[Kinetic study of the physicochemical properties of normal and neoplasm DNA].
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Animals↗
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Results for “DNA, NEOPLASM”
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[Effect of exogenous neoplasm DNA on the course of Swetz leukemia in non-inbred rats of different age groups].
Experiments on 150 non-inbred white rats have shown that preliminary administration of high polymer native DNA isolated from Swetz leukemia tumor suppresses the tumor growth. Tumor DNA combined with BCG vaccine in young animals suppresses and in old ones stimulates the tumor growth. These results correlate with DNA and CIC content in the blood serum. Due to the tumor growth suppression the animals' life increases by 40%. Administration of BCG vaccine only does not prevent the development of tumor in usual terms.
Age Factors↗
Molecular biological observations in some rare neoplasms: DNA ploidy and cell cycle data in liposarcoma and malignant fibrous histiocytoma.
INTRODUCTION: The prognostic significance of tumor DNA ploidy and cell cycle analysis for long-term survival has been examined in 19 patients with liposarcoma or malignant fibrous histiocytoma. In many cases, different tumor areas of primary tumors and local recurrences have been analyzed to reveal intratumoral heterogeneity. RESULTS: Among the primary tumors, there were eight aneuploid tumors, three of which showed diploid and aneuploid tumor regions. Correlations among DNA ploidy, grading, percentage of S-phase cells and infiltrative growth pattern of the tumors could be demonstrated. Poorly differentiated tumors (G3) showed aneuploidy in six of eight patients. Aneuploid tumors showed S-phase cells in 17.2% (range 3.2-38.1%), which was higher than the percentage of S-phase cells in diploid tumors (9.4%, range 2.1-27.4%). Aneuploid tumors showed a more infiltrative growth pattern (6 of 8 patients) than diploid tumors (6 of 11 patients). The median survival time of patients with diploid tumors was 86.5 months (8-144 months), compared with 40.9 months (11-54 months) for patients with aneuploid tumors. CONCLUSION: DNA ploidy and percentage of S-phase cells may be considered as prognostic factors.
Aneuploidy↗
[DNA methylation and neoplasms].
DNA methylation and acetylation of histone proteins represent two global mechanisms controlling the gene expression. DNA methylation profiles alter during the development of the organism and during progression of neoplasia. Three types of alterations of the DNA methylation profiles were observed in the tumor cells: hypomethylation, hypermethylation and the loss of imprinting. Beside the intra-gene mutation and the heterozygosity absence, DNA methylation can be understood as the third mechanism of tumor-suppressor gene inactivation in the genesis of neoplasia. Our review article brings recent findings and hypotheses on the role of DNA methylation in the carcinogenesis and its possible application in the diagnostics and therapy of the malignant proliferation.
DNA Methylation↗
Quantitative DNA analysis of small renal cortical neoplasms.
DNA aneuploidy is common in large renal cortical neoplasms (RCNs), but the incidence in small RCNs is not known. This study was undertaken to investigate whether the traditional 3.0-cm size distinction between small (benign) and large (malignant) tumors might have an objective correlate in the form of abnormal DNA content. Quantitative DNA analysis was performed retrospectively, by image analysis, on 59 RCNs measuring 5.0 cm or less from 30 nephrectomy specimens with solitary tumors and 17 with multiple tumors. DNA indices and the proportion of cells with DNA content greater than that of the G0/G1 population were evaluated with respect to tumor size, stage, and histologic parameters. There was a relationship between the presence of detectable nondiploid stem lines (NDSLs) and tumor size, stage, nuclear grade, and proportion of non-G0/G1 cells, but not histologic pattern. The relationship of NDSLs to tumor size was more apparent in the solitary tumor group, while the relationship of a high proportion of non-G0/G1 cells to tumor size was stronger in the multiple tumor group. Our results show that the incidence of NDSLs increases with tumor size and nuclear grade, and suggest that as RCNs enlarge, the emergence of NDSLs heralds potential biologic aggressiveness. Further, solitary tumors and multiple synchronous tumors may be biologically different in terms of etiologic factors and growth potential.
Adenoma↗
DNA copy number amplification profiling of human neoplasms.
