TaqI RFLP of the TGF alpha gene in breast cancer.
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Breast Neoplasms↗
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Results for “DNA, Neoplasm”
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Homoharringtonine induces heat protection and facilitates dissociation of heat shock transcription factor and heat shock element complex.
We investigated the effects of combined treatment with homoharringtonine (HHT) and hyperthermia on cytotoxicity and transcriptional regulation of heat shock genes in human colon carcinoma (HT-29) cells. The drug (100 ng/ml) which inhibited protein synthesis by 93% protected cells from killing at 43 degrees C. For example, treatment with HHT 2 hr before and during heating produced a 9-fold increase in survival from 3.7 x 10(-2) to 3.2 x 10(-1) after 10 hr at 43 degrees C. Little or no protection was observed if the drug was added only during heating. Interestingly, adding the drug (100 ng/ml) 2 hr before and during heat facilitated the dissociation of heat shock transcription factor-heat shock element (HSF-HSE) complex during continuous heating at 43 degrees C. These findings related to the literature suggest that the free pool of HSC70 is increased by inhibiting protein synthesis. An increase in the level of free HSC70 may more effectively protect or repair thermolabile targets and consequently affect regulation of heat shock response.
Antineoplastic Agents, Phytogenic↗
Association between single nucleotide polymorphisms in the hMSH3 gene and sporadic colon cancer with microsatellite instability.
The association between three single nucleotide polymorphisms (SNPs) in the hMSH3 gene and sporadic colon cancer with microsatellite instability (MSI) was analyzed. Of the three SNPs observed in this population, SNPs at residues 235 and 693 were novel, while that at residue 3133 was previously described. The SNPs at residues 235 and 3133 caused amino acid substitutions, V79I and T1045A, respectively. We analyzed the allele frequencies of the three SNPs in samples from 19 patients with sporadic colon cancer with MSI and 90 healthy controls. We found that the V79 allele frequency was significantly higher in the tumor samples than in controls. In addition, the frequency of the G693 allele showed a higher trend in the tumor samples than in controls. These results indicated that some SNPs in the hMSH3 gene were associated with colon cancer with MSI.
Alleles↗
Characterization of the viral inhibitory factor (VIF) demonstrable in adenovirus-induced tumor and transformed cells. I. Effect on DNA and viral capsid protein synthesis.
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Adenoviridae↗
PTEN gene mutations in colorectal cancers displaying microsatellite instability.
To determine the relationship between the mutation of the PTEN gene and genomic instability in human colorectal cancer, we screened the PTEN gene in 32 colorectal cancers (eight cell lines and 24 tissues) displaying microsatellite instability (MSI) and 32 colorectal cancers (six cell lines and 26 tissues) displaying microsatellite stability (MSS). Of 64 samples, six frameshift mutations were identified in six MSI colorectal cancers (two cell lines and four tumor tissues) but not in MSS colorectal cancers. Of the six MSI colorectal cancers containing PTEN mutation, two case (one cell line and one tumor tissue) showed biallelic mutation of PTEN. Furthermore, to compare the frequency of PTEN mutation with that of other MSI target genes, the mononucleotide repeat sequences of TGF-betaRII, BAX, IGFIIR, hMSH6 and hMSH3 were analyzed. The frequencies of frameshift mutation were revealed 78% in TGF-betaRII, 56% in BAX, 46.9% in hMSH3, 37.5% in hMSH6, 21.9% in IGFIIR, and 18.8% in PTEN. These results suggest that the PTEN gene is a target of genomic instability in MSI colorectal tumorigenesis.
Colorectal Neoplasms↗
Mutation detection by pyrosequencing: sequencing of exons 5-8 of the p53 tumor suppressor gene.
The ability to sequence a large number of DNA samples rapidly and accurately for detection of all possible mutations is a critical goal for the future application of DNA sequencing in routine medical diagnostics. Pyrosequencing() is a non-electrophoretic real-time DNA sequencing method that uses the luciferase-luciferin light release as the detection signal for nucleotide incorporation into target DNA. For pyrosequencing of the human p53 gene, a nested multiplex PCR method for amplification of exons 5-8 was prepared. In order to investigate the use of pyrosequencing in mutation detection, DNA samples from skin-cancer patients were used. Two forms of nucleotide dispensation strategy were used, cyclic and programmed. Bi-directional pyrosequencing was performed and the overlapping sequence data produced were assembled to determine the sequence of the gene. Reliable sequencing data were obtained with both dispensation strategies, but some advantages were obtained using the programmed nucleotide dispensation approach, such as longer and faster reads, and fewer out-of-phase problems. The accuracy of pyrosequencing for detection of p53 mutations and allele distribution was demonstrated.
