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1.
Iatreia ; 34(4): 370-374, oct.-dic. 2021. graf
Article in Spanish | LILACS | ID: biblio-1350837

ABSTRACT

RESUMEN Las alteraciones genéticas en el gen TP53 están presentes entre el 5 al 8 % de los pacientes de leucemia linfocítica crónica (LLC) en el momento del diagnóstico. Estos casos se relacionan con un mal pronóstico debido a su resistencia al tratamiento estándar. Presentamos el caso de un paciente masculino de 52 años diagnosticado con LLC, expresión del marcador CD38 y una deleción en el gen TP53 (17p13.1). Tras la evaluación posterior del tratamiento, se observó enfermedad mínima residual lo que llevó a un trasplante haploidéntico de progenitores hematopoyéticos. Debido al alto riesgo de recaída, su edad y la ausencia de comorbilidades, era la única opción curativa hasta la fecha para la LLC. El objetivo de este trabajo es realizar una revisión de la literatura que sirva como base para analizar el caso clínico presentado, en el marco de las implicaciones clínicas, pronóstico y respuesta al tratamiento en los individuos con LLC que presentan alteraciones en el gen TP53.


SUMMARY Genetic alterations in the TP53 gene are present in 5 to 8% of chronic lymphocytic leukemia (CLL) cases at the time of diagnosis. These cases are typically associated with poor prognosis due to their resistance against standard CLL treatment. In our report a 52-yearold male patient was diagnosed with CLL, CD38 expression and a deletion in the TP53 gene (17p13.1). Upon evaluation post-treatment, minimal residual disease (MDR) was observed, and a haploidentical stem cell transplant was performed. Because of the high risk of relapse, his age, and the absence of comorbidities it was the only curative option to date for CLL. The purpose of this article is to complete a literature review that will give a basis to analyze the clinical case presented, within the framework of the clinical implications, prognosis, and response to treatment in patients with CLL who present with aberrations of the TP53 gene.


Subject(s)
Humans , Leukemia, Lymphocytic, Chronic, B-Cell , Genes, p53 , Research Report
2.
Rev. ADM ; 78(5): 258-263, sept.-oct. 2021. ilus, tab
Article in Spanish | LILACS | ID: biblio-1344709

ABSTRACT

Introducción: La displasia epitelial oral (DEO) es la presencia de alteraciones celulares y tisulares, lo que puede significar una etapa anterior al desarrollo del cáncer. Múltiples marcadores han sido considerados para estimar su potencial neoplásico y evolución a carcinoma, incluyendo a la molécula p53, se considera como participe de diversos fenómenos de la homeostasis celular. Objetivo: Determinar la relación entre la inmunoexpresión de p53 DO-7 y PAb 240 con el grado de severidad de la displasia epitelial oral. Material y métodos: Se analizaron nueve muestras de DEO (tres para cada grado de severidad). La inmunoexpresión de p53 tipo silvestre (DO-7) y forma mutada (PAb 240), fue determinada a través de ensayo de inmunohistoquímica por peroxidasa. Se obtuvieron la media y desviación estándar y se realizó la prueba χ2 (p < 0.05). Resultados: La edad media fue de 65.7 ± 11.4 años, la zona anatómica con mayor presencia de DEO es el borde lateral de la lengua. Ocho de nueve muestras fueron positivas para DO-7 y solo dos para PAb 240. Conclusiones: Nuestros resultados indican que, aunque la expresión de p53 DO-7 podría estar relacionada parcialmente con la patogénesis de la displasia epitelial, no todas las displasias presentaron la forma mutada de p53 (PAb 240). Lo cual coincide con el comportamiento biológico incierto de las displasias al poder permanecer sin cambios, involucionar o transformarse


Introduction: Oral epithelial dysplasia (OED) is the presence of cellular and tissue alterations, which may mean a stage prior to the development of cancer. Multiple markers have been considered to estimate its pathogenic potential and evolution to neoplasms, including the p53 molecule, considered as participating in various phenomena of cellular homeostasis. Objective: To determine the relationship between the immunoexpression of p53 DO-7 and PAb 240 with the degree of severity of oral epithelial dysplasia. Material and methods: Nine OED samples were analyzed (three for each degree of severity). The immunoexpression of wild-type p53 (DO-7) and mutated form (PAb 240) was determined through a peroxidase immunohistochemical assay. The mean and standard deviation were obtained, and χ2 test (p < 0.05) were performed. Results: The mean age was 65.7 ± 11.4 years, with a greater presence of OED in the anatomical area of the lateral side of the tongue. Eight out of nine samples were positive for DO-7 and only two for PAb 240. Conclusions: Our results indicate that, although the expression of p53 DO-7 could be partially related to the pathogenesis of epithelial dysplasia, not all dysplasias presented the mutated form of p53 (PAb 240), which coincides that not all dysplasias have a potential for malignant transformation and that could be related to other oncogenic mechanisms (AU)


Subject(s)
Humans , Male , Female , Child , Adolescent , Adult , Middle Aged , Aged , Precancerous Conditions , Immunohistochemistry , Genes, p53 , Gingival Neoplasms , Tongue Neoplasms , Pilot Projects , Statistical Analysis , Carcinogenesis , Observational Study , Mexico
3.
Rev. colomb. obstet. ginecol ; 72(3): 307-318, July-Sept. 2021. tab, graf
Article in Spanish | LILACS | ID: biblio-1351955

