Transforming genes of neoplasms.
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Animals↗
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Results for “Genes, Neoplasm”
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p53 gene therapy in vivo of herpatocellular and liver metastatic colorectal cancer.
Tumor suppressor genes such as p53 contribute to the oncogenic process via loss-of-function mechanisms such as genetic mutation or complex formation with other cellular or viral proteins. p53 is mutated in approximately 50% of human tumors and has an important role in the genesis or progression of both colorectal and hepatocellular cancers. Colorectal cancer is leading cause of cancer mortality in the United States, whereas hepatocellular cancer is the leading worldwide cause of cancer death; the liver is a primary site of morbidity in both diseases. Because systemic tumor suppressor gene therapy is currently not feasible, we have chosen to develop a regional form of such therapy directed at primary or metastatic liver neoplasms. Gene replacement therapy with p53 is a promising new strategy to treat advanced human cancers.
Adenoviridae↗
Novel region within the V kappa gene promoter is responsible for tissue and stage-specific expression of immunoglobulin genes in human lymphoid neoplasms.
Immunoglobulin gene-specific transacting factors have been shown to play a role in lymphoid tissue-specific expression of immunoglobulin genes. The role of these factors in B-cell differentiation and stage-specific expression of these genes is, however, not fully understood. We have used a model of human lymphoid neoplasia to address this question. Different fragments of unrearranged human variable region of immunoglobulin kappa gene (V kappa) were used for cell-free in vitro transcription and DNA mobility shift assays. Previously described enhancement of in vitro transcription that was only seen with nuclear extracts derived from B-cell neoplasms corresponding to the late stages of B-cell differentiation was shown to be dependent on the actions of these factor(s) on the DNA region within the V kappa gene promoter. This region is located within the 920 bp fragment located 210 bp upstream from the coding region and this fragment represents a possible novel DNA region, which plays a role in the stage- and tissue-specific expression of immunoglobulin genes.
B-Lymphocytes↗
[Immunoglobulin and T-cell receptor gene rearrangements as markers of lineage and clonality in malignant lymphoma].
In the process of lymphocyte differentiation, genes encoding variable regions of immunoglobulin and T-cell receptor undergo rearrangement. Such gene rearrangements represent markers of lineage and clonality of lymphocytes, allowing molecular diagnosis of human lymphoid neoplasms. Gene rearrangements are analyzed by Southern hybridization, using DNA probes specific for immunoglobulin heavy chain (IgH) and T-cell receptor beta (TCR beta) chain. This approach can detect monoclonal lymphoid populations that constitute 1-5% of total cells in tissues, and can be used successfully to distinguish lymphoid neoplasms from polyclonal lymphoid proliferations and to determine the lymphocytic lineage of neoplasms; i.e., rearrangement of IgH genes without TCR beta gene rearrangement strongly supports B-lineage, while rearrangement of TCR beta without IgH gene rearrangement implies T-lineage.
B-Lymphocytes↗
Mutations of the p53 tumour suppressor gene in haematologic neoplasms.
Mutations of the p53 tumour suppressor gene have frequently been observed in several types of solid tumours and are believed to be implicated in the development of these tumours. To determine the relevance of p53 mutations in haematologic neoplasms, we performed polymerase chain reaction-single strand conformation polymorphism analysis on the p53 gene in 45 patients with various types of haematologic neoplasms. In exons 5-8 containing highly conserved regions, mobility shifts indicating sequence alterations were detected in four of the 45 patients, and subsequent sequencing was performed. A point mutation resulting in a novel stop codon was detected at codon 213 in one of 23 cases of chronic myelogenous leukaemia (one of five cases of blast crisis). Point mutations causing amino acid substitutions were detected in one of four cases of myelodysplastic syndrome at codon 195, one of three cases of adult T-cell leukaemia at codon 281, and one of eight cases of acute lymphoblastic leukaemia at codon 281, and these missense mutations were accompanied by loss of the wild type allele. Patients harbouring these nonsense and missense mutations were in advanced disease stages. These findings suggest that mutational inactivation of the p53 gene is infrequent but is involved in the tumorigenesis of several types of haematologic neoplasms at least in some cases.