Base Sequence↗
Inactivation of both alleles of the DPC4/SMAD4 gene in advanced colorectal cancers: identification of seven novel somatic mutations in tumors from Japanese patients.
Loss of heterozygosity (LOH) of loci on chromosome 18q occurs in a majority of colorectal cancers. The DPC4/SMAD4 gene, lying in close proximity to the DCC gene at 18q21.1, was recently identified as a candidate tumor suppressor for the genesis of pancreatic cancer as well as a predisposing gene for Juvenile Polyposis Syndrome (JPS). The gene product functions as a cytoplasmic mediator in the signaling pathway of transforming growth factor beta (TGF-beta). To investigate the potential role of DPC4/SMAD4 gene in colorectal cancers, we examined 73 tumors of clinical stages II or III from Japanese patients, for LOH at 18q21 and also for subtle mutations anywhere within the coding region of DPC4/SMAD4. LOH was identified in 50 (78%) of the 64 tumors that were informative for polymorphic markers in the region. Somatic mutations were identified in seven of those tumors: two frameshift mutations, a 1-bp deletion (326 del T) in exon 8 and a 1-bp insertion (50-51 ins A) in exon 1; two nonsense mutations, Arg445Ter in exon 10 and Glu538Ter in exon 11; and three missense mutations, Asn129Lys in exon 2, Tyr95Asn in exon 2, and Asp355Glu in exon 8. Three of the seven mutations were observed in the mad homology 1 (MH1) domain encoded by exons 1 and 2. In all of the tumors carrying intragenic mutations of one allele, LOH analysis had shown that the other allele was missing. The results demonstrated that inactivation of both alleles of the DPC4/SMAD4 gene occurs in a substantial proportion of advanced colorectal cancers, and that the DPC4/SMAD4 gene probably exerts a tumor-suppressor effect for colorectal carcinogenesis that fulfills the criterion of the two-hit concept proposed by Knudson [A.G. Knudson, Hereditary cancer, oncogenes, and anti-oncogenes, Cancer Res. 45 (1985) 1437-1443.].
Alleles↗
Relationship between grade of microsatellite instability and target genes of mismatch repair pathways in sporadic colorectal carcinoma.
Microsatellite instability (MSI) induces carcinoma through the alteration of target genes; TGF-beta RII, BAX, IGFIIR, hMSH3, and hMSH6. The grade of M
Adult↗
An immunophenotypic and molecular study of primary large B-cell lymphoma of bone.
Primary non-Hodgkin's lymphomas of bone (PNHLB) is a rare form of extranodal lymphoma. Many studies have reported the clinical, radiologic, and histopathologic characteristics of PNHLB; however, their molecular features have not been well studied. In this report, we present the immunophenotypic and molecular characteristics of 20 primary large B-cell lymphoma (PLBCL) of bone from 20 adults. Most demonstrated centroblastic morphology, with the majority exhibiting nuclear multilobation. One case (5%) demonstrated anaplastic features with strong CD30 expression but was ALK-1 negative. BCL-6 expression was seen in 6 of 20 cases, and strong p53 protein expression was seen in 11 of 20 (55%) cases. The majority of cases analyzed (13/18 = 72%) demonstrated a clonal B-cell process by IgH gene rearrangement studies. Of the five cases that did not demonstrate a clonal population, two expressed BCL-6 protein. No cases demonstrated a bcl-2/JH rearrangement, but BCL-2 protein expression was seen in 11 of 20 (55%) cases. In summary, primary lymphoma of bone is largely a non-Hodgkin's lymphoma of large B-cell type. Our studies demonstrate that p53 and BCL-2 expression may play a role in the pathogenesis of PLCBL of bone. In addition, a subset of the cases are of putative germinal center B-cell origin based on the expression of BCL-6 protein and may be genetically distinct from follicle center lymphomas. The results provide evidence for molecular heterogeneity within primary large B-cell lymphomas of bone.
Adult↗
SMAD4 is a predictive marker for 5-fluorouracil-based chemotherapy in patients with colorectal cancer.
