Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to clarify genetic changes in flat adenomas, K-ras codon 12 point mutations were examined in 56 flat adenomas, 81 polypoid adenomas and 42 cancers of colon and rectum. The mutation frequency in flat adenomas was 23% (13/56), significantly lower than that in polypoid adenomas (67%: 54/81) and cancers (76%: 32/42). Even mildly dysplastic adenomas or small (less than 5 mm) adenomas showed higher mutation incidence in polypoid type (62%, 57%) than in flat type (23%, 19%). Among flat adenomas, flat elevated lesions exhibited relatively higher mutation frequency than completely flat or depressed ones. As for cancers, 14 tumors (33%) contained mutations only in a minor tumor cell population, indicating that these mutations occur at a late stage of tumorigenesis. These results suggest that the adenoma-carcinoma sequence through flat adenomas may be different from that through polypoid adenomas, and genetic changes may be heterogeneous in colorectal carcinogenesis.
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PMID:Lower incidence of K-ras codon 12 mutation in flat colorectal adenomas than in polypoid adenomas. 814 96

Molecular mechanisms of pituitary tumorigenesis were studied using Polymerase chain reaction-single stranded conformational polymorphism with DNA sequencing to identify potential mutations in the ras protooncogenes and the tumor suppressor gene p53 in invasive pituitary adenomas and carcinomas. Sequencing of exons 5 through 8 of the p53 gene revealed no mutations, nor were mutations detected in the N- or K-ras protooncogenes in four of the carcinomas and their respective metastatic deposits. Point mutations of H-ras however, were identified in three distant metastatic pituitary tumor secondaries, but not in their respective primary pituitary carcinomas, or in six invasive adenomas. Two of the mutations included a G to C substitution at codon 12, and a G to A substitution at codon 18, resulting in a glycine to arginine, and an alanine to threonine change at these amino acids, respectively. A third mutation involved a single base pair (adenine) deletion in codon 3 of H-ras which causes a frame shift, resulting in a termination signal at codon 19. These results suggest that point mutations in p53 and ras are not associated with pituitary tumorigenesis, however, point mutations of the H-ras gene may be important in the formation and or growth of pituitary metastases. This observed genomic instability will be of value in predicting the potential metastatic behavior of these aggressive pituitary tumors.
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PMID:H-ras mutations in human pituitary carcinoma metastases. 815 9

Clinicopathological evidence is accumulating that a superficial-type (flat) colorectal tumor is a distinct neoplastic entity. To clarify the genetic characteristics of this tumor, we investigated the K-ras gene mutations and morphological features of 43 tumors of this type. A mutation of the K-ras codon 12 was detected in only 5 (16%) of 31 adenomas and 2 (17%) of 12 adenocarcinomas. The presence or absence of this mutation was not correlated with the tumor size or stage or with histopathological findings. None of these tumors had a mutation in codon 13 or exon 2, including codon 61. This low incidence of K-ras mutations (16%) suggests that superficial-type colorectal tumors are etiologically distinct from ordinary colorectal polypoid tumors and that there may be an alternative pathway of colorectal tumorigenesis.
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PMID:Infrequent K-ras activation in superficial-type (flat) colorectal adenomas and adenocarcinomas. 818 64

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.
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PMID:K-ras mutations in aberrant crypt foci, adenomas and adenocarcinomas during azoxymethane-induced colon carcinogenesis. 840 99