Amino Acid Sequence↗
Polymerase chain reaction-based approaches for detection of allelic loss in the p53 tumor suppressor gene in colon neoplasms.
OBJECTIVES: Inactivation of the p53 tumor suppressor gene is considered to be a late event involved in the malignant transformation of colorectal adenoma to cancer. Thus, its detection is thought to provide useful information for the clinical management of colorectal neoplasms. We devised a rapid screening test for allelic loss of the p53 gene by non-radioisotopic single-strand conformation polymorphism analysis. METHODS: Biopsy materials from 119 colorectal tumors obtained at endoscopy were examined. Three intragenic polymorphic sites were amplified by polymerase chain reaction using DNA extracted from these materials, and amplified DNA fragments were subjected to non-radioisotopic single-strand conformation polymorphism. RESULTS: This method can detect a loss of heterozygosity (LOH) of the p53 locus from samples containing over 40% tumor derived DNA, and the combination of the three polymorphic markers encompassed 62.4% of Japanese patients as informative. In adenocarcinoma, an LOH was detected in 51.5% (17 of 33) of the samples and in 12.2% (4 of 33) of tubular and/or tubulovillous adenomas. The p53 gene was mutated only in samples carrying an LOH, that is 64.7% (11 of 17) of carcinomas and 25.0% (1 of 4) of adenomas, but there were no mutation in samples retaining both alleles. The presence of an LOH was statistically correlated both with p53 mutation and malignant histology (chi 2 test, p < 0.05). CONCLUSIONS: This method can detect LOH from biopsy material obtained at endoscopy. LOH in the p53 locus precedes mutation of the p53 gene, and its detection provides useful information of malignancy in colorectal tumors.
Adenocarcinoma↗
Amplification of the AML1(CBFA2) gene on ring chromosomes in a patient with acute myeloid leukemia and a constitutional ring chromosome 21.
In the genesis of hematologic neoplasms gene amplification is a mechanism for illegitimate activation of proto-oncogenes. We report a phenotypically normal patient with a constitutional ring chromosome 21 who developed acute myeloid leukemia (AML). The leukemic cells revealed size-variable ring chromosomes 21 with amplification of the proto-oncogene AML1, located in the chromosomal band 21q22, within the rings. Hitherto, amplification of the proto-oncogene AML1-also in form of a ring chromosome-has been described recently only in one patient with myelodysplastic syndrome (MDS). In AML, gene amplification by ring formation has been demonstrated only in another three patients (amplification of the MLL gene in two cases and of the ETV6 gene in one case). Here we present the new evidence that the internal rearrangement of a constitutional ring chromosome 21 resulted in multiplication of a proto-oncogene in bone marrow cells and provided obviously a selective growth advantage. Moreover the amplification of ribosomal DNA was observed in the ring chromosomes of the tumor cells.
Acute Disease↗
[Significance of ALK gene expression in neoplasms and normal tissues].
OBJECTIVE: This study was designed to investigate the clinicopathologic significance of the ALK gene expression in neoplasms and normal tissues. METHODS: Using the immunohistochemical method, the expressions of ALK gene were examined on 14 anaplastic large cell lymphoma (ALCL). 10 Hodgkin's lymphoma, 46 B lymphoma, 13 T lymphoma, 21 malignant astrocytoma, 5 medulloblastoma, 5 ependymoma, 69 carcinomas, 19 sarcomas, and many normal tissues. RESULTS: (1) The expression rate of ALK was 64.3% in ALCL, it is significantly higher than that in Hodgkin's lymphoma, B lymphoma, and other T lymphoma(P < 0.01). (2) There was strongly expression of ALK in hepatocellular carcinoma, malignant astrocytoma, and medulloblastoma. (3) There was weakly expression of ALK in placenta tissue and astrocyte. CONCLUSIONS: (1) The ALK protein is a very important molecular marker in ALCL, it is very helpful for diagnosing and distinquishing ALCL. (2) ALK gene may take part in the origin and development of hepatocellular carcinoma, malignant astrocytoma, and medulloblastoma and may be an important gene associated with neoplasms.