ABSTRACT

Objetivo: describir el caso de una paciente con Síndrome de Li-Fraumeni (SLF) y cáncer de mama, en quien se cuestionó el beneficio en la supervivencia de la mastectomía profiláctica contralateral (MPC); asimismo, se pretende hacer una discusión crítica acerca de la evidencia que soporta este procedimiento en esta población. Presentación del caso: mujer de 37 años con cáncer de mama y múltiples antecedentes familiares de cánceres de temprana aparición del espectro del SLF, en quien, durante la adyuvancia hormonal, se confirmó una variante patogénica en el gen TP53. La paciente fue presentada en la Junta Multidisciplinaria del Servicio de Mama de un Centro Oncológico de referencia en Colombia, con el fin de discutir el beneficio de la MPC. La decisión de la junta fue no realizar la MPC. Después de 30 meses de seguimiento la paciente se encuentra libre de enfermedad. Conclusión: no existe evidencia que analice, de forma particular, el impacto de la MPC en la supervivencia de las pacientes con SLF y cáncer de mama. Sin embargo, a la luz del conocimiento actual no es posible generalizar la conducta de omitir esta cirugía profiláctica. Es importante reportar los casos en los que se decida realizar u omitir este procedimiento con el fin de incrementar el cuerpo de la evidencia, dado que existen limitaciones para construir grandes cohortes o estudios experimentales exclusivos para esta alteración genética.


Objective: To describe the case of a patient with Li-Fraumeni syndrome (LFS) and breast cancer in whom the benefit of contralateral prophylactic mastectomy (CPM) was challenged; and to offer a critical discussion regarding the evidence supporting this procedure in this patient population. Case presentation: A 37-year-old woman with breast cancer and a family history of multiple early onset cancer of the LFS spectrum in whom a pathogenic variant of the TP53 gene was confirmed during adjuvant hormonal therapy. The case was presented during the multidisciplinary meeting of the Breast Service of a referral oncology center in Colombia, in order to discuss the benefit of CPM. The decision of the board meeting was not to perform CPM. After 30 months of follow-up, the patient is disease-free. Conclusion: There is no evidence on the impact of CPM on survival of patients with LFS and breast cancer in particular. However, in light of the current knowledge, it is not possible to generalize the approach of withholding this prophylactic surgery. It is important to report those cases in which the decision is made to either perform or omit this procedure in order to increase the body of evidence, considering the limitations that make it difficult to build large cohorts or conduct trials exclusively for this genetic disorder.


Subject(s)
Female , Adult , Breast Neoplasms , Li-Fraumeni Syndrome , Genes, p53 , Prophylactic Mastectomy
4.
Arch. argent. pediatr ; 119(1): e11-e17, feb. 2021. tab
Article in English, Spanish | LILACS, BINACIS | ID: biblio-1147183

ABSTRACT

El cáncer en pediatría es una entidad infrecuente. Se estima que más de un 10-15 % de los tumores son secundarios a una variante patogénica en un gen de predisposición al cáncer.Se conocen más de 100 genes de predisposición al cáncer y su asociación con síndromes o tumores aislados. Uno de los más descritos es el síndrome de Li-Fraumeni.Los pacientes con este síndrome tienen alto riesgo de desarrollar uno o más tumores. Su conocimiento permite realizar un protocolo de seguimiento del paciente y de sus familiares afectos, con el que detectar precozmente nuevos tumores y disminuir la morbimortalidad del tumor y de su tratamiento.Esta revisión pretende ser una guía útil para el pediatra. Utilizando como caso guía a una familia, se revisarán los motivos de sospecha de un síndrome de Li-Fraumeni, su diagnóstico clínico y genético, y el protocolo de seguimiento de los familiares portadores de la misma mutación


Pediatric cancer is rare. It is estimated that more than 10-15 % of tumors are secondary to a pathogenic variant in a cancer predisposition gene.More than 100 cancer predisposition genes and their association with syndromes or isolated tumors have been identified. Li-Fraumeni syndrome is one of those who have been most widely described.Patients with this syndrome present a high risk of developing one or more tumors. Its knowledge allows to establish a follow-up protocol for the patient and affected family members, so as to detect new tumors in an early manner and reduce tumor- and treatment-related morbidity and mortality.The objective of this review is to offer useful guidelines for pediatricians. Based on a family case, reasons for Li-Fraumeni syndrome suspicion, clinical and genetic diagnosis, and the follow-up protocol of family members who carry the same mutation will be reviewed.


Subject(s)
Humans , Infant , Child, Preschool , Child , Li-Fraumeni Syndrome/diagnosis , Pediatrics , Neoplastic Syndromes, Hereditary , Genes, p53 , Li-Fraumeni Syndrome/epidemiology
5.
Hematol., Transfus. Cell Ther. (Impr.) ; 42(3): 261-268, July-Sept. 2020. tab
Article in English | LILACS | ID: biblio-1134048

ABSTRACT

ABSTRACT Chronic lymphocytic leukemia is the most common hematologic malignancy among adults in Western countries. Several studies show that somatic mutations in the TP53 gene are present in up to 50% of patients with relapsed or refractory chronic lymphocytic leukemia. This study aims to review and compare the methods used to detect somatic TP53 mutations and/or 17p deletions and analyze their importance in the chronic lymphocytic leukemia diagnosis and follow-up. In chronic lymphocytic leukemia patients with refractory or recurrent disease, the probability of clonal expansion of cells with the TP53 mutation and/or 17p deletion is very high. The studies assessed showed several methodologies able to detect these changes. For the 17p deletion, the chromosome G-banding (karyotype) and interphase fluorescence in situ hybridization are the most sensitive. For somatic mutations involving the TP53 gene, moderate or high-coverage read next-generation sequencing and Sanger sequencing are the most recommended ones. The TP53 gene mutations represent a strong adverse prognostic factor for patient survival and treatment resistance in chronic lymphocytic leukemia. Patients carrying low-proportion TP53 mutation (less than 20-25% of all alleles) remain a challenge to these tests. Thus, for any of the methods employed, it is essential that the laboratory conduct its analytical validation, documenting its accuracy, precision and sensitivity/limit of detection.


