11 stage I cases (27.3%), in 1 of 3 stage II cases (33.3%), in 1 of 14 stage III cases (7.1%) and in neither of 2 stage IV cases. PM was therefore seen in relatively early stages. (3) The occurrence of PM according to the histologic type was found in 3 of 16 serous tumors (18.8%), in 2 of 5 mucinous tumors (40.0%) and in none of 7 clear cell carcinomas or 2 endometrioid carcinomas. (4) Concerning the relation of PM to the involvement of serosal surface of ovarian tumors and to the ascitic cytology, no particular correlation was observed in our study. (5) Regarding the cytologic findings in imprint smears of the tumors in reference to PM, such as nuclear size, shape, N/C ratio, chromatin pattern, nucleolar size and number, the cases with PM tended to have more multiple nucleoli than PM negative cases. No other findings seemed to indicate the clinical progress of cancer. In conclusion, our study indicated that PM in ovarian cancers was a relatively early event in carcinogenesis.
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PMID:[Studies on the point mutation of ras oncogene in ovarian tumor]. 825 28

Ras mutations are an important early event in a number of carcinogen-induced rodent tumors. Colon carcinogenesis induced in rats by azoxymethane is a useful model as it mimics the adenoma-carcinoma sequence observed in humans. In addition, aberrant crypt foci develop in the rat and these lesions appear to be potentially important precursors to adenomas in colorectal cancer. Recent studies have shown that specific K-ras codon 12 and 13 mutations are present in up to 66% of carcinogen-induced rat colon adenocarcinomas. We studied the frequency of these mutations during the aberrant crypt focus-adenoma-carcinoma sequence in azoxymethane-induced Fisher F344 rats. K-ras codon 12 GAT and codon 13 GAC mutations were detected with a sensitive assay based on the amplification of DNA using the polymerase chain reaction. No mutations were present in normal mucosa. Of 27 aberrant crypt foci, K-ras mutations were identified in 2 lesions containing 5 and 10 aberrant crypts, respectively. Mutations were present in 1 of 23 and 10 of 27 adenomas and adenocarcinomas, respectively. These data suggest that K-ras mutations play a role during the stages of carcinogenesis in azoxymethane-induced rat colon cancer. The demonstration of a genetic mutation in aberrant crypt foci provides further evidence for the significance of these lesions as precursor markers of malignant potential during colorectal tumorigenesis.
Carcinogenesis 1993 Sep
PMID:K-ras mutations in aberrant crypt foci, adenomas and adenocarcinomas during azoxymethane-induced colon carcinogenesis. 840 99

The frequency of K-ras point mutation(PM) at codon 12 was studied in 45 patients with endometrial carcinoma. In vitro amplification of target sequences of DNA extracted from endometrial cancer tissues by polymerase chain reaction and dot blotting with oligonucleotide hybridization were performed. Ten of 45 endometrial carcinomas disclosed K-ras PM at codon 12 (22.2%). Transition from GGT to GAT was most frequent in PM(41.7%). Simultaneously, double PM (GAT/GCT) were also detected in 2 cases. No relationship appeared to be present between PM and clinical prognosis such as clinical stage, histological type, histological grade of differentiation, depth of myometrial invasion, and ascitic cytology. The positive rates of lymph node metastasis tended to be higher in the group with positive PM than in the group without PM. K-ras and C-myc gene amplifications were found in 2 (5.1%) and 3 (7.7%) of 39 cases, respectively. No PM of H-ras at codons 12 and 61 was detected. Our results showed that the PM of K-ras gene at codon 12 was a fairly common event in genetic abnormality and suggested it would have some role in the progression of carcinogenesis in endometrial carcinoma.
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PMID:Studies on ras oncogene activation in endometrial carcinoma. 842 91


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