DNA copy number amplifications activate oncogenes and are hallmarks of nearly all advanced tumors. Amplified genes represent attractive targets for therapy, diagnostics and prognostics. To investigate DNA amplifications in different neoplasms, we performed a bibliomics survey using 838 published chromosomal comparative genomic hybridization studies and collected amplification data at chromosome band resolution from more than 4500 cases. Amplification profiles were determined for 73 distinct neoplasms. Neoplasms were clustered according to the amplification profiles, and frequently amplified chromosomal loci (amplification hot spots) were identified using computational modeling. To investigate the site specificity and mechanisms of gene amplifications, colocalization of amplification hot spots, cancer genes, fragile sites, virus integration sites and gene size cohorts were tested in a statistical framework. Amplification-based clustering demonstrated that cancers with similar etiology, cell-of-origin or topographical location have a tendency to obtain convergent amplification profiles. The identified amplification hot spots were colocalized with the known fragile sites, cancer genes and virus integration sites, but global statistical significance could not be ascertained. Large genes were significantly overrepresented on the fragile sites and the reported amplification hot spots. These findings indicate that amplifications are selected in the cancer tissue environment according to the qualitative traits and localization of cancer genes.
DNA Damage↗
Protooncogene amplification and tumor ploidy in human ovarian neoplasms.
DNA from 24 ovarian tumors, including 16 carcinomas, was examined for amplification of the proto-oncogenes c-myc, int-2, and rc-erbB-2. All cases of carcinoma were also examined by flow cytometry for DNA ploidy and cell cycle analysis, and eight cases of carcinoma were examined for estrogen and progesterone receptors. Protooncogene amplification was not detected in the DNA of benign ovarian neoplasms, or of ovarian carcinomas with low malignant potential. Amplification of c-myc was detected in six of 12 cases of invasive carcinoma, int-2 amplification was present in one case, and c-erbB-2 amplification was not detected in any case. Among the seven cases evidencing protooncogene amplification, three cases showed aneuploidy in tumor DNA, while four showed diploidy. Two cases which showed aneuploidy in tumor DNA did not demonstrate any degree of protooncogene amplification. Protooncogene amplification was frequently associated with morphologic nuclear anaplasia and high mitotic count. Six of the seven cases demonstrating c-myc or int-2 were of the serous type or showed some degree of serous differentiation, while none of the four cases of purely mucinous carcinoma had evidence of amplification. While the total number of cases in the study was limited, it would appear from the trend demonstrated by the data that protooncogene amplification (particularly c-myc) may be involved in the pathogenesis of aggressive common epithelial tumors of the ovary.
Adenocarcinoma, Mucinous↗
[Increase of the effectiveness of radiotherapy of the neoplasms with DNA synthesis inhibitor, oxyurea].
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Animals↗
DNA image cytometric analysis of paraffin-embedded sections of small renal cortical neoplasms.
DNA ploidy analysis of neoplasms is most frequently performed by flow cytometry of single nuclear suspensions or image analysis of Feulgen-stained cytologic specimens. To assess the prognostic significance of ploidy in renal adenomas (less than 3 cm in diameter), nuclear DNA content of 21 renal cortical neoplasms was analyzed by image cytometry (CAS 200, Cell Analysis Systems, Inc., Elmhurst, IL) on Feulgen-stained 5 microns fixed embedded tissue sections. Five (36%) of 14 small neoplasms (so-called renal adenomas; (mean diameter, 7.2 mm; range, 2-24 mm) were in the aneuploid range. Four (57%) of seven carcinomas (mean diameter, 6.3 cm; range, 3.5-10 cm) were aneuploid, a frequency not significantly different from that in the adenomas (P = 0.4). Mean DNA index (1.38) for aneuploid adenomas and carcinomas was identical. Diploid renal adenomas (mean diameter, 5.9 mm) were smaller, although not significantly so (P > 0.05), than the aneuploid ones (mean, 9.7 mm). Size of diploid (mean, 6.7 cm) and aneuploid (mean, 6.1 cm) renal carcinomas was similar. Clinical follow-up studies to evaluate utility of DNA ploidy and proliferative activity in prognosis and management of small renal cortical neoplasms are indicated.