In order to identify relevant genetic lesions in gastric carcinoma, we searched for tumor suppressor gene inactivation and K-ras gene mutations by analyzing tumor and control DNAs from 34 patients. These were from an epidemiologically defined area of Italy characterized by one of the world's highest incidences of stomach cancer. Allele losses were investigated by the Southern blotting procedure at 16 polymorphic loci on 11 different chromosomes. Our data demonstrate that chromosomal regions 5q, 11p, 17p and 18q are frequently deleted, and that 7q and 13q chromosome arms are also involved, although at a lower frequency. Loss of heterozygosity (LOH) at region 11p was not found during other surveys carried out on patients of different geographic origins. No specific combination of allelic losses could be recognized in the samples analyzed, the only exception being that tumors with 17p allelic loss also showed LOH on the 18q region. When matching frequent LOH events and the stage of progression of the tumors, we observed a trend of association between advanced stages and allelic losses on 17p and 18q chromosome arms. The analysis of K-ras, carried out by the polymerase chain reaction and denaturing gradient gel electrophoresis, demonstrated transforming mutations in only 3 out of 32 cases. Colorectal tumorigenesis proceeds by the accumulation of genetic alterations, including K-ras mutations and inactivation of tumor suppressor genes on the 5q, 17p and 18q regions. Our data indicate that, although gastric and colorectal neoplasias share common genetic alterations, they probably progress through different pathways.
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PMID:Loss of heterozygosity and K-ras gene mutations in gastric cancer. 840 32

We had studied the histogenesis and p21 expression in ovarian tumor induced by 7,12-dimethylbenz(a)anthracene (DMBA). The present study was done to elucidate point mutation of the ras gene in tumors. Cases with immunohistological p21 expression; 3 adenomas, 5 adenocarcinomas and 2 sarcomas were examined by polymerase chain reaction (PCR). 1) The products of PCR were confirmed the presence of amplified sequences by electrophoresis. 2) No point mutation of H-ras (Codon 12,61) or K-ras (Codon 12,61) genes was found in the ovarian tumors induced by DMBA. 3) These results suggested that the mutational activation of ras genes in tumorigenesis was dependent on another mechanism.
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PMID:[Mutational activation of H-ras and K-ras (Codon 12,61) genes in 7,12 dimethylbenz(a)anthracene induced rat ovarian tumors]. 842 45

The H-ras-1 protooncogene is activated by single base substitutions occurring in either codon 12, 13, or 61. These mutations have been described with varying frequencies in several human tumor types. Since ras oncogenes were first discovered as the transforming sequences of Harvey and Kirsten murine sarcoma viruses (which also contain activating point mutations compared to the homologous cellular sequences), we wished to investigate the possibility that ras mutations might also occur in human sarcomas. We extracted DNA from six malignant fibrous histiocytomas (MFH), three embryonal rhabdomyosarcomas (ER), one alveolar rhabdomyosarcoma, one pleomorphic rhabdomyosarcoma, and one leiomyosarcoma. The DNA from regions flanking codons 12/13 and codon 61 was amplified by the polymerase chain reaction and sequenced with an automated DNA sequencer. As controls, we amplified and sequenced normal DNA (placenta) and DNA with known point mutations (T24 bladder carcinoma cells). We found three cases with mutations, all occurring in codon 12. One ER showed a G-to-T mutation in the second position of codon 12 (coding for valine instead of glycine). Two MFHs showed G-to-A mutations in the second position of codon 12 (coding for aspartic acid instead of glycine). Although a limited number of cases were sampled, we conclude that study of H-ras-1 mutations may be relevant to MFH and ER. Additional studies of N and K-ras mutations as well as more cases investigating H-ras will be required before we can ascertain the significance of ras mutations in the oncogenesis of human soft tissue sarcomas.
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PMID:H-ras-1 point mutations in soft tissue sarcomas. 848 82