The gene for the transducer of transforming growth factor-beta/bone morphogenetic protein signalling SMAD4, a potential suppressor of colorectal carcinogenesis, is located at the chromosomal region 18q21. In order to evaluate the clinical relevance of SMAD4 deletion, gene copy alterations were determined by copy dosage using real-time quantitative PCR in 202 colorectal tumour biopsies from a previous randomised study of adjuvant chemotherapy. Patients with normal SMAD4 diploidy turned out to have a three-fold higher benefit of 5-fluorouracil-based adjuvant chemotherapy with a border line significance (overall survival: 3.23, P=0.056; disease-free survival: 2.89, P=0.045). These data are consistent with the previous observation that patients whose cancer had retention of the 18q21 region had a significantly higher benefit from 5-fluorouracil-based therapy. Moreover, these results may provide a refinement at the gene level of the clinical relevance of 18q21 deletion, thereby suggesting SMAD4 as a predictive marker in colorectal cancer. This data also indicate that integrity of this component of the transforming growth factor-beta/bone morphogenetic protein signalling pathway may be a critical factor for benefit of chemotherapy in patients with colorectal cancer.
Antimetabolites, Antineoplastic↗
Rearrangements of minisatellites in the human telomerase reverse transcriptase gene are not correlated with its expression in colon carcinomas.
Telomerase activation is crucial in human carcinogenesis. The limiting component of telomerase, the catalytic subunit (hTERT), is undetectable in normal somatic cells but present in most tumor cells, including the earliest stages of colon carcinoma. The mechanisms involved in the differential expression in normal and tumor cells are not understood. In normal cells hTERT expression is shut down by a repressor, and upregulation could be a consequence of cis-acting changes in the hTERT gene, making it resistant to repression. We have identified a polymorphic and a monomorphic minisatellite in the second intron of the hTERT gene, and polymorphic one in intron 6. The polymorphic minisatellite in intron 2 contains binding sites for c-Myc, which has been shown to upregulate hTERT transcription. Screening colon carcinoma DNAs for rearrangements of hTERT minisatellites we detected no changes in 33 samples from tumors, most of which express hTERT. This indicates that size rearrangements of the hTERT minisatellites are not required for telomerase expression in colon carcinomas. Minor changes and one LOH were seen in five tumors.
Base Sequence↗
The developmentally regulated transcription factor AP-2 is involved in c-erbB-2 overexpression in human mammary carcinoma.
Overexpression of the c-erbB-2/HER2 protooncogene in breast carcinoma is controlled not only by the degree of amplification of the gene but also at the level of gene transcription. Thus, whether or not the gene is amplified, the activity of the c-erbB-2 promoter is enhanced in overexpressing cells through the binding of an additional transcription factor, OB2-1, whose activity is increased in these lines. Here we describe further characterization of OB2-1 and show that it is identical to the developmentally regulated transcription factor AP-2. Functional assays confirm that AP-2 is able to regulate c-erbB-2 expression in mammary-derived cell lines. Furthermore, although AP-2 is barely detectable in cells with the low c-erbB-2 expression phenotype, protein levels are clearly elevated in a panel of c-erbB-2-overexpressing lines. These findings demonstrate an important role for this transcription factor in human cancer.
Base Sequence↗
Identification of a novel repressive element in the proximal lck promoter.
The T-cell-specific protooncogene lck, a src-related tyrosine kinase, is under the control of two promoters that give rise to transcripts differing only in their 5'-untranslated regions. The distal promoter is transcriptionally active in both peripheral and thymic T-cells, whereas expression of the proximal promoter is highest in developing thymocytes. The proximal promoter has also been shown to be selectively activated in a number of colon carcinoma cell lines. Approximately 570 base pairs of proximal promoter sequence is required for expression in both T-cells and colon carcinoma cell lines. Protein binding studies were initiated with an oligonucleotide homologous to a region that, when deleted, causes an increase in promoter activity in transgenic animals. Two proteins with approximate molecular masses of 35 and 75 kDa were found to bind to this region as determined by UV cross-linking studies. Absence of specific protein binding is correlated with a high level of proximal promoter expression. Competitive gel retardation analysis identified a 9-base pair binding site within the proximal lck promoter that is necessary for repression of transcription in cells that contain specific binding activity. Mutants of this binding site do not repress transcription. Repression does not occur in a cell line that expresses lck and lacks this activity. These data support the hypothesis that activation of lck transcription in colon carcinoma is due, at least in part, to the loss of a transcriptional repressor.
Base Sequence↗
Human MRE11 is inactivated in mismatch repair-deficient cancers.