Adolescent↗
[Mutations of oncogenes and tumor suppressor genes in prostate neoplasms].
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Animals↗
[Role of p53 gene in colorectal neoplasms].
A prospective study on the role of the p53 gene in sporadic colorectal neoplasms is presented and the level of mutant p53 protein was measured in the tissue removed during colonoscopy from: patients previously operated for colorectal malignant neoplasms, patients with active neoplasms, first degree relatives and during regular checks. 72% of patients with an active tumour showed a positive p53 and 38% in follow-up checks. Longer follow-up periods and a major number of patients are necessary to assess the prognostic importance of the p53 protein.
Colorectal Neoplasms↗
Epigenetic down-regulation of CDKN1C/p57KIP2 in pancreatic ductal neoplasms identified by gene expression profiling.
PURPOSE: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is an increasingly identified precursor to infiltrating ductal adenocarcinoma. Although our knowledge of the clinical and pathologic features of IPMNs is increasing, the molecular mechanisms underlying these neoplasms remain poorly understood. EXPERIMENTAL DESIGNS: To provide further insight into the molecular pathobiology of IPMNs, global expression profiling was done to determine genes that are inactivated/down-regulated in IPMNs using oligonucleotide microarrays (Affymetrix). RESULTS: In total, 300 unique transcripts (217 known genes) were identified as highly underexpressed in 12 IPMNs (<10-fold lower and P < 0.05) compared with five normal pancreatic ductal epithelium samples obtained by laser capture microdissection. The differential expression of a selection of genes was confirmed using reverse-transcription PCR. One of the genes underexpressed at both the transcriptional and protein level in a significant proportion of IPMNs was the cyclin-dependent kinase inhibitor, CDKN1C/p57KIP2. CDKN1C expression was also decreased in many pancreatic cancer cell lines and was restored following treatment with a DNA methylation inhibitor (5-aza-2'-deoxycitidine) or, more potently, with a histone deacetylase inhibitor (trichostatin A). Partial methylation of the CDKN1C promoter CpG island was found in most, but not all, pancreatic cancer cell lines with reduced CDKN1C expression, and was also detectable in IPMNs. Furthermore, a subset of pancreatic cancers showed complete hypomethylation of LIT1, an imprinting control region important for the regulation of CDKN1C expression. Complete hypomethylation in these cancers was the result of deletion of the methylated LIT1 allele at 11p15.5 rather than loss of imprinting. CONCLUSIONS: These findings suggest that CDKN1C is commonly down-regulated in pancreatic ductal neoplasms through a combination of promoter hypermethylation, histone deacetylation, and loss of the maternal allele expressing CDKN1C.
Adenocarcinoma, Mucinous↗
Rearrangements of T-cell antigen receptor delta chain gene in hematologic neoplasms.
Rearrangements of the T-cell antigen receptor (TCR) delta chain gene were studied in primary neoplastic cells from 137 patients with leukemia or lymphoma. TCR delta gene rearrangements or deletions were observed in all 50 T-cell neoplasms: 5 of 8 CD3- T-cell neoplasms showed rearrangements, whereas biallelic deletion of TCR delta gene was the most common pattern in CD3+ T-cell neoplasm (39 of 42 patients). Rearrangements of TCR delta gene were also detected in 23 of 40 immature B-cell leukemias, including 22 of 25 patients with rearrangements of TCR gamma gene, 2 of 17 mature B-cell neoplasms, and 3 of 30 myeloid leukemias. Thus, TCR delta gene rearrangement or deletion is always found in T-cell neoplasms and is frequently found in immature B-cell leukemias associated with TCR gamma gene rearrangement. Furthermore, TCR delta gene rearrangements associated with the germline configuration of the TCR beta, gamma, and immunoglobulin heavy chain genes were observed in two immature T-cell leukemias, suggesting that TCR delta gene rearrangements precede TCR gamma and beta gene rearrangements. These results indicate that an analysis of TCR delta gene rearrangement provides potential tools to establish the clonality of immature T-cell neoplasms and to identify the normal stages of lymphocyte differentiation.
