Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ras signaling pathway controls important cellular responses to growth factors, and somatic mutations in RAS genes and other components of the Ras pathway, such as PTPN11 (encoding the protein-tyrosine phosphatase SHP-2) and BRAF, are found in human malignancies. Ras proteins are guanosine nucleotide-binding proteins that cycle between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound conformations. Neoplasia-associated Ras mutations frequently affect amino acids G12, G13, or Q61 and decrease the intrinsic guanosine triphosphatase (GTPase) activity by ten- to twentyfold. The GTPase activity is crucial for Ras inactivation by hydrolysis and release of a phosphate group from Ras.GTP to produce Ras.GDP. We and others have recently discovered germline mutations in the KRAS gene in individuals diagnosed with Noonan and cardio-facio-cutaneous (CFC) syndrome, two clinically overlapping disorders characterized by short stature, distinct facial anomalies, heart defects, and other abnormalities. Noonan syndrome-associated mutations V14I and T58I K-Ras activate Ras but have milder biochemical effects than somatic mutations encountered in cancers, offering an explanation why these K-Ras lesions are tolerated during embryonic development. Together with recent findings of BRAF, MEK1, and MEK2 mutations in CFC syndrome and HRAS mutations in Costello syndrome, another clinically related disorder, it has now become clear that Noonan-like features (short stature, relative macrocephaly, facial anomalies, learning difficulties) that are found in these three related disorders are a result of constitutive activation of the Ras-Raf-extracellular signal-regulated and mitogen-activated protein kinase pathway.
J Mol Med (Berl) 2007 Mar
PMID:An unexpected new role of mutant Ras: perturbation of human embryonic development. 1721 12

Constitutive activation of the phosphatidylinositol-3-OH kinase (PI3K) and RAS signaling pathways are important events in tumor formation. This is illustrated by the frequent genetic alteration of several key players from these pathways in a wide variety of human cancers. Here, we report a detailed sequence analysis of the PTEN, PIK3CA, KRAS, HRAS, NRAS, and BRAF genes in a collection of 40 human breast cancer cell lines. We identified a surprisingly large proportion of cell lines with mutations in the PI3K or RAS pathways (54% and 25%, respectively), with mutants for each of the six genes. The PIK3CA, KRAS, and BRAF mutation spectra of the breast cancer cell lines were similar to those of colorectal cancers. Unlike in colorectal cancers, however, mutational activation of the PI3K pathway was mutually exclusive with mutational activation of the RAS pathway in all but 1 of 30 mutant breast cancer cell lines (P = 0.001). These results suggest that there is a fine distinction between the signaling activators and downstream effectors of the oncogenic PI3K and RAS pathways in breast epithelium and those in other tissues.
Mol Cancer Res 2007 Feb
PMID:Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines. 1731 76

Colorectal cancer patients with lymph node metastasis have a shorter survival and may require adjuvant therapy after surgery of the primary tumor. It is supposed that a more reliable diagnosis can be achieved using tumor-specific DNA mutations for the detection of metastasizing cells. To design a practical approach for a molecular diagnosis of micrometastasis, we applied direct DNA sequencing to screen 48 early stage colorectal carcinomas for the most frequent mutations of the KRAS, P53, and APC tumor genes. KRAS mutations were detected as frequently as described earlier. In contrast, the frequency of P53 and APC hot spot mutations was unexpectedly low, compared with previous studies using other screening methods or including advanced tumor stages. Not more than 31% of early stage tumors showed a mutation in at least 1 of the selected hot spot codons. Applying mutant-enriched polymerase chain reaction (PCR), the mutation of the primary tumor was detected in lymph node DNA from 2 of the KRAS-positive patients. In 1 patient, the result was not verified by subtractive iterative PCR, a principally different molecular method with high sensitivity and specificity. Our data suggest that screening for suitable markers for a molecular detection of occult lymph node metastasis cannot be restricted to small-sized hot spot regions of a few tumor genes and possibly must include tumor-specific epigenetic changes. Furthermore, restriction enzyme-based methods such as mutant-enriched PCR are not suitable to detect any mutation with equal efficiency and they should be carefully controlled to avoid false-positive detection of marker mutations in lymph node DNA.
Diagn Mol Pathol 2007 Jun
PMID:Limitations in molecular detection of lymph node micrometastasis from colorectal cancer. 1752 78

