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

Anomalous junction of the pancreaticobiliary duct (AJPBD) is thought to be an important risk factor for gallbladder carcinoma in Japan. We have reported the characteristic pathology, cellular kinetics, and gene mutations to clarify the mechanism of carcinogenesis in gallbladder mucosa with AJPBD. A comprehensive review of the literature was undertaken, with referencing of major articles on the subject. A sequence of hyperplastic changes, with a corresponding increase in cellular kinetics with progression through dysplasia to carcinoma is important in carcinogenesis of gallbladder mucosa with AJPBD. p53 mutations may contribute to the transition from premalignancy to malignancy in the early stage of carcinogenesis of the gallbladder mucosa, regardless of the presence of AJPBD. The specific mutation of GGT-to-GAT in codon 12 of K-ras may play an important role in carcinogenesis of gallbladder mucosa with AJPBD.
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PMID:Cellular kinetics and gene mutations in gallbladder mucosa with an anomalous junction of pancreaticobiliary duct. 1052 56

Azoxymethane (AOM) is an indirect-acting colon carcinogen that produces a high incidence of precancerous lesions, referred to as aberrant crypt foci (ACF), in rats. This study was undertaken to determine whether high dose gavage administration of the cytochrome P-450 2E1 (CYP2E1) inhibitor and chemopreventive agent, diallyl sulfide, would reduce the incidence and severity of ACF formation in the distal colons of AOM-treated Fischer 344 rats. Seven-week-old male rats received 150 or 50 mg/kg diallyl sulfide by gavage 24 and 2 h prior to two weekly i.p. injections of AOM (20 mg/kg). Ten weeks after the last injection of AOM the rats were sacrificed and the colons removed and stained with 0.2% methylene blue. ACF were visualized using stereomicroscopy. Rats pretreated with diallyl sulfide exhibited a significant increase in the number of ACF/cm in the distal colon compared with rats receiving AOM alone. This increase in ACF number was seen in ACF of all sizes. To examine the effects of diallyl sulfide on the initiation stage of AOM-induced carcinogenesis, mutations in the K-ras proto-oncogene were also investigated. ACF and normal appearing colonic mucosa (0.2-0.5 mm3) were microdissected for subsequent PCR-RFLP analysis of a codon 12 (GGT-GGA) activating mutation in the K-ras gene. Greater than 90% of ACF from AOM-treated animals, regardless of diallyl sulfide treatment, exhibited activating K-ras mutations. K-ras mutations were also detected in normal appearing mucosa of AOM-treated animals, although at a lesser frequency (15-35%). These studies demonstrate that diallyl sulfide given in large gavage doses enhances AOM-induced preneoplasia in rats and suggests that diallyl sulfide may alter the disposition of AOM intermediates and/or enhance colonic promotional activity in the rat.
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PMID:Diallyl sulfide enhances azoxymethane-induced preneoplasia in Fischer 344 rat colon. 1072 75

The Donryu rat has been found to have a high incidence of spontaneous uterine endometrial carcinomas. Moreover the histologic findings, biological nature and pathogenesis of these rat tumors appear similar to those in humans. To determine if the incidence of H- and K-ras gene mutations in these rat tumors is similar to that in human endometrial cancers, we isolated DNA samples from 2 atypical hyperplasias, 5 simple or complex hyperplasia without atypia, 9 adenocarcinomas and 7 histologically normal tissues, amplified exons 1 and 2 of the H- and K-ras genes by PCR and hybridized the products with allele specific oligonucleotide probes. K-ras point mutations were observed in 1/2 of the atypical hyperplasia (codon 12: GGT-->GTT) and 3/9 of the carcinoma (codon 12: GGT-->GAT, GGT-->AGT, codon 61: CAA-->CAC), while they were not detected in 7 of the normal tissues and in 5 of the simple or complex hyperplasia without atypia. H-ras point mutations were not detected in any of these DNA samples. These frequencies in this rat model are similar to those in humans. The absence of K-ras mutations from simple and complex hyperplasia tissue samples suggests that these mutations are associated with cytological atypia. Our findings suggest that alterations in the K-ras gene may be one of the important initiating event in endometrial carcinogenesis in some of the Donryu rat, like the human.
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PMID:K-ras point mutations in spontaneously occurring endometrial adenocarcinomas in the Donryu rat. 1077 52