Antigens, CD↗
Comparison of expression of aldehyde dehydrogenase 3 and CYP1A1 in dominant and recessive aryl hydrocarbon hydroxylase-deficient mutant mouse hepatoma cells.
The mouse hepatoma cell line Hepa-1 is inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for both CYP1A1 (aryl hydrocarbon hydroxylase, AHH) and class 3 aldehyde dehydrogenase (ALDH3) enzymes. To test the hypothesis of a common regulatory mechanism, several AHH deficient mutants of Hepa-1 were studied for their ALDH3 activities and specific mRNA levels before and after TCDD treatment. The recessive (with respect to the wild-type Hepa-1) mutants have defects in Cypla-1 structural gene (mutant c1) or in the Ah (aryl hydrocarbon) receptor (mutants c2 and c6 with decreased levels of Ah receptor; mutant c4 defective in the DNA binding of the Ah receptor). The results with these mutants suggested that Ah receptor nuclear translocator protein, ARNT, is needed for ALDH3 expression. Two dominant mutants, one of which is characterized by preventing the binding of the Ah receptor complex to DNA, were also studied. Surprisingly, these mutants possessed elevated levels of ALDH3 mRNA and enzyme activities which were also inducible by TCDD. The binding of Ah receptor-ligand complex to DNA was thus not needed for the expression of ALDH3. A dominant repressor for Cypla-1 gene transcription did not prevent the derepression or induction of ALDH3. The results thus suggest that Aldh-3 gene is regulated by a mechanism independent of the Ah receptor.
Aldehyde Dehydrogenase↗
Transthyretin (prealbumin) gene in human primary hepatic cancer.
From a subtracting cDNA library constructed from normal liver versus human primary hepatic cancer (PHC) a cDNA clone pG8 was isolated. Using it as a probe, RNA extracted from one human liver and 9 PHC samples were analyzed by Northern hybridization. As expected, its mRNA was highly expressed in liver; however, the expression was strikingly suppressed in PHC. Only weak signal was observed in 2 out of 9 PHC, while no signal was detectable in the other 7 samples. Utilizing pG8 as a probe, DNA from the same PHC specimens was analyzed after MspI digestion and Southern hybridization. Deletion of DNA fragment was observed in 4 out of 9 samples. In further study of cancer and non-cancerous liver from other 7 PHC patients, similar deletion of DNA fragments in cancer was observed in 4 out of 7 samples. After sequencing of the clone of 572 bp, it was unexpectedly found that pG8 was completely homologous to the coding sequence of transthyretin, TTR gene, as TTR (or prealbumin) gene has been known to be linked to a hereditary disorder, familial amyloidosis (FAP), and related to thyroxine transport and binding to retinol-RBP (the retinol binding protein) complex. This is the first report of a study on TTR in human primary hepatic cancer. Since TTR gene was strikingly suppressed in mRNA expression and possibly defective in its gene structure, it was strongly implicated that TTR might be an important gene marker or a candidate of anti-oncogene for human PHC. The biological activity of TTR gene is under study.
Base Sequence↗
Perillyl alcohol-mediated inhibition of lung cancer cell line proliferation: potential mechanisms for its chemotherapeutic effects.
