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)

We have investigated UV-B-induced skin tumors of hairless SKH-HRA mice for alterations in the p53 gene and for mutations in either of the three ras genes. Out of 32 tumors screened, only one contained a ras mutation, i.e. in codon 12 of the K-ras gene. Alterations in the p53 gene were much more abundant, as illustrated immunohistochemically by the accumulation of p53 protein in 75% of the tumor sections examined. Immunoreactivity was observed primarily in the proliferative cell compartment, but no clear correlation between p53 staining in tumor cells and histological parameters for malignancy was observed. Subsequent sequence analysis showed that point mutations in the p53 gene are detectable in 30% (nine out of 30) of the skin tumors examined. The majority of the mutations are located in codons 267 and 272, most likely originating from UV-B-induced photo-adducts at dipyrimidine sites in the non-transcribed strand. Codon 272 corresponds to the human codon 278, which is also a hotspot for p53 mutations in human non-melanoma skin cancers. Codon 267 matches the human codon 273, which does not contain a dipyrimidine site, but represents a CpG hotspot for p53 mutations in internal malignancies. Our results demonstrate that this hairless mouse model for UV-induced skin cancer corresponds closely to human non-melanoma skin cancers with respect to mutations in the p53 gene.
Carcinogenesis 1995 May
PMID:Frequent p53 alterations but low incidence of ras mutations in UV-B-induced skin tumors of hairless mice. 776 77

Pancreatic ductal adenocarcinomas induced in the Syrian golden hamster (SGH) by N-nitrosobis(2-oxopropyl)amine share many similarities with the human disease, including mutations of the K-ras oncogene. In vitro carcinogenesis studies with immortal SGH pancreatic duct cells indicate that neoplastic transformation in this system can occur without mutational inactivation of p53 suppressor gene. In this study we extend the genetic analysis of the in vivo SGH model to increase the number of cases analyzed for the status of K-ras and to determine further the spectrum of alterations involved; we have studied the status of the p53, DCC, and Rb-1 suppressor genes and the status of the mdm2 oncogene, which can involve p53 indirectly. The partial SGH-coding sequence of mdm2 and DCC was determined. K-ras mutation in the second position of codon 12 was present in 17 of 19 (90%) of tumors. Immunohistochemistry and single strand conformation polymorphism analysis showed no evidence of p53 mutation in 21 tumors. RNase protection assays showed overexpression of mdm2 in 5 of 19 (26%) tumors. Semiquantitative reverse transcription-PCR analysis showed a complete or partial loss of DCC expression in 10 of 19 (53%) neoplasms and of Rb-1 (42%) expression in 8 of 19 tumors when compared to matched controls. Deregulation of these genes appears to be significant in SGH pancreatic carcinogenesis as indicated by their frequencies. However, the fact that 6 tumors showed either only a K-ras mutation or the absence of alterations of the 5 genes analyzed indicates that additional as yet unstudied or unknown genes are also involved in SGH pancreatic duct carcinogenesis.
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PMID:Multiple genetic alterations in hamster pancreatic ductal adenocarcinomas. 778 Sep 69

p16Ink4 and p15Ink4B are cyclin-dependent kinase 4 inhibitors and link to the regulation of cell cycle in mammalian cells. The genes encoding these inhibitors are located at 9p21, which is a frequent site of allelic loss in various types of tumors. Twenty-five primary biliary tract cancers were examined for somatic mutations in p16Ink4/CDKN2, p15Ink4B/MTS2, p53, and K-ras genes and allelic loss of 9p21 by microsatellite analysis. Four biliary tract cancer cell lines were analyzed for homozygous deletions and point mutations. We found frequent homozygous deletions in p16Ink4/CDKN2 and p15Ink4B/MTS2 genes in the biliary tract cancer cell lines. Each cancer cell line had alteration of either p16Ink4/CDKN2, p15Ink4B/MTS2, or p53 genes. In primary tumors, 16 of 25 (64%) biliary tract cancers had point mutations in the p16Ink4/CDKN2 gene. These include 14 missense and 2 silent mutations. The frequency of mutations in gall bladder cancer and hilar bile duct cancer were 80% (8 of 10) and 63% (5 of 8), respectively. Each of codons 1, 80, and 111 was changed in two cases of these cancers. One of three intrahepatic bile duct cancers, one of two common bile duct cancers, and one of two ampullary cancers had mutations in the p16Ink4/CDKN2 gene. In contrast, no mutation in the p15Ink4B/MTS2 gene, one base change in the K-ras gene, and one loss of heterozygosity at the IFN alpha locus in 25 cancers and one base change in the p53 gene in 19 cancers were observed. These results suggest that p16Ink4/CDKN2, rather than p15Ink4B/MTS2 or p53 genes, and its inactivation may be important in biliary tract carcinogenesis.
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PMID:Mutations of p16Ink4/CDKN2 and p15Ink4B/MTS2 genes in biliary tract cancers. 779

