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At least 163 records · Page 9Linked to original sources
PubMed1989

Activated N-ras oncogenes in human neuroblastoma.

Fifteen primary neuroblastomas and four bone marrow samples from neuroblastoma patients, representing clinical Stages I to IV, have been screened for mutations in codons 12, 13, and 61 of N-ras. Neuroblastoma DNAs were subjected to the polymerase chain reaction to amplify the relevant sequences and were then hybridized with specific oligonucleotides to locate and identify point mutations. The results show that one Stage I tumor contained an N-ras gene that was activated by a GC-CG transversion of the first base of codon 61, while in one Stage II tumor, activation of N-ras involved a GC-CG transversion of the first position of codon 13. N-ras activations were not detected in the six Stage III tumors and eight Stage IV tumors that were examined.

DNA, Neoplasm↗
PubMed2004

A new mixture model approach to analyzing allelic-loss data using Bayes factors.

BACKGROUND: Allelic-loss studies record data on the loss of genetic material in tumor tissue relative to normal tissue at various loci along the genome. As the deletion of a tumor suppressor gene can lead to tumor development, one objective of these studies is to determine which, if any, chromosome arms harbor tumor suppressor genes. RESULTS: We propose a large class of mixture models for describing the data, and we suggest using Bayes factors to select a reasonable model from the class in order to classify the chromosome arms. Bayes factors are especially useful in the case of testing that the number of components in a mixture model is n0 versus n1. In these cases, frequentist test statistics based on the likelihood ratio statistic have unknown distributions and are therefore not applicable. Our simulation study shows that Bayes factors favor the right model most of the time when tumor suppressor genes are present. When no tumor suppressor genes are present and background allelic-loss varies, the Bayes factors are often inconclusive, although this results in a markedly reduced false-positive rate compared to that of standard frequentist approaches. Application of our methods to three data sets of esophageal adenocarcinomas yields interesting differences from those results previously published. CONCLUSIONS: Our results indicate that Bayes factors are useful for analyzing allelic-loss data.

Adenocarcinoma↗
PubMed1989

Sodium butyrate suppresses the transforming activity of an activated N-ras oncogene in human colon carcinoma cells.

The transforming activity of DNA from a newly established undifferentiated human colon carcinoma cell line (MIP-101) was tested in the NIH-3T3 transfection assay. Southern blot analysis of the transfectant DNA revealed the presence of a human N-ras oncogene. Treatment of MIP-101 cells with the maturational agent sodium butyrate induced a more normal phenotype, including diminished growth rate, elimination of anchorage independent growth, and decreased tumorigenicity (R. Niles, S. Wilhelm, P. Thomas, and N. Zamcheck (1988) J. Cancer Invest. 6, 39). Here we report that there is a significant reduction in the transforming efficiency of the DNA from butyrate-treated MIP-101 cells. A nonspecific reduction in total DNA uptake as an explanation for these findings was eliminated by showing that there was similar uptake and expression of the thymidine kinase gene from the DNA of butyrate-treated and control MIP cells. Butyrate treatment had no detectable effect on the overall structure, methylation, and level of expression of the human N-ras gene from MIP-101 cells. An NIH-3T3 transformant ability after treatment with sodium butyrate. Although butyrate suppressed several transformed properties similar to MIP-101 cells, DNA from control and treated cultures had an identical level of transforming activity. The results suggest that the environment of the MIP cells may contain additional elements not present in the NIH-3T3 transformants which are required to observe the effect of butyrate on reduction of transforming activity.

Butyrates↗
PubMed1989

Ras oncogene mutation in multiple myeloma.

The frequency of ras (H-, K-, and N-ras) and c-myc oncogenes was investigated in multiple myeloma (MM). By means of the polymerase chain reaction (PCR)/oligonucleotide hybridization method, DNA from 56 tumor biopsies was analyzed for the presence of activating mutations involving codons 12 and 61 of the H-, K-, and N-ras genes and codon 13 of the N-ras gene. Mutations, involving the N- or K-ras genes, were detected in 18 of 56 (32%) cases of which 12/43 (27%) were at diagnosis and 6/13 (46%) were after treatment. In some cases, multiple mutations affecting different ras alleles were detected. Direct nucleotide sequence analysis of PCR products indicated that a more heterogeneous nature of the base pair changes than previously shown for other tumors along with a preferential involvement of N-ras codon 61. The heterogeneity of MM cases with respect to the presence of ras oncogenes prompted an analysis of possible correlations with different clinico-pathologic characteristics of MM from which a correlation between the presence of ras oncogenes and a partial or complete lack of response to therapy emerged. The frequency of activating rearrangements or mutations of the c-myc gene were studied by Southern blot analysis and PCR sequencing, respectively. However, contrary to previous reports involving mostly MM cell lines, no structural alterations of the c-myc gene were found. These results indicate that ras, but not c-myc, oncogenes are activated in vivo in MM cells, representing the first oncogene alteration that has been associated at appreciable frequency with this type of malignancy. While the mechanism of occurrence and biological role of ras activation in MM remains to be elucidated, the preliminary correlations observed in this study between the presence of ras oncogenes and poor therapeutic response suggest that further investigations of the possible prognostic significance of these alterations are necessary.