To elucidate genetic alteration in relation to morphology and also to confirm more directly the proposed adenoma-carcinoma sequence, we analyzed thirty-eight colorectal "cancer in adenoma" lesions exhibiting areas of different atypia, in terms of K-ras codon 12 point mutation. The mutation incidence was 26.3% (10/38) for all cancerous areas. Well-differentiated and very well-differentiated carcinoma exhibited values of 17.6% (3/17) and 30.4% (7/23), respectively (statistically not significant). Positive cases of adenoma with severe atypia and adenoma with moderate or slight atypia were 26.7% (8/30) and 8.3% (3/36) respectively (statistically significant). Thus, K-ras point mutation, as indicated previously, may play an important role in the early stages of colorectal tumorigenesis. As for the nature of the mutation, GGT(Gly) to GAT(Asp) was the most frequent (80%). Eight cases had mutations concurrently in different areas of the same tumor and in all of these the mutation was homogeneous (6 cases to GAT, 1 case to TGT and 1 case to GTT). This provides genetic support for the "adenoma-carcinoma sequence" theory proposed on the basis of morphological considerations. All lesions with a mutation were of polypoid type, and no mutation was found in the flat type.
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PMID:Variation in K-ras codon 12 point mutation rate with histological atypia within individual colorectal tumors. 851 5

Point mutations of the K-ras gene were analyzed in 25 periampullary cancers (21 ampulla vater cancers, two common bile duct cancers and two duodenal cancers), two gallbladder cancers and six cholangiocarcinomas. DNA extracted from the paraffin-embedded tissues was amplified with the polymerase chain reaction and subsequently analyzed by direct cycle sequencing at codons 12, 13 and 18 of the K-ras gene. Codon 61 was first screened with single strand conformation polymorphism and then sequenced by direct cycle sequencing. No point mutation was found in any of the 25 periampullary cancers or the two gallbladder cancers. These results are similar to previous reports. Mutation of the K-ras gene seems not to play an important role in tumorigenesis of periampullary cancer. In two of six (33%) cholangiocarcinoma patients, point mutations were found. Both mutations were transitions, GGT to GAT at codon 12. The incidence of mutation was greater than that in Thailand (about 8%) but less than that in Japan (about 60%). Mutation of the K-ras gene may play varied roles in the tumorigenesis of cholangiocarcinoma, depending on geographic area.
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PMID:Analysis of K-ras gene mutations in periampullary cancers, gallbladder cancers and cholangiocarcinomas from paraffin-embedded tissue sections. 854 32

The ras p21 proto-oncogenes (ie, K-ras, H-ras, N-ras) encode a family of proteins vital to cellular signaling and function. Point mutations in these genes have been found in a wide diversity of human cancers, suggesting a strong association in the development of the malignant phenotype. Although the precise mechanisms leading to tumorigenesis are not fully understood, it has been proposed that point mutations in the ras p21 proto-oncogenes contribute to the transformation process through constitutive transduction of growth-promoting signals. These oncoproteins are distinct from normal ras p21 in both DNA and protein sequences at specific sites, typically positions 12, 13, 59, or 61. A large frequency of human cancers harbor point mutations in the ras gene at codon 12, where the normal Gly residue is substituted with either a Val, Asp or Cys residue. From an immunologic perspective, these "neo-determinants" may now represent unique and highly specific epitopes for T cell (CD4+ and/or CD8+) recognition in cancer immunotherapy. Evaluation of point-mutated ras as a T-cell epitope could be determined biologically with short synthetic peptides that precisely mimic those altered sites. Several laboratories have established approaches in both murine and human systems to evaluate the point-mutated ras p21 oncogene product as a potential tumor-specific target and characterization of the resulting cellular immune responses. It has been demonstrated that (1) active immunization of mice with the appropriate mutant protein or peptides leads to the production of cytotoxic CD4+ (Th1 subtype) or CD8+ T lymphocytes, which mediate MHC-restricted, antigen-specific lysis of tumor cells in vitro bearing endogenous mutant ras epitopes; and (2) in vitro stimulation of human lymphocytes from some normal individuals or carcinoma patients with mutant ras peptides results in the expansion of CD4+ and CD8+ precursors, which may exhibit cytotoxicity against autologous or MHC-matched, antigen-bearing target cells. Taken collectively, these preclinical findings provide the rationale for the development of potential immunotherapies directed against point-mutated ras oncogene products.
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PMID:Mutant ras epitopes as targets for cancer vaccines. 860 22


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