In order to define whether all colonic tumors develop from a single transformed cell, we compared two sites each in 40 early-stage colonic carcinomas by K-ras mutation and DNA ploidy pattern. These 40 colonic carcinomas consisted of 26 protruding-type carcinomas and 14 superficial-type carcinomas. The two sites were selected in every tumor tissue and then DNA ploidy pattern and occurrence of K-ras mutation were detected. In cases of "cancer in adenoma", we compared clonality between cancer cells and adenoma cells. In a cytofluorometrical study, it was shown that diploid patterns were predominantly seen in protruding-type carcinomas (76.9%), whereas many superficial-type carcinomas (64.3%) consisted of aneuploid cells. K-ras mutations were more frequently observed in protruding-type carcinomas: 42.3% in protruding-type compared to 21.4% in superficial-type carcinomas. These findings suggested that superficial-type carcinomas have a different mode of carcinogenesis from that of protruding-type carcinomas. Frequently, each pair of sites of the carcinoma tissue carried the same K-ras mutation, and DNA ploidy patterns were essentially the same. However, we encountered some cancers that showed different K-ras mutations in the cancer tissues. In particular, one case of cancer in adenoma demonstrated different K-ras mutations in the cancer and adenoma tissue. These findings suggest that most colonic cancers develop monoclonally, but there are a few cancers (fewer than 5%) that start multiclonally.
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PMID:A possible multiclonal development in human colonic carcinomas. 779 96

Patients with a primary cancer in the lung or in the upper aerodigestive tract have an increased risk of developing synchronous or metachronous second primary lung tumors. This phenomenon has been related to the chronic exposure of the bronchial tree to carcinogens through a so-called "field cancerization" process. This study was designed to investigate at the somatic level the genetic basis of the field cancerization effect in patients having multiple simultaneous neoplastic and preneoplastic lesions of the lung. The pattern of specific genetic changes occurring with high frequency and in early stages of lung carcinogenesis including p53 mutations, deletions of chromosome 3p, and K-ras mutations, was investigated by immunocytochemical, cytogenetic, and molecular approaches in 11 synchronous lesions of five patients with multiple lung cancers. Different genetic lesions were observed in all of the pathological specimens analyzed from each patient. The pattern of these changes was different both in topographically distant or adjacent lesions and in tumors with the same histopathological diagnosis supporting their independent origin. The present data provide further evidence of the clinical relevance of the field cancerization process, and support the use of genetic markers in the differential diagnosis of recurrence or metastasis versus second primaries of the lung.
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PMID:Genetic evidence for an independent origin of multiple preneoplastic and neoplastic lung lesions. 780 23

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

We examined the point mutations of codons 12, 13 and 61 in K-ras gene by slot blot hybridization analysis following polymerase chain reaction and genotypes of polymorphic N-acetyltransferase (NAT) by Southern blot analysis in 36 colorectal carcinoma tissues obtained at surgery. NAT genotypes of 36 autopsied livers from patients without colorectal carcinoma were also determined to compare the populations of each polymorphic NAT genotype in the patients with or without the neoplasm. Genetically, 44.4% (16 cases), 47.2% (17 cases) and 8.3% (3 cases) of patients with colorectal carcinoma were classified as rapid, intermediate and slow acetylators, respectively. Point mutations of K-ras gene were detected in eight carcinomas out of 16 rapid acetylators, two out of 17 intermediate acetylators and one out of three slow acetylators. In control livers, 52.8% (19 cases), 38.9% (14 cases) and 8.3% (3 cases) were classified as rapid, intermediate and slow acetylators, respectively. The occurrence of K-ras gene point mutations was closely linked to rapid acetylator genotype, although there was no statistical difference of NAT genotypes between the group of patients with colorectal carcinoma and the group of controls.
Carcinogenesis 1994 Jul
PMID:Relation between the occurrence of K-ras gene point mutations and genotypes of polymorphic N-acetyltransferase in human colorectal carcinomas. 791 23