Base Sequence↗
PubMed1986

[Rearrangements of immunoglobulin and T-cell-antigen receptor genes as diagnostic markers in lymphatic neoplasms].

During recent years cloning of the genes encoding the immunoglobulin (Ig) and T-cell (TCR) antigen receptor has made it possible to analyze clonal expansions of B- or T-cells at the molecular level. We here describe the usefulness of the Ig- and TCR-gene rearrangements in selected cases of malignant lymphoma. In contrast to all other cases investigated, one non-Hodgkin's lymphoma (NHL) exhibited the infrequent phenomenon of oligoclonality, i.e. three distinct B-cell clones were discerned by Southern blot analysis. Detection of clonal TCR- and Ig-gene rearrangements unequivocally documented bone marrow involvement in four of eight NHL-patients, where conventional histologic and cytologic examination remained inconclusive. As expected, analysis of bone marrow DNA revealed clonal Ig-gene rearrangements in three cases with clear histologic evidence of bone marrow infiltrations by the NHL. In one case of a patient with acute mixed lymphoid-myeloid lineage leukemia a previously identified clonal Ig-gene rearrangement vanished after successful chemotherapy. Analysis of Ig- and TCR-gene rearrangements promises to be a very useful diagnostic tool in selected cases of lymphoid neoplasia.

Acute Disease↗
PubMed2004

Computational BAC clone contig assembly for comprehensive genome analysis.

Comparative genomic hybridization (CGH) has proved to be a powerful tool for the detection of genome copy number changes in human cancers and in other diseases caused by segmental aneusomies. Array versions of CGH allow the definition of these aberrations, with resolution determined by the size and distribution of the array elements. Resolution approaching 100 kb can be achieved by use of arrays comprising bacterial artificial chromosomes (BACs) distributed contiguously across regions of interest. We describe here a computer program that automatically assembles contigs of minimally overlapping BAC clones, using information about BAC end-sequences and the normal genome DNA sequence. We demonstrate the characteristics of contigs assembled and annotated by use of this approach for regions of recurrent abnormality in human ovarian and breast cancers at chromosome bands 3q25-q27 and 8q24 and chromosome arm 20q. We also show illustrative analyses of regions of amplification in these regions in breast and ovarian tumor cell lines by use of array CGH with arrays comprising contiguous BACs.

Breast Neoplasms↗
PubMed1978

Analysis of rat repetitive DNA sequences.

Parameters of repetitive sequence organization have been measured in the rat genome. Experiments using melting, hydroxylapatite binding, and single strand specific nuclease digestion have been used to measure the number, length, and arrangement of repeated DNA sequences. Renaturation and melting or S1 nuclease digestion of 1.0 kbp DNA fragment show about 20% of rat DNA sequences are 3000-fold repeated. Renatured duplexes from 4.0 kbp DNA fragments display two repetitive size fractions after nuclease digestion. About 60% of the repeated sequences are 0.2-0.4 kbp long while the remainder are longer than 1.5 kbp. The arrangement of the repeated sequences has been measured by hydroxylapatite fractionation of DNA fragments of varying lengths bearing a repeated sequence. Repeated DNA sequences are interspersed among 2.5 kbp long nonrepeated sequences throughout more than 70% of the rat genome. There are approximately 350 different 3000-fold short repeated sequences in the rat interspersed among 600,000 nonrepeated DNA sequences.

Animals↗
PubMed1979

Passage of phenotypes of chemically transformed cells via transfection of DNA and chromatin.

DNA was prepared from 15 different mouse and rat cell lines transformed by chemical carcinogens in vitro and in vivo. These DNAs were applied to NIH3T3 mouse fibroblast cultures by using the calcium phosphate transfection technique. DNAs of five donor lines were able to induce foci on the recipient monolayers. Ten other donor DNAs yielded few or no foci. DNAs from control, nontransformed parental cell lines induced few or no foci. Chromosomes were transfected from one donor whose naked DNA was unable to induce foci, and morphologic transformation of recipients was observed. These experiments prove that in five of these cell lines the chemically induced phenotype is encoded in DNA, and the sequences specifying the transformed phenotype behave as a dominant allele in the NIH3T3 recipient cells. The sequences encoding the transformation are likely found on a single fragment of DNA.

