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Ras Gene Mutations (ras + gene_mutation)
Selected AbstractsLack of association between BRAF V600E mutation and mitogen-activated protein kinase activation in papillary thyroid carcinomaPATHOLOGY INTERNATIONAL, Issue 1 2007Hui Zuo The BRAF V600E mutation has been identified in a high proportion of papillary thyroid carcinoma (PTC). In cell lines and a transgenic mouse model it has been demonstrated that the mutation constitutively activates the mitogen-activated protein kinase (MAPK) pathway but in human PTC samples its effects remain unexamined. Herein the correlation of BRAF mutation and MAPK activation was examined in 42 human PTC samples. Activating mutations of the BRAF gene and all three RAS genes were detected by polymerase chain reaction-direct sequencing, and RET/PTC1 rearrangements were screened by nested reverse transcription,polymerase chain reaction. MAPK activation was assessed by immunohistochemistry and western blot analysis. Twenty-eight cases (66.7%) of BRAF V600E mutation, three cases (7.1%) of RET/PTC1 rearrangement but no cases of RAS genes mutation were identified. Activated MAPK was found in six cases (14.3%) with only two cases of mutant BRAF. In total 7.1% of PTC with BRAF mutation had activated MAPK. Furthermore, BRAF mutations were more prevalent in patients 0e;45 years, but did not correlate with aggressive clinical behaviors. Absence of association between BRAF mutation and activation of MAPK pathway in PTC suggests the presence of mechanisms that downregulate MAPK activation. [source] Relevance of Ras gene mutations in the context of the molecular heterogeneity of multiple myelomaHEMATOLOGICAL ONCOLOGY, Issue 1 2007Daniela Intini Abstract Ras gene mutations are a recurrent genetic lesion in multiple myeloma (MM). Here, we report a mutation analysis of N- and K- Ras genes in purified plasma cell populations from a panel of 81 newly diagnosed MM patients stratified according to the most frequent genetic and molecular features associated with the neoplasia. Ras gene mutations, mostly involving the N- Ras gene, were detected in 20% of the patients. Ras mutations did not correlate with the presence of chromosome 13q deletion, trisomy of chromosome 11, 1q amplification or hyperdiploidy. In addition, despite an appreciable association with tumours overexpressing Cyclin D1, Ras mutations did not correlate at significant levels with any of the proposed groups in the TC classification, based on the presence of the major IgH chromosomal translocations and expression of Cyclin D genes. Finally, transcription analyses revealed the presence of differentially expressed transcripts in human multiple myeloma cell lines carrying the Ras gene mutations but not in primary tumours. Overall, these data suggest that Ras gene mutations are not likely to represent a master lesion in MM but its relevance needs to be considered in the context of other genetic abnormalities. Copyright © 2006 John Wiley & Sons, Ltd. [source] Induction of cytotoxicity in human lung adenocarcinoma cells by 6- O -carboxypropyl-,-tocotrienol, a redox-silent derivative of ,-tocotrienolINTERNATIONAL JOURNAL OF CANCER, Issue 5 2005Yoshihisa Yano Abstract Tocotrienols are one of the most potent anticancer agents of all natural compounds and the anticancer property may be related to the inactivation of Ras family molecules. The anticancer potential of tocotrienols, however, is weakened due to its short elimination half life in vivo. To overcome the disadvantage and reinforce the anticancer activity in tocotrienols, we synthesized a redox-silent analogue of ,-tocotrienol (T3), 6- O -carboxypropyl-,-tocotrienol (T3E). We estimated the possibility of T3E as a new anticancer agent against lung adenocarcinoma showing poor prognosis based on the mutation of ras gene. T3E showed cytotoxicity against A549 cells, a human lung adenocarcinoma cell line with a ras gene mutation, in a dose-dependent manner (0,40 ,M), whereas T3 and a redox-silent analogue of ,-tocopherol (T), 6- O -carboxypropyl-,-tocopherol (TE), showed much less cytotoxicity in cells within 40 ,M. T3E cytotoxicity was based on the accumulation of cells in the G1-phase of the cell-cycle and the subsequent induction of apoptosis. Similar to this event, 24-hr treatment of A549 cells