Perillyl alcohol (POH) is currently being tested in clinical trials as an anticancer agent, though its mechanism of action has not been definitively established. We treated two human lung cancer cell lines, H322 and H838, with POH to determine its antitumor properties. A sulforhodamine B (SRB) cell proliferation assay was used to determine the effects of POH after 1 and 5 days of treatment with 0.25, 0.5, 0.75, 1.0, and 1.5 mM POH. After 1 day of treatment, little difference could be seen between the lowest and highest concentrations of POH. However, after 5 days, both cell lines showed a dose-dependent decrease in cell proliferation that ranged from 15% to 83%. A clonogenic assay confirmed these results-while there was no significant effect of POH after 1 day of exposure, a dose-dependent decrease in colony formation, ranging from 15% to 100%, was seen after 5 days of treatment. Time-lapse video microscopy revealed that apoptotic cells were evident within 24-48 h of treatment with 1.5 mM POH. The appearance of apoptotic cells was preceded by increased caspase-3 activity and cleavage of poly (ADP-ribose) polymerase (PARP) as POH activated caspase-3 activity 3-6-fold. Nuclear staining with 4',6-diamidino-2-phenylindole (DAPI) confirmed the classical characteristics of apoptosis in POH-treated cells. DNA microarray expression analysis was performed following 8 and 24 (H322) or 8 and 48 (H838) h of treatment with 1.5 mM POH. While a large number of genes were up- or downregulated in the two cell lines at various times after POH treatment, the levels of expression of only eight genes were up- or down-related in both cell lines at both of the time points examined. The significance of these genes as potential mediators of POH action is still uncertain, but the limited number of commonly up- or downregulated genes detected by microarray expression analysis suggests that POH may mediate its effects via posttranscriptional mechanisms. Our results suggest that POH may have potential use as an anticancer drug that stimulates or sensitizes lung tumor cells to apoptosis, and this effect may depend on genetic lesions present in tumor cells.
Antineoplastic Agents↗
Cell cycle alterations and lung cancer.
It is now widely accepted that human carcinogenesis is a multi-step process and phenotypic changes during cancer progression reflect the sequential accumulation of genetic alterations in cells. The recent progress of scientific research has notably increased knowledge about biological events involved in lung cancer pathogenesis and progression, thanks to the use of molecular biology and immunohistochemistry techniques. Lots of the genetic alteration found in small cells lung cancer (SCLC) and in not small cells lung cancer (NSCLC) concern the expression of cell cycle genes, actually recognized as onco-suppressor genes and the lack of equilibrium between oncogenes and oncosuppressor genes. The present review of literature widely describes the cell cycle control, the lung cancer molecular pathogenesis, the catalog of known genetic alterations and the recent advances in global expression profiles in lung tumors, on the basis of the various hystological types too. Such data suggest the potential use of this knowledges in clinical practice both as prognostic factors and innovative therapeutic possibilities and they impose the necessity of new studies about cell cycle control and lung carcinogenesis.
Carcinoma, Non-Small-Cell Lung↗
Alterations in the structural gene and the expression of p53 in rat liver tumors induced by aflatoxin B1.
Rat hepatocellular carcinomas (HCCs) induced by aflatoxin B1 (AFB) treatment were examined for changes in the p53 tumor suppressor gene and in p53 suppressor gene expression. A high proportion of HCCs (nine of 11 tumors in six of eight animals) exhibited new p53 restriction fragments, indicating genomic alterations of one of the p53 alleles. Each tumor with an altered p53 restriction-fragment pattern exhibited a new fragment in one of two size classes (3 kb or 7 kb with EcoRI digestion) that were missing portions of the 3' end of the p53 gene. These findings indicate that apparently similar genomic rearrangements or deletions occurred independently in AFB-induced tumors. When compared with nontumor liver tissue from the same animal, the tumors with p53 gene alterations showed dramatically reduced levels of p53 mRNA and protein and greatly increased levels of histone H2B and retinoblastoma tumor suppressor (Rb) mRNA. In two HCCs showing no evidence of p53 restriction-fragment alterations, mutant p53 protein was detected. Mutant protein was also detected in two liver samples containing an adenoma and altered foci. These data suggest that alterations of the p53 tumor suppressor gene are involved in the induction of rat HCC by AFB.
Aflatoxin B1↗