Subject(s)
Humans , Leukemia, Lymphocytic, Chronic, B-Cell , Genes, p53 , Chromosome Deletion , Mutation
6.
Hematol., Transfus. Cell Ther. (Impr.) ; 42(3): 269-274, July-Sept. 2020. ilus
Article in English | LILACS | ID: biblio-1134046

ABSTRACT

ABSTRACT Recent advances in chronic lymphocytic leukemia (CLL) includes description of disease genomic landscape, inclusion of prognostic relevant genetic tests in CLL workflow and evaluation of minimal residual disease (MRD)1 in parallel with the increase availability of novel therapy agents.In this review, the theoretical and practical aspects of response assessment have been discussed. These are based on updated recommendations of the European Research Initiative on Chronic Lymphocytic Leukemia (ERIC) for genetic tests (TP53 mutation and IGHV status) and flow cytometry analysis for CLL. Methodological approaches and interpretation of results were also discussed.2,3


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Genes, p53 , Neoplasm, Residual , Flow Cytometry , Mutation
8.
Repert. med. cir ; 28(2): 105-110, 2019. Il., tablas
Article in English, Spanish | LILACS, COLNAL | ID: biblio-1009958

ABSTRACT

Introducción: la mutación en el gen TP53 se ha asociado con la oncogénesis de los tumores de ovario tipo II. Se ha propuesto que las mutaciones de p53 se inician en las células de la trompa uterina y después migran al ovario. El objetivo de este estudio es establecer la frecuencia de la expresión de p53 en ovario y trompa uterina en carcinoma epitelial primario de ovario. Materiales y métodos: estudio de corte transversal en tumores primarios epiteliales de ovario. Se evaluó la expresión de p53 por inmunohistoquímica en el ovario y en las trompas uterinas. Resultados: se incluyeron 45 pacientes con edad media de 55 años. Se estudiaron 24 casos de carcinomas serosos, 6 endometrioides, 5 mixtos, 3 de células claras, 3 carcinosarcomas, 2 carcinomas mucinosos y 2 indiferenciados. Se observó positividad fuerte y difusa en 68% de los tumores tipo II. En 52 hubo positividad en trompa uterina y ovario, 92% con compromiso bilateral. En 3 de estos casos se reconoció carcinoma intraepitelial tubárico con positividad de p53 en el área tumoral, no tumoral y en el carcinoma seroso. Conclusión: como se ha observado en estudios previos, el gen TP53 está involucrado en la oncogénesis de los tumores tipo II y se ha demostrado que existe una relación entre una mutación inicial de p53, seguida por STIL, STIC, evolucionando a un carcinoma seroso de ovario.


Introduction: a TP53 gene mutation has been associated with the oncogenesis of type II ovary tumors. Mutations of the p53 gene in the fallopian tube cells which migrate to the ovary have been proposed as an alternative origin. This study focuses on establishing the frequency of p53 ovary and uterine tube expression in primary epithelial ovarian cancer. Materials and Methods: a cross-sectional study on primary epithelial ovarian tumors. Expression of p53 in the ovary and uterine tubes was assessed using immunohistochemistry. Results: 45 patients, median age 55 years, were included. Twenty-four (24) cases of serous carcinomas, 6 endometrioid carcinomas, 5 mixed carcinomas, 3 clear-cell carcinomas, 3 carcinosarcomas, 2 mucinous carcinomas and 2 undifferenciated tumors were studied. Positivity was strong and diffuse in 68% of type II tumors. Positivity was detected in the tubes and ovaries in 52 cases, 92% with bilateral compromise. Intraepithelial tube carcinoma was recognized in 3 cases with p53 positivity in the tumor, outside the tumor and in the serous carcinoma. Conclusion: as observed in previous studies, TP53 gene is involved in the oncogenesis of type II tumors and a correlation between the initial p53 mutations followed by STIL, STIC progressing to an ovary serous carcinoma has been demonstrated.


Subject(s)
Humans , Carcinoma, Ovarian Epithelial , Genes, p53 , Neoplasms
10.
Journal of Breast Cancer ; : 172-184, 2019.
Article in English | WPRIM | ID: wpr-764271

ABSTRACT

PURPOSE: Tumor protein p53-regulated apoptosis-inducing protein 1 (TP53AIP1) functions in various cancers. We studied the effect and molecular mechanism of TP53AIP1 in breast cancer. METHODS: The degree of correlation between TP53AIP1 expression and overall survival in patients with breast cancer was obtained from the online The Cancer Genome Atlas database. Six of the TP53AIP1 levels in the tumor and adjacent non-tumor tissues randomly selected from 38 breast cancer patients were determined. Transgenic technology was used to enhance the expression of TP53AIP1 in breast cancer cell lines, MDA-MB-415 and MDA-MB-468, and to observe the effects of gene overexpression on the proliferation, cell cycle, and apoptosis of breast cancer cells. The molecular mechanism of association between cell cycle- and apoptosis-related factors and the phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) pathway was also studied. RESULTS: The messenger RNA and protein expression levels of TP53AIP1 in cancer tissues were significantly lower than those in the control group. TP53AIP1 overexpression inhibits cell viability. The mechanism of TP53AIP1 inhibition of proliferation and growth of breast cancer cells includes cell cycle arrest, apoptosis promotion (p < 0.01), promotion of the expression of cleaved-caspase-3 (p < 0.01), cleaved-caspase-9 (p < 0.01), B cell lymphoma/leukemia-2 (Bcl-2)-associated X protein, and p53 (p < 0.01), and the inhibition of Bcl-2, Ki67, and PI3K/Akt pathways (p < 0.01). CONCLUSION: TP53AIP1 may be a novel tumor suppressor gene in breast cancer and can potentially be used as an effective target gene for the treatment of breast cancer.