Alleles↗
PubMed2005

Accurate genotyping from paraffin-embedded normal tissue adjacent to breast cancer.

Genetic polymorphism analysis for disease risk is widely used in epidemiology studies; blood or oral cavity cells are the most widely used source of DNA. However, these types of samples are not always available, particularly for studies that were conducted years ago. An alternative potential source of patient DNA exists in the form of paraffin-embedded normal tissue adjacent to tumor samples, which are collected and stored routinely for clinical use. The use of such samples can be conceptually problematic, however, due to the presence of field cancerization in the surrounding normal tissue, with the possible presence of chromosomal loss. Specifically, loss of heterozygosity (LOH) might bias the genotyping results and cause genotype misclassification. However, field cancerization and LOH might not be an issue because LOH is not easily found unless there is careful microdissection of only tumor cells (leaving stromal, inflammatory and fat cells), for example, laser-capture microdissection. In this study, we set out to determine the degree of genotype misclassification from normal tissues adjacent to tumors, if any, by comparing these results with blood genotyping. We examined samples from 106 subjects with breast cancer, analyzing five different genotypes selected from regions commonly known to have LOH in breast cancer. These genotypes were methylenetetrahydrofolate reductase (MTHFR), oxoguanosine glycosylase 1 (hOGG1), dopamine beta-hydroxylase (DBH), dopamine receptor D2 (DRD2) and NAD(P)H dehydrogenase quinone 1 (NQO1), conducted by using real-time PCR and TaqMan genotyping analyses. We found that among these five genotypes and 106 comparisons, there was a 100% concordance for genotyping from normal tissue adjacent to tumor and from blood. Our findings indicate that the use of adjacent normal tissues provides accurate genotyping results with high specificity. Although this study only used breast tumor samples, and may be applicable only to breast cancer studies, we expect the results to be applicable to other types of cancers also.

Biopsy↗
PubMed2005

Expression and prognostic significance of 14-3-3sigma and ERM family protein expression in periampullary neoplasms.

Aberrant gene expression in pancreatic ductal adenocarcinomas contributes to the dismal outcome of patients who develop this disease. The 5' region of 14-3-3sigma (stratifin) is hypomethylated in pancreatic adenocarcinomas and is associated with gene overexpression. In multiple experimental systems, ezrin (ERM, Radixin, Moesin) has been identified as being important in the metastatic behavior of pancreatic and other cancers. We investigated the prognostic significance of aberrant expression of 14-3-3sigma and the ERM proteins (Ezrin, radixin, Moesin) in a series of invasive periampullary adenocarcinomas including 300 infiltrating pancreatic adenocarcinomas, 54 ampullary adenocarcinomas, and 33 noninvasive intraductal papillary mucinous neoplasms from patients who underwent pancreaticoduodenal resection at The Johns Hopkins Hospital, Baltimore, MD, between 1991 and 2003. Two-hundred fourty-four (82%) primary infiltrating adenocarcinomas of the pancreas demonstrated positive expression of the 14-3-3sigma, 45 (15%) showed weak immunolabelling, and 9 (3%) were negative. 201 (68%) showed positive immunolabeling of the ERM proteins, 75 (25%) demonstrated weak expression and 20 (7%) no expression. A similar proportion of ampullary cancers showed 14-3-3sigma and ERM protein expression. Expression of 14-3-3sigma and ERM protein was more likely in poorly differentiated cancers (p = 0.00005), and their expression was associated with poor survival in univariate analysis (p = 0.09). By multivariate analysis, patients whose cancers expressed 14-3-3sigma, but not ERM tended to have a poorer prognosis (Hazard ratio, 1.4; 0.9-2.2, p = 0.14). Aberrant expression of 14-3-3sigma may contribute to the outcome of patients with pancreatic ductal adenocarcinoma.

14-3-3 Proteins↗
PubMed1994

Cloning, structure, cellular localization, and possible function of the tumor suppressor gene lethal(3)malignant blood neoplasm-1 of Drosophila melanogaster.

The tumor suppressor gene, lethal(3)malignant blood neoplasm-1+, of Drosophila melanogaster is required for the differentiation of the phagocytic blood-cell type, the plasmatocyte. In the homozygously mutated state it causes the malignant transformation of these blood cells. We present here the cloning, sequencing, structure, and expression of the l(3)mbn-1+ gene during development. The cloned gene was identified by germ-line transformation, generation of revertants, and the detection of the corresponding mRNA in blood cells and other tissues. Homologies of the G-S-rich C-terminus of the putative MBN83 protein to human cytokeratins K1, K10, and mouse loricrin were found. The structure and possible function of the wild-type l(3)mbn-1+ gene are discussed.

Alleles↗