Neoplastic transformation of Syrian golden hamster (SGH) pancreatic duct cells was induced by in vitro treatment with the direct-acting carcinogens N-methylnitrosourea (MNU) and N-(2-hydroxypropyl)nitrosourea (HPNU), with subsequent selection by sustained culture in serum- and epidermal growth factor (EGF)-deprived medium. The present study examines the efficacy of serum and EGF deprivation as a selection pressure and the effect of the carcinogen dose, frequency and interval of exposure on tumorigenesis and K-ras mutation. Selection of carcinogen-initiated duct cells by serum and EGF deprivation is highly reproducible and effective, increasing the incidence of tumors from 26 to 93% for MNU or from 0 to 100% for HPNU. SGH pancreatic duct cells exposed to 0.5 mM MNU for 13 weeks (long-treatment schedule) produced K-ras mutations at codon 12 in six of six tumors. However, when cells were exposed to 0.125, 0.25 or 0.5 mM MNU daily for 5 days (short-treatment schedule), mutations of K-ras at codon 13 were identified in four of 16 tumors, the remaining 12 showing no mutations. Duct cells exposed to 0.5 mM HPNU by the short-treatment schedule produced K-ras mutations in codon 13 in six of six tumors, as contrasted to 12 tumors that developed from cells exposed to 0.125 or 0.25 mM HPNU, which all contained K-ras codon 12 mutations. The current experiments demonstrate that K-ras mutation in pancreatic carcinogenesis in vitro by MNU or HPNU can be modified by the nature and dose of the carcinogen as well as the frequency and duration of exposure.
Carcinogenesis 1994 Sep
PMID:In vitro carcinogenesis of hamster pancreatic duct cells: cellular and molecular alterations. 792 93

A mouse hybrid, (C3H x A/J)F1 or C3A, was developed by crossing male A/J mice (high lung tumor susceptibility) with female C3H mice (low lung tumor susceptibility). The lung tumor responses of the C3A mice to dimethylnitrosamine (DMN) or benzo[a]pyrene (B[a]P) were found to be intermediate between those of the two parental strains. Mutational activation of the K-ras gene was found at a high frequency in both the B[a]P- and DMN-induced C3A lung tumors. To explore the genetic basis of the K-ras gene involvement in mouse lung tumor susceptibility, the parental origin of the K-ras oncogene in the chemically induced C3A lung tumors was determined. K-ras oncogenes were found on the allele inherited from the susceptible A/J parent in 14/16 of DMN-induced tumors and 15/17 of B[a]P-induced tumors from C3A mice. Furthermore, the K-ras mRNA transcribed from the A/J allele was 5-20 times more than C3H K-ras transcripts in 10/10 DMN-induced and 10/10 B[a]P-induced C3A lung tumors. These data suggest that an activated A/J K-ras allele could be more tumorigenic than an activated C3H allele due to the differential expression of the two alleles in lung cells.
Carcinogenesis 1994 Sep
PMID:Allele-specific activation and expression of the K-ras gene in hybrid mouse lung tumors induced by chemical carcinogens. 792 98

We investigated preneoplastic lesions associated with lung cancer to determine at what stage in lung carcinogenesis K-ras mutations appear. We selected six archival lung cancer resection cases that had ras mutations. We precisely microdissected 74 relevant areas from paraffin-embedded sections. K-ras mutations at codons 12, 13, and 61 were determined by the designed restriction fragment length polymorphism method using mismatched nested primers and confirmed by direct sequencing. All samples of invasive and metastatic cancers had K-ras mutations, as did four of five lesions of noninvasive cancer. Mutations were detected in only 1 of 12 dysplastic lesions and were absent from hyperplastic and normal-appearing cells. In all cases, the specific point mutations and the mutational pattern in the tumors, metastases, and the corresponding noninvasive lesions were identical. These results indicate that K-ras mutations arise relatively late in the pathogenesis of lung cancer and may be associated with the appearance of the malignant phenotype.
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PMID:K-ras mutations are a relatively late event in the pathogenesis of lung carcinomas. 795 6


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