Adenoma↗
Flow cytometric analysis of DNA synthetic phase fraction of the normal appearing colonic mucosa in patients with colorectal neoplasms.
DNA synthetic (S) phase fractions of normal appearing colonic mucosa in Japanese and British patients with colorectal neoplasms were compared with those in patients without colonic neoplasms. Normal crypts were isolated from fresh surgical specimens of the large intestine by the use of EDTA. After fixation with 70% ethanol, isolated crypts were digested with pepsin into single nuclei suspensions. These were stained with propidium iodide and examined by flow cytometry. S phase fraction was calculated from the flow cytometry DNA histogram using Baisch's method. S phase fractions of normal appearing crypts in Japanese and British patients with colorectal tumours were not significantly different and analysed together. S phase fraction of normal appearing colonic crypts in 14 patients with familial adenomatous polyposis (FAP) was 10.23 (2.59%) (mean SD)) ranging from 5.8 to 18.8. S phase fraction of background normal mucosal in patients with large adenomas (over 2 cm) and adenocarcinomas were 9.74 (3.76%) (range, 2.7-16.1) and 8.93 (3.54%) (range, 2.9-18.9) respectively. In normal mucosa of patients without any colorectal neoplasms, S phase fraction was 8.99 (3.94)% (range, 3.9-17.7). There was no statistically significant difference in S phase fractions of normal mucosa in the four groups. Our results show that an increase in proliferative activity of background colonic crypts is not necessary for tumour development.
Adenocarcinoma↗
Analysis of DNA surrounding the breakpoints of chromosomal translocations involving the beta T cell receptor gene in human lymphoblastic neoplasms.
DNA containing breakpoints of two different t(7;9) chromosomal translocations was cloned from the T lymphoblastic tumor cell lines SUP-T1 and SUP-T3. Sequence analysis of DNA from the t(7;9)(q34;q34.3) translocation of SUP-T1 revealed that chromosome 9 DNA had recombined with DNA 5' to rearranged D-J regions in the beta T cell receptor gene of chromosome 7. Restriction analysis and hybridization studies using DNA fragments cloned from the t(7;9)(q34;32) translocation of SUP-T3 confirmed that beta T cell receptor DNA is also joined to the DNA of chromosome 9 in these cells. Using hybridization probes for the two breakpoints, several other cases of T lymphoblastic tumors were shown to possess DNA rearrangements near the 9q34.3 and 9q32 sites. Hybridization with the 9q34.3 probe detected multiple transcripts in SUP-T1 RNA and small amounts of larger transcripts in T cells lacking the t(7;9)(q34;q34.3) translocation. This work directly demonstrates that the beta T cell receptor locus may frequently be involved in chromosomal translocations within T lymphoblastic neoplasms.
Chromosome Mapping↗
Most null large cell lymphomas are B lineage neoplasms.
DNA of immunoglobulin and the beta T cell receptor genes was analyzed for rearrangements in 34 diffuse large cell lymphomas that failed to express immunoglobulins or T cell antigens. Twenty-eight cases had both heavy and light chain immunoglobulin rearrangements, two cases had only heavy chain gene rearrangements, three cases had only light chain gene rearrangements, and one case failed to show rearrangements for any of the immunoglobulin genes. None of the cases showed rearrangements for the beta T cell receptor gene. These results indicate that the vast majority of diffuse large cell lymphomas that lack definitive B or T cell phenotypic markers are actually B cell in origin.
Antigens, Differentiation, B-Lymphocyte↗
Flowcytometric and histopathological correlation of primary intracranial neoplasms.