with 40 ,M T3E caused the inhibition of Ras farnesylation, and a marked decrease in the levels of cyclin D required for G1/S progression in the cell-cycle and Bcl-xL, a key anti-apoptotic molecule. Moreover, the T3E-dependent inhibition of RhoA geranyl-geranylation is an inducing factor for the occurrence of apoptosis in A549 cells. Our results suggest that T3E suppresses Ras and RhoA prenylation, leading to negative growth control against A549 cells. In conclusion, a redox-silent analogue of T3, T3E may be a new candidate as an anticancer agent against lung adenocarcinoma showing poor prognosis based on the mutation of ras genes. © 2005 Wiley-Liss, Inc. [source] p53 expression, K- ras gene mutation and microsatellite instability in gastric B-cell lymphomasJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 9 2003TORU HIYAMA Abstract Background and Aims:, Genetic mechanisms involved in the development of gastric B-cell lymphomas remain unclear. The aim of the present study was to clarify the roles of mutations of the p53 and K- ras genes, and microsatellite instability (MSI) in the development of gastric B-cell lymphomas. Methods:, We investigated p53 immunoreactivity, mutations of the K- ras gene, and MSI in 27 gastric marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue type (MZBCL) and 24 diffuse large B-cell lymphomas (DLBCL). p53 immunoreactivity was examined using a monoclonal antibody, DO-7. Mutation of the K- ras gene was detected by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. MSI was examined at five microsatellite loci with a microsatellite assay. Cases were classified as having high-frequency MSI (MSI-H) (, 2 loci showing instability), low-frequency MSI (MSI-L) (only one locus showing instability), or as microsatellite stable. Results:, p53 immunoreactivity was detected in 1 of 16 (6%) MZBCL and 8 of 19 (42%) DLBCL. Frequency of p53 immunoreactivity in DLBCL was significantly higher than that in MZBCL (P = 0.018). MSI-H was detected only in 1 of 20 (5%) DLBCL. None of the cases examined showed mutation of the K- ras gene. Conclusions:, These data suggest that mutations of the p53 gene may play an important role in the development of gastric DLBCL, and that mutations of the K- ras gene and MSI may be involved in little part of the development of gastric B-cell lymphomas. [source] Characterization of Hprt mutations in cDNA and genomic DNA of T-cell mutants from control and 1,3-butadiene-exposed male B6C3F1 mice and F344 ratsENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 2 2004Quanxin Meng Abstract A multiplex PCR procedure for analysis of genomic DNA mutations in the mouse hypoxanthine-guanine phosphoribosyltransferase (Hprt) gene was developed and then used with other established methods for the coincident identification of large- and small-scale genetic alterations in the Hprt gene of mutant T-cell isolates propagated from sham- and 1,3-butadiene (BD)-exposed mice and rats. The spectra data for RT-PCR/cDNA analysis and multiplex PCR of genomic DNA from Hprt mutants were combined, and statistical analyses of the mutant fractions for the classes of mutations identified in control versus exposed animals were conducted. Under the assumption that the mutant fractions are distributed as Poisson variates, BD exposure of mice significantly increased the frequencies of (1) nearly all types of base substitutions; (2) single-base deletions and insertions; and (3) all subcategories of deletions. Significantly elevated fractions of G:C,C:G and A:T,T:A transversions in the Hprt gene of BD-exposed mice were consistent with the occurrence of these substitutions as the predominant ras gene mutations in multiple tumor types increased in incidence in carcinogenicity studies of BD in mice. BD exposure of rats produced significant increases in (1) base substitutions only at A:T base pairs; (2) single-base insertions; (3) complex mutations; and (4) deletions (mainly 5, partial and complete gene deletions). Future coincident analyses of large- and small-scale mutations in rodents exposed to specific BD metabolites should help identify species differences in the sources of deletion mutations and other types of mutations induced by BD exposures in mice versus rats. Environ. Mol. Mutagen. 43:75,92, 2004. © 2004 Wiley-Liss, Inc. [source] | ||||||||||