Mutations of the ATM and NBS1 genes are responsible for the inherited Ataxia-Telangiectasia and Nijmegen Breakage Syndrome, both of which are associated with a predisposition to cancer. A related syndrome, the Ataxia-Telangiectasia-like disorder, is due to mutations of the MRE11 gene. However, the role of this gene in cancer development has not been established. Here we describe an often homozygous mutation of the poly(T)11 repeat within human MRE11 intron 4 that leads to aberrant splicing, impairment of wild-type MRE11 expression and generation of a truncated protein. This mutation is present in mismatch repair-deficient, but not proficient, colorectal cancer cell lines and primary tumours and is associated with reduced expression of the MRE11--NBS1--RAD50 complex, an impaired S-phase checkpoint and abrogation of MRE11 and NBS1 ionizing radiation-induced nuclear foci. Our findings identify MRE11 as a novel and major target for inactivation in mismatch repair-defective cells and suggest its impairment may contribute to the development of colorectal cancer.
Amino Acid Sequence↗
Chromosomal locations of satellite DNA in the MSWBS ascites tumor cell line.
In situ hybridization of mouse satellite complementary RNA to the chromosomes of the mouse ascites tumor line MSWBS revealed that the distribution of satellite DNA sequences paralleled the location of constitutive heterochromatin as defined by the C-banding technique.
Chromosomes↗
Frameshift mutations and a length polymorphism in the hMSH3 gene and the spectrum of microsatellite instability in sporadic colon cancer.
Mutations in the hMVSH3 gene in sporadic colon cancer with microsatellite instability (MSI) were investigated, since several mismatch repair genes were known to be mutated in cancers with MSI, but only deletions in the (A)8 region in the hMSH3 gene have been reported. We also analyzed the relationships between hMSH3 mutations and the spectrum of MSI. We screened MSI in 79 sporadic colon cancer samples using mono- and dinucleotide repeat markers and the samples with MSI were further analyzed for tri- and tetranucleotide repeat instability and mutations in the hMSH3 gene by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. Five (6%) out of 79 tumors were MSI-H and 15 (19%) were MSI-L. Two MSI-H tumors showed insertion in the (C)8 region in the hMSH6 gene and one tumor showed insertion and deletion in the (A)8 region in the hMSH3 gene, and two of the three above tumors showed MSI in tri-and tetranucleotide repeats. One MSI-L tumor showed somatic alteration in a 9-bp repeat sequence in hMSH3. No frameshift mutations were found in the (A)7 and (A)6 regions in hMSH3. Thus, we confirmed that the (A)8 region in hMSH3 is a hot spot and mutations in the (A)7 and (A)6 regions in hMSH3 are not common. The hMSH3 mutation may enhance genomic instability in some colorectal cancers.
Base Pair Mismatch↗
Multiple copies of human adenovirus 12 genomes are integrated in virus-induced hamster tumors.
Tumors induced in hamsters by highly oncogenic human adenovirus 12 contain multiple copies of 90 to 100% of the viral genome in an integrated form.
Adenoviruses, Human↗
SMAD4 as a prognostic marker in colorectal cancer.
More than 50% of patients with Dukes C colorectal cancer have disease recurrence and die within 5 years after surgical removal of their primary tumor. It is currently not possible to distinguish patients with good and bad prognosis. SMAD4 is an important tumor suppressor gene that mediates transforming growth factor-beta superfamily signaling and is located in chromosome 18q21, a region with frequent genetic losses in these tumors. Allelic imbalance in 18q has been linked to poor prognosis in a subset of colorectal cancer patients. Therefore, we generated a tissue microarray containing triplicate tumor samples from 86 Dukes C patients and used immunohistochemistry to assess the relative expression level of SMAD4 and its value as a prognostic marker. In addition, SMAD4 was screened for mutations and two polymorphic microsatellite markers were used to assess the presence of allelic imbalance in these tumors. Patients with tumors expressing high SMAD4 levels had significantly better overall (P < 0.025) and disease-free (P < 0.013) survival than patients with low levels. This identifies SMAD4 as a prognostic marker for Dukes C colorectal cancer. Although all tumors with absent SMAD4 staining showed allelic imbalance in 18q21, tumors with 18q21 allelic imbalance as a group showed no difference in SMAD4 levels compared with tumors without allelic imbalance, suggesting that additional mechanisms of SMAD4 down-regulation exist. In addition, although SMAD4 mutations were found in five tumors, they were not associated with shorter survival. In conclusion, the level of expression of SMAD4 was found to be a more sensitive marker than 18q21 allelic imbalance and SMAD4 mutations, which were of no prognostic significance for these patients.
Aged↗