Subject(s)
Apoptosis , Breast Neoplasms , Breast , Cell Cycle Checkpoints , Cell Line , Cell Proliferation , Cell Survival , Genes, p53 , Genes, Tumor Suppressor , Genome , Humans , Phosphotransferases , RNA, Messenger
11.
J. pediatr. (Rio J.) ; 94(4): 432-439, July-Aug. 2018. tab, graf
Article in English | LILACS | ID: biblio-954624

ABSTRACT

Abstract Objective: To evaluate the clinical features associated with adrenocortical hormone overexpression and familial cancer profiling as potential markers for early detection of adrenocortical tumors in children from South and Southeast Brazil. Methods: The clinical manifestations and anthropometric measurements of 103 children diagnosed with adrenocortical tumors were analyzed. Results: Between 1982 and 2011, 69 girls and 34 boys diagnosed with adrenocortical tumors were followed-up for a median time of 9.0 years (0-34 years). Signs of androgen overproduction alone (n = 75) or associated with cortisol (n = 18) were present in 90.3%. TP53 p.R337H mutation was found in 90.5% of patients. Stages I, II, III, and IV were observed in 45.6%, 27.2%, 19.4%, and 7.8% of patients, respectively. At diagnosis, there were no significant differences in height (p = 0.92) and weight (p = 0.22) among children with adrenocortical tumors, but children with virilization alone had significantly higher height-for-age Z-scores (0.92 ± 1.4) than children with hypercortisolism alone or combined (−0.32 ± 1,8; p = 0.03). The five-year overall survival was 76.7% (SD ± 4.2). Patients with advanced-stage disease had a significantly worse prognosis than those with limited disease (p < 0.001). During follow-up, ten of 55 p.R337H carrier parents developed cancer, whereas none of the 55 non-carriers did. Conclusions: Signs of adrenocortical hormone overproduction appear early, even in cases with early-stage. These signs can be identified at the physical examination and anthropometric measurements. In southern Brazil, pediatric adrenocortical tumor is a sentinel cancer for detecting families with germline p.R337H mutation in TP53 gene.


Resumo Objetivo: Avaliar as manifestações clínicas da hiperexpressão de hormônios do córtex da adrenal e câncer familiar como marcadores para a detecção precoce de tumores adrenocorticais em crianças do Sul e Sudeste do Brasil. Pacientes e métodos: Foram analisadas as manifestações clínicas e antropométricas de 103 crianças diagnosticadas com tumores adrenocorticais. Resultados: Entre 1982 e 2011, 69 meninas e 34 meninos diagnosticados com tumores adrenocorticais foram acompanhados por um tempo mediano de nove anos (0-34). Ao diagnóstico, sinais de virilização isolada (n = 75) ou associada ao cortisol (n = 18) estavam presentes em 90,3% dos pacientes; a mutação do gene TP53 p.R337H foi identificada em 90,5% dos pacientes. Os pacientes foram classificados em estádio I (45,6%), II (27,2%), III (19,4%) e IV (7,8%). Ao diagnóstico, não houve diferença significativa para as medidas de altura (p = 0,92) e de peso (p = 0,22) entre as crianças com tumores adrenocorticais, mas crianças com virilização tiveram escore-Z mais elevado para a idade (0,92 ± 1,4) do que aquelas com hipercortisolismo isolado ou combinado (−0,32 ± 1,8; p = 0,03). A sobrevida global de cinco anos foi de 76,7% (DP ± 4,2). Pacientes com estádios avançados tiveram pior prognóstico (p < 0,001). Durante o seguimento, 10 dos 55 genitores portadores da p.R337H desenvolveram câncer, enquanto que nenhum caso ocorreu entre os 55 não portadores. Conclusões: Os sinais de hiperprodução de hormônios adrenocorticais aparecem precocemente no desenvolvimento do tumor e podem ser identificados pelo exame físico e pelas medidas antropométricas na consulta pediátrica de rotina. O tumor adrenocortical pediátrico é sentinela para a detecção de câncer em famílias que segregam a mutação germinativa p.R337H do gene TP53.


Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Child , Genes, p53/genetics , Tumor Suppressor Protein p53/genetics , Adrenal Cortex Neoplasms/diagnosis , Adrenal Cortex Neoplasms/genetics , Germ-Line Mutation/genetics , Genetic Predisposition to Disease/genetics , Pedigree , Longitudinal Studies , Neoplasm Staging
12.
São Paulo; s.n; 2018. 83 p.
Thesis in Portuguese | LILACS, Inca | ID: biblio-1247978

ABSTRACT

Recentes indicações de um fenótipo mais variável e uma menor penetrância de câncer na síndrome de Li-Fraumeni (LFS) levantaram questões a respeito da verdadeira prevalência populacional da síndrome. Investigações anteriores, baseadas em contextos clínicos, propuseram que as estimativas de prevalência populacional de LFS poderiam variar entre um portador a cada 5.000 a 20.000 indivíduos. O primeiro artigo demonstrou que a prevalência populacional de variantes patogênicas e provavelmente patogênicas no gene TP53, as principais causas de LFS, é mais alta do que a esperada em uma população não selecionada pelo histórico de câncer. Nós sugerimos que a prevalência populacional poderia ser de até 10x mais alta do que previamente descrita. O segundo artigo teve como objetivo avaliar e validar as estimativas de prevalência de variantes germinativas em TP53 no banco de dados do gnomAD, que inclui variações genéticas de mais de 130.000 individuos. Variantes em TP53 foram selecionadas e classificadas com base em nosso algoritmo previamente descrito. Além disso, nós fornecemos estimativas de prevalência alternativas com base na classificação de três bancos de dados, ClinVar, HGMD e o portal UMD_TP53. Com base nessa nova análise, nós observamos que a prevalência populacional de variantes germinativas patogênicas e provavelmente patogênicas no gene TP53 é, de fato, maior do que previamente descrita. Contudo, as estimativas podem variar drasticamente (0,02-0,25%) devido a diferentes classificações e a algumas variantes específicas em TP53 que podem estar associadas a um risco inflacionado (p.N235S, p.V31I e p.R290H). Abordagens interdisciplinares são necessárias para melhor entender a interação entre classificação de variantes em TP53, estimativas de prevalência, penetrância de câncer e fenótipo em LFS