Preconceptional exposure of male NIH Swiss mice to chromium(III) chloride resulted in increased incidence of neoplastic and non-neoplastic changes in their progeny, including lung tumors in females [Toxicol. Appl. Pharmacol. 158 (1999) 161-176]. Since mutations in the K-ras protooncogene are frequent, early changes in mouse lung tumors, we investigated possible mutational activation of this gene as a mechanism for preconceptional carcinogenesis by chromium(III). These offspring had lived until natural death at advanced ages (average 816+/-175 days for controls, 904+/-164 for progeny of chromium-treated fathers). Mutations of K-ras, analyzed by single-strand conformation polymorphism and sequencing, were, in codon 12, wild type GGT (glycine), to GAT (aspartic acid); to GTT (valine); and to CGT (arginine); and in codon 61, wild-type CAA (glutamine), to CGA (arginine). K-ras mutation frequencies in lung tumors were very similar in control progeny (4/14) and in progeny of chromium-treated fathers (5/15). Thus, germline mutation or tendency to spontaneous mutation in K-ras does not seem to be part of the mechanism of preconceptional carcinogenesis here. However, an additional interesting observation was that K-ras mutations were much more frequent in lung carcinomas (8/16) than in adenomas (1/13) (P=0.02), for all progeny combined. This was not related to age of the tumor-bearing mice or the size of the tumors. K-ras mutations may contribute to malignant tumor progression during aging, of possible relevance to the putative association of such mutations with poor prognosis of human lung adenocarcinomas.
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PMID:K-ras mutations in mouse lung tumors of extreme age: independent of paternal preconceptional exposure to chromium(III) but significantly more frequent in carcinomas than adenomas. 1115 72

To elucidate involvement of the transforming growth factor-beta (TGF-beta) signaling pathway in endogenous and exogenous liver carcinogenesis, we investigated mutations of TGF-beta receptor type II (TGF-betaRII), Smad2 and Smad4 genes, and expression of TGF-betaRII in hepatocellular carcinomas (HCCs) induced by a choline-deficient L-amino acid-defined (CDAA) diet and by N-nitrosodiethylamine (DEN). Male Fischer 344 rats received a CDAA diet continuously and HCCs were sampled after 75 weeks. Administration of DEN was followed by partial hepatectomy (PH), with colchicine to induce cell cycle disturbance and a selection pressure regimen, HCCs being obtained after 42 weeks. Total RNAs were extracted from individual HCCs and mutations in TGF-betaRII, Smad2 and Smad4 were investigated by reverse transcription (RT)-polymerase chain reaction (PCR)-restriction-single-strand conformation polymorphism (SSCP) analysis followed by sequencing analysis. Mutations of Smad2 were detected in 2 out of 12 HCCs (16.7%) induced by the CDAA diet, a GGT-to-GGC transition (Gly to Gly) at codon 30 and a TCT-to-GCT (Ser to Ala) transversion at codon 118, without any TGF-betaRII or Smad4 alterations. No mutations of TGF-betaRII, Smad2 and Smad4 were encountered in eleven HCCs induced by the exogenous carcinogen. Semi-quantitative RT-PCR revealed reduced expression of TGF-betaRII in 2 HCCs (16.7%) without Smad2 mutations out of 12 HCCs induced by the CDAA diet and none of 11 induced by DEN. These results suggest that the TGF-beta signaling pathway may be disturbed in endogenous liver carcinogenesis in rats.
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PMID:Alterations of the transforming growth factor-beta signaling pathway in hepatocellular carcinomas induced endogenously and exogenously in rats. 1117 39

Pancreatic ductal adenocarcinoma has been reported to carry a rate mutation high in codon 12 of the K-ras oncogene. To avoid the pitfalls of conventional methods of tissue dissection that might affect the sensitivity and specificity of detecting K-ras mutation, laser capture microdissection (LCM) technique was used. Pancreatic adenocarcinoma tissues were obtained from 15 patients who underwent Whipple's procedure. Selected tissues procured by LCM were analyzed by direct sequencing after polymerase chain reaction amplification of K-ras sequences at codon 12. K-ras mutation was noted in nine patients. All mutations showed G to A substitution at codon 12. The mutational pattern (GGT to GAT) is similar in both western and eastern reports. LCM is a feasible method to effectively obtain pure tumor cells from a surgical specimen. It remains to be determined whether this low mutation rate is a result of relatively early stage of disease or different carcinogenesis in different geographic regions.
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PMID:K-ras mutation at codon 12 in stage I pancreatic adenocarcinoma: analysis by laser capture microdissection and direct sequencing. 1143 18

Point mutations of c-K-ras in ovarian cancer were detected by replacement of GGT of codon 12 by GAT, AGT, TGT and GTT, polymerase chain reaction, agarose gel electrophoresis and Southern blot hybridization with a digoxigenin detection system. The incidence of four-typed point mutations of c-K-ras oncogene in 37 ovarian cancers was 35.1% (13/37) and the distributions were 32.4% (12/37), 2.7% (1/37), 0% and 0% of GGT to GAT, GGT to AGT, GGT to TGT, and GGT to GTT, respectively. The incidence of c-K-ras point mutations on codon 12 among 37 patients with ovarian cancer was 35.5% (8/22) in those with serous cystadenocarcinomas and 28.6% (2/7) in those with mucinous cystadenocarcinomas. c-K-ras point mutations on codon 12 were detected in 14.3% (1/7) of patients with stage I disease, 28.6% (2/7) with stage II disease, and in 43.5% (10/23) with stage III/IV disease, and there was a statistically significant increase in point mutations of c-K-ras oncogene with advancing clinical stage. The incidence of c-K-ras point mutations on codon 12 among 33 patients who had a pelvic lymph node dissection was 52.4% (11/21) in those with pelvic lymph node metastases and 16.7% (2/12) in those without pelvic lymph node metastases, a statistically significant difference. Furthermore, point mutation of c-K-ras gene was found most frequently in patients with advanced stage disease, and in those with pelvic lymph node metastases. Activation of c-K-ras oncogene seems to be a major factor in ovarian carcinogenesis and tumor progression.
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PMID:Detection of c-K-ras point mutation in ovarian cancer. 1157 63