The CpG island methylator phenotype (CIMP or CIMP-high) with extensive promoter methylation is a distinct phenotype in colorectal cancer. However, a choice of markers for CIMP has been controversial. A recent extensive investigation has selected five methylation markers (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1) as surrogate markers for epigenomic aberrations in tumor. The use of these markers as a CIMP-specific panel needs to be validated by an independent, large dataset. Using MethyLight assays on 920 colorectal cancers from two large prospective cohort studies, we quantified DNA methylation in eight CIMP-specific markers [the above five plus CDKN2A (p16), CRABP1, and MLH1]. A CIMP-high cutoff was set at > or = 6/8 or > or = 5/8 methylated promoters, based on tumor distribution and BRAF/KRAS mutation frequencies. All but two very specific markers [MLH1 (98% specific) and SOCS1 (93% specific)] demonstrated > or = 85% sensitivity and > or = 80% specificity, indicating overall good concordance in methylation patterns and good performance of these markers. Based on sensitivity, specificity, and false positives and negatives, the eight markers were ranked in order as: RUNX3, CACNA1G, IGF2, MLH1, NEUROG1, CRABP1, SOCS1, and CDKN2A. In conclusion, a panel of markers including at least RUNX3, CACNA1G, IGF2, and MLH1 can serve as a sensitive and specific marker panel for CIMP-high.
J Mol Diagn 2007 Jul
PMID:Evaluation of markers for CpG island methylator phenotype (CIMP) in colorectal cancer by a large population-based sample. 1759 25

Somatic mutations in the epidermal growth factor receptor gene (EGFR) are detected in a subset of lung adenocarcinomas, particularly bronchioloalveolar carcinoma (BAC) and adenocarcinoma with bronchioloalveolar features (AWBF), and correlate with clinical response to tyrosine kinase inhibitors (TKIs). In contrast, lung adenocarcinomas refractory to TKIs often have activating mutations in KRAS but lack EGFR mutations. Some adenocarcinomas have mucinous histology, but the clinical and molecular significance of the mucinous pattern is less well studied. We analyzed 43 BAC and AWBF tumors submitted for EGFR mutation testing to identify histopathological features that predicted EGFR or KRAS mutations. EGFR mutations were detected in 14 of 30 (47%) nonmucinous tumors, whereas 0 of 13 mucinous tumors harbored an EGFR mutation (P = 0.003). Missense mutations in KRAS codon 12 were detected in six of seven (86%) mucinous adenocarcinomas but only 3 of 18 (17%) nonmucinous adenocarcinomas (P = 0.003). Thus, in BAC/AWBF mucinous differentiation was significantly correlated with the absence of EGFR mutation and presence of KRAS mutation, suggesting that mucinous BACs/AWBFs are unlikely to respond to TKIs. Therefore, our data suggest that EGFR sequence analysis could be avoided in BAC/AWBF when true mucinous morphology is identified, avoiding the associated testing costs.
J Mol Diagn 2007 Jul
PMID:Mucinous differentiation correlates with absence of EGFR mutation and presence of KRAS mutation in lung adenocarcinomas with bronchioloalveolar features. 1759 31

Germ line missense mutations in HRAS and KRAS and in genes encoding molecules that function up- or downstream of Ras in cellular signaling networks cause a group of related developmental disorders that includes Costello syndrome, Noonan syndrome, and cardiofaciocutaneous syndrome. We performed detailed biochemical and functional studies of three mutant K-Ras proteins (P34R, D153V, and F156L) found in individuals with Noonan syndrome and cardiofaciocutaneous syndrome. Mutant K-Ras proteins demonstrate a range of gain-of-function effects in different cell types, and biochemical analysis supports the idea that the intrinsic Ras guanosine nucleotide triphosphatase (GTPase) activity, the responsiveness of these proteins to GTPase-activating proteins, and guanine nucleotide dissociation all regulate developmental programs in vivo.
Mol Cell Biol 2007 Nov
PMID:Biochemical and functional characterization of germ line KRAS mutations. 1787 37