DNA ploidy and synthetic phase fraction (SPF) of 52 cases of primary intracranial neoplasms have been determined from fresh tissues and the data was correlated with histopathological typing and grading. Fresh tumour tissues from 52 random surgical biopsies (28 malignant and 24 benign) were obtained from neurosurgical operations during the period 1994-1996. The cells were analysed in Becton Dickinson flowcytometer fitted with Consort 30 programme and 'Sober' software. Percentage of diploid cells, proliferative cells and DNA aneuploidy were evaluated. The tumours were classified and graded according to WHO classification (1993). On histology, there were 28 malignant (grade II to IV) and 24 benign cases (grade I). All the histologically benign tumours in this study showed diploid DNA content with the exception of a pituitary adenoma which had a heterogeneous population of cells. The S phase fraction in all the benign cases was less than 10% except in the case of choroid plexus papilloma (S-phase 54%) and an atypical meningioma (S-phase 14%). Out of the 28 malignant tumours, 12 cases were aneuploid (43%) and the rest were diploid (57%). Among the 16 diploid tumours, SPF was more than 10% in eight cases. DNA aneuploidy and high SPF are more common in histologically malignant tumours than benign tumours. SPF is a reflection of proliferation potential of a tumour and may have some role in prognostication of brain tumours.
Brain Neoplasms↗
Angiogenic factor VEGF is decreased in human colorectal neoplasms showing DNA microsatellite instability.
Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are two important determinants of angiogenesis in human cancers. Expression of VEGF and bFGF was examined by immunohistochemistry in 120 colorectal cancers. Neoplasms were classified according to the presence or absence of microsatellite instability determined at six microsatellite loci and labelled as a high microsatellite instability (MSI-H), low microsatellite instability (MSI-L) or microsatellite stable (MSS). Only 4/30 MSI-H cancers expressed VEGF (13 per cent), compared with 24/64 MSS cancers (38 per cent; p< 0.01). Fewer MSI-H cancers showed bFGF expression (38 per cent) than MSS cancers (53 per cent; p< 0.09). MSI-L cancers showed the same pattern as MSS cancers. Western blotting and immunohistochemistry showed that the tumour suppressor gene p53 was mutated infrequently in MSI-H cancers (8 per cent; p< 0. 001). Microvessel density counts using CD31 and UEA-1 demonstrated no difference in the number of blood vessels in MSI-H and MSS cancers. Although these results are consistent with the known role of wild-type p53 in down-regulating VEGF, no association was found between a mutation in p53 and VEGF or bFGF levels in all colonic neoplasms. This is the first evidence that MSI-H cancers may follow a different pathway to angiogenesis. The low frequency of VEGF expression amongst MSI-H cancers may partially explain why these cancers are less aggressive, with a better overall prognosis.
Adenocarcinoma↗
Hypomethylation of the rat glutathione S-transferase pi (GSTP) promoter region isolated from methyl-deficient livers and GSTP-positive liver neoplasms.
DNA methylation at the 5-position on the cytosine ring in CpG dinucleotides (CpG sites) appears to play an important role in regulating gene expression. In general, there is an inverse relationship between promoter CpG site methylation and the potential for transcription. Thus, changes in DNA methylation density may lead to altered levels of proteins such as glutathione S-transferase pi (GSTP), which is frequently used as a marker to detect hepatocellular foci and neoplasms in the rat. In the present study, the level of CpG methylation in the rat GSTP promoter region was determined in bisulfite-treated DNA isolated from control (untreated) rat livers, chemically induced, GSTP-positive rat liver neoplasms, and methyl-deficient rat livers that contained numerous GSTP-positive foci after administration of a defined diet deficient in folate and choline and low in methionine (0.18%). Eight cytosines between -235 and + 140 in the GSTP promoter region were methylated in a site-specific manner in GSTP-negative control liver, whereas these same sites were hypomethylated in all four chemically-induced, GSTP-positive neoplasms. Similarly, all CpG sites were unmethylated in methyl-deficient liver DNA within 3 weeks of the rats receiving the methyl-deficient diet, and they remained unmethylated throughout the 36-week treatment period. Five of the eight CpG sites are located within consensus sequences for the DNA binding proteins Spl and E2F. This indicates at least one possible mechanism that could potentially lead to transcriptional activation of GSTP in hepatocellular foci and neoplasms during rat hepatocarcinogenesis. These findings suggest that methylation of critical cytosines within the promoter region rather than all CpG-associated cytosines may be a determining factor in regulation of GSTP expression.
Animals↗
Molecular diagnosis of haematological neoplasms.