Recent suggestions of a variable Li-Fraumeni syndrome (LFS) phenotype and a lower LFS-associated cancer penetrance have raised questions regarding the true disease population prevalence. Earlier investigations, based on clinical contexts, had proposed that the estimated population prevalence of LFS could be between the range of one carrier in every 5,000-20,000 individuals. The first article reported a higher-than-expected population prevalence of pathogenic and likely pathogenic germline TP53 variants in a population unselected for cancer history. We suggested that the population prevalence could be up to 10x higher than previously described in clinically-based studies. The second article aimed to further evaluate germline TP53 variant prevalence estimates in the gnomAD database, which includes germline variation from over 130,000 individuals. Variants were selected and classified based on our previously published algorithm. In addition, we provided alternative prevalence estimates based on three other classifications databases, ClinVar, HGMD, and the UMD_TP53 website. Based on the new analysis, we observed that the population prevalence of pathogenic and likely pathogenic TP53 variants is indeed higher than previously described. However, the estimates can vary widely (0.02-0.25%) due to differences in variant classifications and due to some specific TP53 variants that may be associated with inflated risk (p.N235S, p.V31I, and p.R290H). Comprehensive approaches are needed to better understand the interplay of germline TP53 variant classification, prevalence estimates, cancer penetrance and phenotype of LFS


Subject(s)
Genetic Variation , Genes, p53 , Li-Fraumeni Syndrome , Germ-Line Mutation
13.
São Paulo; s.n; 2018. 108 p. ilust, tabelas, quadros.
Thesis in Portuguese | LILACS, Inca | ID: biblio-1255263

ABSTRACT

O carcinoma epidermóide do pênis tem incidência significativa em países em desenvolvimento como o Brasil. O tratamento dos tumores invasivos consiste na ressecção da lesão primária e linfadenectomia bilateral, procedimento associado a alta taxa de morbidade. O estudo de fatores prognósticos do tumor primário pode ajudar na seleção dos pacientes candidatos às linfadenectomias. A expressão imunoistoquímica do ki-67, do p53 e da nucleofosmina (NPM) se associam a pior prognóstico em diversas neoplasias. Estudamos retrospectivamente 112 pacientes portadores de carcinoma epidermóide do pênis, submetidos a cirurgia do tumor primário no Departamento de Cirurgia Pélvica do AC Camargo Cancer Center. Os blocos de parafina foram revisados e submetidos a coloração imunoistoquímica para NPM, ki-67 e p53. A leitura foi realizada no dispositivo Aperio®. A imunorreatividade da NPM, Ki67 e p53 foi relacionada a fatores clínicos e patológicos: idade, estado civil, raça, tempo de evolução da doença, antecedentes venéreos, estadiamento clínico, espessura do tumor, grau de diferenciação, embolização linfovascular, estadiamento patológico, tipo de invasão. Analisamos quais fatores influenciaram o risco de metástases linfonodais e sobrevida global (SG) e livre de doença (SLD). Os testes estatísticos de associação utilizados foram o Qui-quadrado, teste de Fischer, a regressão logística múltipla. Na análise de sobrevida utilizamos o Kaplan e Meier, o Log-rank e o modelo de riscos proporcionais de cox. A imunorreatividade do p53 estava alta em 42,3% dos casos e se associou a maior ocorrência de recidivas, mas não a outras variáveis. A imunorreatividade do Ki67 estava alta em 89,1% dos casos e não se associou a nenhuma variável. A NPM apresentou imunoexpressão baixa em 50% dos casos e se associou a maiores estadios clínicos T e N e invasão de corpo cavernoso. A imunorreatividade do p53, da NPM e do Ki67 não se associaram a metástases linfonodais. A ocorrência de metástases linfonodais foi influenciada pelo estadiamento clínico N (p=0,001), grau de diferenciação (p=0,007), invasão vascular (p=0,004), invasão perineural (p<0,001), infiltração de corpos cavernosos (p=0,004), infiltração da uretra (p=0,013) e espessura tumoral (p=0,008). No modelo multivariado, estadiamento clínico N (RR=5,5); IC [1,4-20,8], infiltração de corpos cavernosos (RR=3,9); IC [1,2-12,3] e invasão perineural (RR=4,9); IC [1,5-16,2] foram fatores independentes de risco de metástases linfonodais. A SG ao final de 120 meses foi de 47,3% e foi influenciada por raça (p=0,009), recidivas (p=0,018), grau moderado e alto (p=0,031), infiltração de corpos cavernosos (p=0,037), invasão vascular (p=0,02), invasão perineural (p=0,030), espessura tumoral >5 mm (p=0,015) e metástases linfonodais (p=0,003). A imunoexpressão da NPM, do Ki67 e do p53 não influenciou a SG. Na análise multivariada, a invasão vascular (RR=1,9; IC [1,0-3,6]) se associou a menor SG. A SLD foi influenciada por infiltração de corpo cavernoso (p<0,001), infiltração da uretra (p=0,032), infiltração vascular (p<0,001), metástases linfonodais (p<0,001) e alta imunoexpressão do p53 (p=0,008). A imunorreatividade do Ki67 e da NPM não influenciaram a SLD. Na análise multivariada apenas a invasão de corpo cavernoso (RR=4,0; IC [1,4-11,3]) e a ocorrência de metástases linfonodais (RR=4,2;IC[1,4-13,1]) se associaram a menor SLD. Os resultados permitem concluir que a alta expressão do p53 se associou a pior SLD na análise univariada e a perda de expressão da NPM se associou a maiores estadios clínico e patológico