Although the effects of polychlorinated biphenyls (PCBs) on human lung carcinogenesis are suggested from the massive PCBs poisoning that occurred in Japan designated "Yusho," the detailed molecular mechanism are unknown. 1 nitropyrene (1-NP), an ubiquitous and abundant environmental pollutant, is known to be detected in lung tissues derived from patients with lung cancer in Japan, and its relation to lung carcinogenesis is also suggested. We investigated the effects of PCBs (Kanechlor-400) on 1-NP-induced lung tumorigenesis in A/J mice. PCBs were administered intraperitoneally followed by ip injection of 1-NP. The lung lesions were examined 18 weeks after the final treatment. In the control group, no neoplastic lesions were induced in the lung. In the PCB group, preneoplastic lesions such as hyperplasia and adenoma were induced in 2/10 (20%) mice. In 1-NP group and in PCB + 1-NP group, lung lesions including adenocarcinoma were induced in 16/20 (80%) and 13/13 (100%) mice, respectively. Both the number and the size of tumors in PCB + 1-NP group were significantly greater than those in 1-NP group. K-ras gene mutation, CAA to CGA in codon 61 or GGT to GAT in codon 12, was found in either 1-NP group or PCB + 1-NP group but not in the PCB group. There was no difference in the pattern of K-ras mutation associated with the pretreatment with PCBs. These results suggest that PCBs promote 1-NP-induced lung tumorigenesis and may support, at least in part, the mechanism of the high incidence of lung cancer in patients with Yusho.
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PMID:Polychlorinated biphenyls promote 1-nitropyrene-induced lung tumorigenesis without the induction of K-ras gene mutation in A/J mice. 1174 53

Occupational exposure to hydrocarbon solvents has been found to be associated with an increased risk of exocrine pancreatic cancer (EPC), the human tumor with the highest prevalence of K-ras mutations. Ras genes are critical DNA targets for chemical carcinogens. We analysed the relationship between past occupational exposure to hydrocarbon solvents and mutations in codon 12 of the K-ras gene in 107 incident cases of EPC. Information on occupational factors and life-style was obtained from personal interviews conducted during hospital stay. Occupational exposure to hydrocarbon solvents (aliphatic, aromatic, chlorinated, benzene, other organic solvents) was examined using two methods: expert assessment and the Finnish job-exposure matrix (Finjem). Exposure among K-ras mutated EPC cases (n = 83) was compared with that of K-ras wild-type EPC cases (n = 24). An association between K-ras mutations and solvent exposure was observed with Finjem but barely so with the expert assessment. Over 7-fold increased odds ratios (OR) were found for every group of solvents evaluated with Finjem (all P < 0.05). On the basis of the expert assessment, K-ras mutations were significantly associated only with exposure to benzene in men (OR = 7.07, P < 0.05). When requiring exposure to have occurred according to both the experts and Finjem, over 4-fold risks were obtained for aromatic, aliphatic, and for "any hydrocarbon solvent". A significantly higher proportion of cases with a mutation from glycine to valine (GGT-->GTT) or to aspartic acid (GGT-->GAT) were exposed to a hydrocarbon solvent. The results raise the possibility that hydrocarbon solvents might be involved in the pathogenesis of EPC, possibly through indirect modulation of K-ras activation. Since this is only the first study on occupational exposures and K-ras mutations in EPC, studies able to refute or to confirm the findings are required before public health implications, if any, are assessed.
Carcinogenesis 2002 Jan
PMID:Occupational exposure to organic solvents and K-ras mutations in exocrine pancreatic cancer. 1175 30

The feasibility of histochemical detection of GGT activity in decalcified bone tissue is proved and the activity distribution pattern of GGT in normal rat cartilage and bone is described. The results suggest the association, in this model, between GGT activity and differentiation mechanisms rather than proliferative processes. The fact that GGT activity in adult tissues which are normally GGT negative has been linked to premalignant transformation confers significance to the study of GGT activity in normal tissues. The results contribute to the knowledge of the biological mechanisms in which GGT activity is involved and to the understanding of the behaviour of tissues which can be used as controls in carcinogenesis models.
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PMID:Histochemical demonstration of gamma-glutamyl transpeptidase activity in normal rat cartilage and bone. 1188 63


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