DNA analysis has become of practical value in the diagnosis and classification of leukaemias and lymphomas. This is exemplified by the study of lymphoproliferative disorders using immunoglobulin and T-cell receptor gene probes for the determination of clonality and cell lineage. Chromosomal analysis with DNA probes is now a useful complementary approach to cytogenetics. For example, the study of particular lymphomas or chronic myelogenous leukaemia with DNA probes hybridising to specific chromosomal breakpoints allows the detection of chromosomal translocations at a genomic level. Chromosomal loss in neoplastic cells can be detected by DNA probes in individual heterozygous for particular restriction fragment length polymorphisms, most efficiently by locus-specific hypervariable region probles. These techniques will enable progress to be made in the understanding of the biology of remission and disease progression in haematological malignancies.
DNA↗
DNA mapping of colorectal neoplasms: a flow cytometric study of DNA abnormalities and proliferation.
BACKGROUND: There is some evidence that neoplastic development and progression evolve through a multistep process associated with hyperproliferation and genetic alterations. Therefore, changes of proliferation and of cellular DNA content within the adenoma-carcinoma sequence were studied. METHODS: Using a "mapping" procedure, 12 adenomas and 18 carcinomas were analyzed flow cytometrically and histologically. In addition, normal mucosa adjacent to and distant from the tumors was assessed in the same way. RESULTS: Of 59 adenomatous fractions, 35.6% (n = 21) were aneuploid, whereas the incidence of aneuploidy was 63.5% (54/85) in the carcinomatous sites. Additional tetraploidies were identified in 5 (8.5%) and 13 (15.3%) adenomatous and carcinomatous samples, respectively. Cell proliferation, as determined by the percentage of S-phase cells, was significantly (P < 0.001) higher in the carcinomatous specimens (14.8% +/- 0.8%; mean +/- SEM) than in the adenomatous ones (8.1% +/- 0.7%). It decreased to normal mucosa adjacent to (5.1% +/- 0.5%) and distant (5.3% +/- 0.6%) from the neoplasms. DNA mapping of the tumors revealed both distinct regions and extended areas of aneuploidy and tetraploidy. There is evidence from the mapping data that aneuploid populations arise at a single focus of the adenoma and expand over large areas before a subpopulation of cells acquires the capacity of invasion. CONCLUSIONS: These data showing consecutive DNA content abnormalities within the colorectal adenoma-carcinoma sequence provide support for genomic instability and clonal evolution as important events of tumorigenesis and progression.
Adenoma↗
An image cytometric DNA-analysis in breast neoplasms. Parameters of DNA-aneuploidy and their relationship with conventional prognostic factors.
In this prospective study, an image cytometric DNA-analysis was performed in 86 women with breast neoplasms (72 primary invasive carcinomas and 14 benign lesions). Four DNA ploidy parameters were analysed: histogram type (according to AUER classification), DNA-index, tumor cells with DNA content above the 5n limit and DNA malignancy grade (DNA-MG, calculation according to Böcking). Their correlations with well established prognostic factors in breast carcinomas (tumor size, lymph node status, histologic grade, hormone receptor content) were studied. All but one benign lesions were diploid (13/14 cases), whereas the majority of the primary invasive breast carcinomas were aneuploid (58/72 cases). A predominance of carcinomas with a percentage of cells superior or equal to 1% with DNA content above the 5n limit was observed (54 cases out of 58). Most of the aneuploid tumors had a histogram type III or IV (53 cases) or a high DNA-index (50 cases). Of these 58 aneuploid cases, only 26 tumors had a DNA-MG superior to 1. Interestingly, 26 tumors had the 4 criteria of aneuploidy, 19 had 3 and 9 had 2 and only 4 tumors had one parameter. The DNA-MG was significantly related to hormonal receptors (p less than 0.001) and tumor size (p less than 0.01). The histogram types (Auer classification) and the DNA content above the 5n limit were correlated with histologic grade (SBR or SBRM) (p less than 0.02). Concerning the DNA-index no correlation was observed with well established prognostic factors. On the other hand no significant correlation was found between these new biologic variables and lymph node status.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