Understanding the risk of offspring inheriting rare mutations, and the frequencies at which these mutations are present in germ cells can be explored with direct analysis of human semen samples. The present work utilized the ultrasensitive PCR/RE/LCR mutation assay to detect, identify and determine the prevalence single base substitution mutations in the TP53 and KRAS genes in human sperm. Four disease-associated base sites in the TP53 and KRAS genes, three of which are known to be heritable to live, term offspring, were studied in sperm from eleven human semen specimens. Eight of the specimens (73%) displayed single base substitution mutations, and 30% of all base sites tested were found to harbor mutations ranging in prevalence from 1 x 10(-6) to 1 x 10(-5) wild type sperm. These germ cell single base substitution mutation frequencies are very similar to somatic tissue TP53 and KRAS mutation frequencies. Equivalent single base mutation frequencies in both germ and somatic cells suggest that there is no unusual selection or mutation protective process operating premeiotically in the germline, and that a selection bias at the level of sperm viability, conception, early cleavage, implantation, and/or embryogenesis operates to exclude the majority of these TP53 mutations and all of the activating KRAS mutations.
Environ Mol Mutagen 2008 Jul
PMID:Human germline and somatic cells have similar TP53 and Kirsten-RAS gene single base mutation frequencies. 1841 64

The panel of 60 human cancer cell lines (the NCI-60) assembled by the National Cancer Institute for anticancer drug discovery is a widely used resource. We previously sequenced 24 cancer genes in those cell lines. Eleven of the genes were found to be mutated in three or more of the lines. Using a pharmacogenomic approach, we analyzed the relationship between drug activity and mutations in those 11 genes (APC, RB1, KRAS, NRAS, BRAF, PIK3CA, PTEN, STK11, MADH4, TP53, and CDKN2A). That analysis identified an association between mutation in BRAF and the antiproliferative potential of phenothiazine compounds. Phenothiazines have been used as antipsychotics and as adjunct antiemetics during cancer chemotherapy and more recently have been reported to have anticancer properties. However, to date, the anticancer mechanism of action of phenothiazines has not been elucidated. To follow up on the initial pharmacologic observations in the NCI-60 screen, we did pharmacologic experiments on 11 of the NCI-60 cell lines and, prospectively, on an additional 24 lines. The studies provide evidence that BRAF mutation (codon 600) in melanoma as opposed to RAS mutation is predictive of an increase in sensitivity to phenothiazines as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay (Wilcoxon P = 0.007). That pattern of increased sensitivity to phenothiazines based on the presence of codon 600 BRAF mutation may be unique to melanomas, as we do not observe it in a panel of colorectal cancers. The findings reported here have potential implications for the use of phenothiazines in the treatment of V600E BRAF mutant melanoma.
Mol Cancer Ther 2008 Jun
PMID:In vitro differential sensitivity of melanomas to phenothiazines is based on the presence of codon 600 BRAF mutation. 1852 47

This commentary highlights a novel assay for detection of mutations in KRAS, which have recently emerged as a useful negative predictive biomarker.
J Mol Diagn 2008 Nov
PMID:KRAS mutations: an old oncogene becomes a new predictive biomarker. 1883 58

Previously, the smart amplification process version 2 (SMAP-2) was developed to detect mutations from tissue and in crude cell lysates and has been used for rapid diagnosis of specific somatic mutations with single-nucleotide precision. The purpose of this study was to develop a rapid and practical method to detect cancer and metastasis in specimens using the SMAP-2 assay. We developed modified SMAP-2 assays that enabled detection of any change in a single codon using a single assay. Rapid SMAP-2 screening assays are suitable for routine clinical identification of critical amino acid substitutions such as codon 12 mutations in KRAS. Primers bracketing the first two nucleotides of KRAS codon 12 were designed so that all possible alleles would be amplified by the SMAP-2 assay. In combination with the peptide nucleic acid (PNA) with exact homology to the wild-type allele, our assay amplified all mutant alleles except for the wild-type sequence. With this new assay design (termed PNA-clamp SMAP-2), we could detect KRAS mutations within 60 minutes, including sample preparation. We compared results from PNA-clamp SMAP-2 assay, polymerase chain reaction-restriction fragment length polymorphism, and direct sequencing of clinical samples from pancreatic cancer patients and demonstrated perfect concordance. The PNA-clamp SMAP-2 method is a rapid, simple, and highly sensitive detection assay for cancer mutations.
J Mol Diagn 2008 Nov
PMID:Rapid screening assay for KRAS mutations by the modified smart amplification process. 1883 61


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>