Penile carcinoma still has relevant incidence in developing countries like Brazil. The gold standard for the treatment of invasive lesions remains amputation followed by bilateral lymphadenectomy, procedures associated with high morbidity. The identification of prognostic factors could help to select the best candidates to lymphadenectomies. The immunoreactivity of p53, nucleophosmin (NPM) and ki67 has been associated with the prognosis of many tumors. A retrospective study of 112 patients with penile carcinoma submitted to amputation and lymphadenectomy at the Division of Urology of A.C.Camargo Cancer Center was undertaken to evaluate the prognostic value of immunoreactivity of p53, NPM and Ki67 in the primary tumor. The immunoreactivity of these proteins were correlated with the followed factors: age, race, marital status, time to diagnosis, venereal history, clinical stage, tumor thickness, histological grade, lymphovascular embolization, corpora cavernosa and urethra infiltration, pattern of invasion, lymph node metastasis, overall survival (OS) and disease free survival (DFS). The association among variables was done by the chi-square test and the survival analysis were performed with the Kaplan & Meier technique and the multi-factorial analysis by the Cox regression technique. The p53 immunoreactivity was high in 42,3% of the cases and was associated with high recurrence rates, but not with other variables. Ki67 immunoreactivity was high in 89,1% of the cases and was not associated with any variable. NPM immunostaining was considered low in 50% of the cases and was associated with higher clinical stages N and T and corpora cavernosa invasion, but not with other variables. There was no association between NPM, p53 and Ki67 immunostaining and lymph node metastasis. Clinical stage N (p=0,001), grade of differentiation (p=0,007), vascular invasion (p=0,004), perineural invasion (p<0,001), corpora cavernosa infiltration (p=0,004), urethral infiltration (p=0,013) and tumor thickness (p=0,008) were significant for the incidence of lymph node metastasis. The multivariate analysis revealed that clinical stage N (RR=5,5; CI [1,4-20,8]), corpora cavernosa infiltration (RR=3,9; CI [1,2-12,3]) and perineural invasion (RR=4,9; CI [1,5-16,2]) were significant for the incidence of lymph node metastasis. The OS at the end of 120 months was 47,3% and was influenced by race (p=0,009), recurrences (p=0,018), moderate or high pathologic grade (p=0,031), corpora cavernosa infiltration (p=0,037), lymphovascular embolization (p=0,02), perineural invasion (p=0,030), tumor thickness (p=0,015) and lymph node metastasis (p=0,03). There was no association between p53, NPM and Ki67 immunoreactivity and OS. Multivariate analysis revealed that vascular invasion (RR=1,9; CI [1,0-3,6]) influenced OS. DFS was influenced by corpora cavernosa infiltration (p<0,001), urethra infiltration (p=0,032), lymphovascular embolization (p<0,001), lymph node metastasis (p<0,001) and p53 immunostaining (p=0,008). NPM and Ki67 immunoreactivity did not influence DFS. Multivariate analysis revealed that corpora cavernosa infiltration (RR=4,0; CI [1,4-11,3]) and lymph node metastasis (RR=4,2; CI [1,4-13,1]) influenced DFS. These results showed that higher p53 expression was associated with a worst DFS at univariate analysis and the low NPM imunoexpression was associated with higher clinical and pathological stages


Subject(s)
Humans , Male , Adult , Middle Aged , Aged , Aged, 80 and over , Penile Neoplasms , Prognosis , Immunohistochemistry , Statistical Analysis , Genes, p53 , Lymphatic Metastasis , Survival , Ki-67 Antigen , Anaplastic Lymphoma Kinase
14.
Braz. j. med. biol. res ; 51(1): e6822, 2018. tab, graf
Article in English | LILACS | ID: biblio-889012

ABSTRACT

Cervical cancer is a public health problem and the molecular mechanisms underlying radioresistance are still poorly understood. Here, we evaluated the modulation of key molecules involved in cell proliferation, cell cycle and DNA repair in cervical cancer cell lines (CASKI and C33A) and in malignant tissues biopsied from 10 patients before and after radiotherapy. The expression patterns of epidermal growth factor receptor (EGFR), excision repair cross-complementation group 1 (ERCC1) and p53 were evaluated in cancer cell lines by quantitative PCR and western blotting, and in human malignant tissues by immunohistochemistry. The mutation status of TP53 gene was evaluated by direct sequencing. Among cell lines, absent or weak modulations of EGFR, ERCC1 and p53 were observed after exposure to 1.8 Gy. Conversely, increased expressions of p53 (5/10 patients; P=0.0239), ERCC1 (5/10 patients; P=0.0294) and EGFR (4/10 patients; P=0.1773) were observed in malignant tissues after radiotherapy with the same radiation dose. TP53 mutations were found only in one patient. Here we show that a single dose of radiotherapy induced EGFR, ERCC1 and p53 expression in malignant tissues from cervical cancer patients but not in cancer cell lines, highlighting the gap between in vitro and in vivo experimental models. Studies on larger patient cohorts are needed to allow an interpretation that an upregulation of p53, EGFR and ERCC1 may be part of a radioresistance mechanism.


