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      Neoplasias astrocitárias e correlação com as proteínas p53 mutada e Ki-67 Translated title: Astrocytic neoplasms and correlation with mutate p53 and Ki-67 proteins


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          As neoplasias astrocitárias correspondem a 60% dos tumores do sistema nervoso central, sendo o estudo da biologia molecular um importante passo para a compreensão da gênese e comportamento biológico destas doenças. As proteínas Ki-67, que é um marcador de proliferação celular, e p53, que é o produto do gene supressor de tumor de mesmo nome, são importantes marcadores tumorais. O objetivo deste estudo foi identificar e quantificar as proteínas Ki-67 e produto do gene supressor de tumor TP53 em diferentes graus de malignidade das neoplasias astrocitárias, bem como analisar suas relações com idade e sexo. Foram estudadas por imuno-histoquímica as proteínas Ki-67 e p53 em 47 pacientes com neoplasias astrocitárias ressecadas cirurgicamente, classificadas previamente e revisadas quanto ao grau de malignidade, de acordo com o proposto pela Organização Mundial da Saúde. Os núcleos celulares imunomarcados foram quantificados no programa Imagelab-softium pela razão paramétrica absoluta entre os núcleos de células positivas e o número total de células tumorais, sendo contadas 1000 células. O delineamento utilizado foi transversal não controlado. Para análise estatística as variáveis foram divididas em grupos, que para a Ki-67 foram ausente, <5% e >5% e para a p53 foram ausente (0), <25% (1+), entre 25 e 50% (2+), entre 50 e 75% (3+) e maior que 75% (4+). Ki-67 esteve presente em 37 casos (78,72%) expressando correlação com maior grau de malignidade (p<0,001) . A p53 esteve presente em 14 casos (35,13%) tendo maior correlação com astrocitoma grau IV (p=0,59). Não houve correlação estatisticamente significativa entre p53 e Ki-67, bem com entre estas variáveis, idade e sexo. Concluiu-se que a hipótese de maior presença de Ki-67 e p53 em neoplasias astrocitárias de maior grau de malignidade, com exceção da correlação entre grau III e p53, é corroborada pelos resultados deste estudo.

          Translated abstract

          The astrocytic neoplasms respond by 60% of the central nervous system tumors, being the study of the molecular biology an important step for the understanding of the genesis and biological behavior of these diseases. The Ki-67 proteins, which are markers of the cellular proliferation, and p53, which is the product of the tumor suppressor gene TP53, are both important tumoral markers. This study intends to identify and quantify the Ki-67 and p53 proteins in astrocytic tumors of different grades of malignancy, as well as to analyze their relations with age and gender. Ki-67 and p53 proteins in 47 patients with surgically resected astrocytic neoplasms were studied through immunohistochemistry. They have been previously classified and reviewed concerning their histological grade, as suggested by the World Health Organization. The immunomarked cellular nuclei were quantified by the program Imagelab-softium for the absolute parametric reason between the nuclei of the positive cells and the total amount of tumoral cells, being counted 1000 cells. The lineation used has been transversal not controlled. For the statistical analysis the variables were divided into groups. For the Ki-67 they were absent, <5% and >5% and for p53 they were absent (0), <25% (1+), between 25 and 50% (2+), between 50 and 75% (3+), and higher than 75% (4+). Ki-67 was present in 37 cases (78.72%) evidencing a correlation with a higher malignancy degree (p<0,001). p53 was present in 14 cases (35.13%) with a higher correlation with astrocytoma grade IV (p=0.59). There has not been a statistically significant correlation between p53 and Ki-67, as well as among these variables, age and gender. The hypotheses of a greater presence of Ki-67 and p53 in astrocytic neoplasms with a higher degree of malignancy, except for the correlation between grade III and p53, is corroborated by the results of this study.

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          Most cited references33

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          The Ki-67 protein: from the known and the unknown.