Subject(s)
Humans , Female , Adult , Middle Aged , Aged , Carcinoma, Squamous Cell/radiotherapy , Uterine Cervical Neoplasms/radiotherapy , Genes, p53/radiation effects , Genes, erbB-1/radiation effects , DNA-Binding Proteins/radiation effects , Endonucleases/radiation effects , Immunohistochemistry , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Tumor Stem Cell Assay , Blotting, Western , Prospective Studies , Cell Line, Tumor , Mutation
15.
São Paulo; s.n; s.n; 2018. 112 p. tab, graf.
Thesis in Portuguese | LILACS | ID: biblio-967941

ABSTRACT

A ausência de XPC, uma proteína canonicamente envolvida em reparo de DNA por excisão de nucleotídeos, está associada a vários fenótipos característicos de disfunção mitocondrial como o desequilíbrio entre os complexos da cadeia transportadora de elétrons (CTE), redução no consumo de oxigênio, maior produção de peróxido de hidrogênio, e maior sensibilidade a agentes que causam estresse mitocondrial. Contudo, uma descrição mecanística da relação entre deficiência de XPC e disfunção mitocondrial ainda não está bem estabelecida. Aqui mostramos que a deficiência de XPC está associada ao aumento na expressão do supressor de tumor p53. Essa alteração é acompanhada pelo aumento da expressão de diversas proteínas que participam em importantes funções mitocondriais. A inibição de p53 reverte a superexpressão de algumas dessas proteínas. O tratamento com o inibidor do Complexo III da CTE antimicina A induz aumento da expressão de p53 de forma mais acentuada na linhagem Xpc-/-, enquanto o tratamento com o antioxidante N-acetilcisteína diminue a produção basal de H2O2, expressão de p53 e sensibilidade aumentada ao tratamento com antimicina A. Em conjunto, nossos resultados suportam a hipótese de que o aumento da produção de H2O2 em células Xpc-/- tem um papel causal na regulação da expressão de p53 e na disfunção mitocondrial


Although XPC has been initially implicated in the nucleotide excision DNA repair pathway, its deficiency is associated with mitochondrial dysfunction, including unbalanced electron transport chain (ETC) activity, lower oxygen consumption, increased hydrogen peroxide production, and greater sensitivity to mitochondrial stress. However, a mechanistic understanding of the role of XPC in regulating mitochondrial function is still not well established. Here we show that XPC deficiency is associated with increased expression of the tumor suppressor p53, which is accompanied by increased expression of several proteins that participate in important mitochondrial functions. Inhibition of p53 reverses the overexpression of some of these proteins. In addition, treatment with the ETC inhibitor antimycin A induces p53 expression more robustly in the Xpc-/- cells, while treatment with the antioxidant N-acetylcysteine decreases basal H2O2 production, p53 expression and sensitivity to antimycin A treatment. Together, our results support a model in which increased H2O2 production in Xpc-/- causes upregulation of p53 expression and mitochondrial dysfunction


Subject(s)
Xeroderma Pigmentosum/classification , Tumor Suppressor Protein p53/pharmacokinetics , Mitochondrial Proteins , Hydrogen Peroxide/analysis , Genes, p53/physiology , Antimycin A/adverse effects
16.
Appl. cancer res ; 37: 1-7, 2017. tab, ilus
Article in English | LILACS, Inca | ID: biblio-915118

ABSTRACT

Background: Apoptosis-related gene expression such as BCL2, and p53 has been suggested in predicting the patient response to chemo- or radiotherapy, as well as patient's survival. Methods: The aim of this study was to determine changes in BCL2 and p53 apoptosis related gene expressions in chronic lymphocytic leukemia (CLL) patients in response to different chemotherapy regimens and number of treatment courses. The study was conducted on 55 CLL patients (44 CLL and 11 CLL/SLL; small lymphocytic lymphoma) and 40 healthy individuals as control, over three-months period. The RNA was extracted by exploitation total RNA extraction kit, treated with DNAse, then cDNA was synthesized and qRT-PCR used to analyze antiapoptotic BCL2 and tumor suppresser p53 gene expressions. Results: CLL/SLL showed higher BCL2 and p53 gene expression than CLL. The patients with CLL showed three-fold increase in BCL2 gene expression compared to healthy controls (p < 0.05), and 50% decrease in p53 gene expressions (p < 0.05). BCL2 gene expression was higher, particularly, for those who were treated with higher range of treatment courses and combination of fludarabine, cyclophosphamide and rituximab (FCR) regimen. P53 gene expression reciprocally related with BCL2 and vice versa. Conclusions: In contrary to BCL2, p53 gene was extremely expressed in patients treated with chemotherapy agents, particularly after 24­30 months disease duration; suggesting a late expression of p53 during advanced stages of the disease. A proportional change in BCL2 and p53 gene expression was reported with different treatment regimens; Chlorambucil (Clb) decreased and FCR regimen increased BCL2 gene expression. Higher p53 gene expression reported with the Chlorambucil + (Chlorambucil + Prednisolone) regimen (AU)


Subject(s)
Humans , Male , Female , Leukemia, Lymphocytic, Chronic, B-Cell , Leukemia , Gene Expression , Genes, p53 , Apoptosis , Genes, bcl-2 , Chemoradiotherapy
17.
Appl. cancer res ; 37: 1-7, 2017. tab, ilus
Article in English | LILACS, Inca | ID: biblio-915402

ABSTRACT

Background: SIVA is a transcriptional target of p53 that plays a potential role in the development and progression of cancer. In this study, we analyzed SIVA1 and SIVA2 expression, and its association with clinical features and TP53 and MDM2 expression in bone marrow cells from healthy donors and myelodysplastic syndrome (MDS) patients. Methods: Fifty-five untreated patients with MDS and 22 healthy donors were included. Gene expression was evaluated by quantitative PCR. For statistical analysis, Mann­Whitney test, Spearman correlation analysis and Log-rank (Mantel-Cox) were used, as appropriate. A p value <0.05 was considered statistically significant. Results: SIVA1 and SIVA2 transcripts were significantly decreased in bone marrow samples from MDS patients compared to healthy donors, and positively correlated with MDM2 and TP53 expression in MDS patients (all p < 0.05). MDM2 expression was also downregulated in bone marrow samples from MDS patients compared to healthy donors (p < 0.05). However, SIVA1, SIVA2, MDM2 and TP53 expressions did not impact on MDS outcomes. Conclusions: SIVA1 and SIVA2 transcripts are downregulated in bone marrow samples from MDS patients (AU)