          The expression of the human Ki-67 protein is strictly associated with cell proliferation. During interphase, the antigen can be exclusively detected within the nucleus, whereas in mitosis most of the protein is relocated to the surface of the chromosomes. The fact that the Ki-67 protein is present during all active phases of the cell cycle (G(1), S, G(2), and mitosis), but is absent from resting cells (G(0)), makes it an excellent marker for determining the so-called growth fraction of a given cell population. In the first part of this study, the term proliferation marker is discussed and examples of the applications of anti-Ki-67 protein antibodies in diagnostics of human tumors are given. The fraction of Ki-67-positive tumor cells (the Ki-67 labeling index) is often correlated with the clinical course of the disease. The best-studied examples in this context are carcinomas of the prostate and the breast. For these types of tumors, the prognostic value for survival and tumor recurrence has repeatedly been proven in uni- and multivariate analysis. The preparation of new monoclonal antibodies that react with the Ki-67 equivalent protein from rodents now extends the use of the Ki-67 protein as a proliferation marker to laboratory animals that are routinely used in basic research. The second part of this review focuses on the biology of the Ki-67 protein. Our current knowledge of the Ki-67 gene and protein structure, mRNA splicing, expression, and cellular localization during the cell-division cycle is summarized and discussed. Although the Ki-67 protein is well characterized on the molecular level and extensively used as a proliferation marker, the functional significance still remains unclear. There are indications, however, that Ki-67 protein expression is an absolute requirement for progression through the cell-division cycle. Copyright 2000 Wiley-Liss, Inc.
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            Incidence and timing of p53 mutations during astrocytoma progression in patients with multiple biopsies.

            Mutations of the p53 tumor suppressor gene are a genetic hallmark of human astrocytic neoplasms, but their predictive role in glioma progression is still poorly understood. We analyzed 144 biopsies from 67 patients with recurrent astrocytoma by single-strand conformation polymorphism and direct DNA sequencing. We found that 46 of 67 patients (69%) had a p53 mutation in at least one biopsy. In 41 of these (89%), the mutation was already present in the first biopsy, indicating that p53 mutations are early events in the evolution of diffuse astrocytomas. Double mutations of the p53 gene were observed in three tumors and also present from the first biopsy. Of 28 low-grade astrocytomas with a p53 mutation, 7 (25%) showed loss of the normal allele in the first biopsy. The allele status remained the same in 95% of the cases, irrespective of whether the recurrent lesion had the same or a higher grade of malignancy. Progression of low-grade astrocytomas to anaplastic astrocytoma or glioblastoma occurred at a similar frequency in lesions with (79%) and without (63%) p53 mutations (P = 0.32), indicating that this genetic alteration is associated with tumor recurrence but not predictive of progression to a more malignant phenotype. However, the time interval until progression was shorter in patients with low-grade astrocytomas carrying a p53 mutation (P = 0.055).
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              Influence of p53 mutations on prognosis of patients with glioblastoma.

              The influence of p53 mutations on the biology of astrocytic tumors is controversial. p53 is thought to be inactivated in the early stage of gliomagenesis; however, what role its inactivation plays in the malignancy of gliomas remains unknown. To understand the significance of p53 inactivation, the authors identified the locus of p53 gene mutation in glioma samples at different stages of progression and studied the correlation between the mutation and clinical behavior. Samples from newly diagnosed gliomas, including pure and mixed astrocytomas, were analyzed for p53 mutations using a yeast functional assay. To determine the locus of the gene mutations, DNA sequencing was performed. The incidence of p53 mutations was higher in anaplastic astrocytomas (AA, 48%) than glioblastomas (GBM, 31%). There was no significant difference in the average ages of GBM patients with and without p53 mutations (54.9 years +/- 2.3 and 53.2 years +/- 4.6, respectively). In GBM patients, the mutation did not affect progression free survival or overall survival. Astrocytomas and GBM differed in the distribution of p53 mutation loci. The p53 gene mutation does not markedly affect the survival of GBM patients. The difference in the location of p53 mutations between AA and GBM suggests that in gliomas, the p53 mutation may contribute not only to tumorigenesis (as an early event) but also to progression to malignancy (as a late event). Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10677

                Author and article information

                Arquivos de Neuro-Psiquiatria
                Arq. Neuro-Psiquiatr.
                Academia Brasileira de Neurologia - ABNEURO (São Paulo, SP, Brazil )
                December 2005
                : 63
                : 4
                : 997-1004
                [05] orgnameUNICENP
                [01] orgnameIPEM
                [06] orgnameHUEC
                [03] orgnameFEPAR
                [02] orgnameUFPR
                [04] orgnameUniversidade de São Paulo
                S0004-282X2005000600017 S0004-282X(05)06300417

                This work is licensed under a Creative Commons Attribution 4.0 International License.

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                SciELO Brazil

                astrocytoma, Ki-67, p53, astrocitoma


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