Subject(s)
Humans , Male , Female , Adult , Myelodysplastic Syndromes , Genes, p53 , Apoptosis Inducing Factor
18.
Rio de Janeiro; s.n; 2017. 195 p.
Thesis in Portuguese | LILACS, Inca | ID: biblio-1119188

ABSTRACT

O câncer de esôfago (CE) é um tumor altamente frequente e letal, correspondendo ao oitavo lugar em incidência e sexto em letalidade, dentro todos os tipos de tumores. O subtipo histopatológico mais frequente de CE é o carcinoma epidermóide de esôfago (CEE) que corresponde a aproximadamente 80% dos tumores de esôfago. O CEE apresenta uma alta frequência de mutações no gene TP53 que respondem pelas alterações genéticas mais frequentes nesse tumor e parecem contribuir significativamente para a carcinogênese esofágica. A proteína p53 exerce um papel central na resposta a sinais de estresse, e já foi descrito que sua associação com SP1 tem um papel importante na regulação de diversos genes, como p21. Resultados obtidos em nosso grupo sugeriram uma associação entre maior expressão da DNMT3B e a presença de mutação no gene supressor de tumor TP53 em CEE. As DNA Metiltransferases (DNMTs) são enzimas que catalisam a transferência do grupamento metil para citosinas em dinucleotideos CpG, sendo esta a modificação epigenética mais estudada em CEE. A associação entre mutações em TP53 e aumento da expressão das DNMTs sugere um papel de p53 na regulação da expressão dessas enzimas e uma interação entre mecanismos genéticos e epigenéticos envolvidos no desenvolvimento desses tumores. Portanto, este projeto teve por objetivo avaliar a regulação da expressão das DNMTs por p53 e SP1 em CEE. Este trabalho demonstrou, pela análise do perfil de expressão das DNMTs e SP1, de acordo com o status mutacional de TP53, em amostras de CEE provenientes de pacientes do INCA e de pacientes cujos dados foram depositados no banco de dados The Cancer Genome Atlas (TCGA), que tanto DNMT1 quanto SP1 encontram-se superexpressos em amostras de CEE que possuem mutação no gene TP53 e que as expressões desses genes se correlacionam positivamente nas amostras mutadas. Além disso, os experimentos in vitro de modulação da expressão de SP1 e/ou p53, seguidos de análise de expressão gênica, de avaliação da ligação dos fatores de transcrição ao promotor de DNMT1 e da investigação da ativação transcricional desse gene, realizados em linhagens celulares derivadas de CEE (que expressam ou não p53 selvagem, ativa), mostraram que SP1 e p53 participam da regulação transcricional de DNMT1, sendo capazes de se ligar ao promotor do gene que codifica esta enzima e ativar a sua transcrição. SP1 é capaz de se ligar ao promotor de DNMT1 mesmo em condições basais da célula, e p53 somente após a indução de sua expressão. Entretanto, especificidades da interação entre SP1 e p53 na regulação transcricional de DNMT1 podem desencadear efeitos distintos. SP1 é capaz de transativar a expressão das DNMT1 independente da presença de p53. No entanto, o aumento da expressão de SP1, em modelos celulares p53 ativo, foi associado à redução da expressão de p53 e das DNMTs. A proteína p53, por sua vez, pode ativar ou reprimir a expressão de DNMT1, e o efeito da interação desta proteína com seus elementos consenso no promotor desse gene é dependente dos níveis disponíveis de p53 nas células. Por fim, nesse estudo foi observado que a diminuição da expressão das DNMTs foi capaz de levar a uma redução dos níveis de metilação global do DNA. Portanto, esses resultados demonstram que a regulação da expressão das DNMTs por p53 é um indicador da interação entre mecanismos genéticos e epigenéticos atuando na carcinogênese esofágica.


Subject(s)
Esophageal Neoplasms/genetics , Carcinoma, Squamous Cell/genetics , Genes, p53 , Sp1 Transcription Factor
19.
National Journal of Andrology ; (12): 142-146, 2017.
Article in Chinese | WPRIM | ID: wpr-812796

ABSTRACT

Objective@#To investigate the correlation of the single nucleotide polymorphism (SNP) rs1042522 of the tumor protein p53 (TP53) gene with the risk of male infertility.@*METHODS@#This casecontrol study included 380 male patients with idiopathic infertility and 398 normal fertile men as controls from the Nanjing area. We genotyped the SNP rs1042522 of the TP53 gene by Sequence Mass Array and analyzed the correlation of the SNP with male infertility using the logistic regression model.@*RESULTS@#Compared with the normal controls, the patients with idiopathic infertility showed significantly decreased sperm concentration ([77.34±49.24] vs [13.13±24.96] ×106/ml), percentage of progressively motile sperm ([42.55±9.57] vs [10.38±5.57]%), serum testosterone level ([14.07±5.36] vs [11.89±4.50] nmol/L), and folliclestimulating hormone level ([16.80±18.20] vs [4.55±7.17] U/L) (P < 0.05) but no statistically significant differences in other parameters. No correlation was observed between the SNP frequencies and male infertility and similar results were found in the subgroups of the cases.@*CONCLUSIONS@#SNP rs1042522 of the TP53 gene is not significantly correlated with the risk of male infertility.


Subject(s)
Case-Control Studies , Follicle Stimulating Hormone , Blood , Gene Frequency , Genes, p53 , Genetics , Genetic Predisposition to Disease , Genotype , Humans , Infertility, Male , Blood , Genetics , Logistic Models , Male , Polymorphism, Single Nucleotide , Sperm Count , Sperm Motility , Testosterone , Blood
20.
Article in English | WPRIM | ID: wpr-168709

ABSTRACT

Schistosoma haematobium is a biocarcinogen of human urinary bladder (UB). The present study investigated developing UB cancer mouse model by injecting S. haematobium eggs into the bladder wall and introduction of chemical carcinogens. Histopathological findings showed mild hyperplasia to epithelial vacuolar change, and high grade dysplasia. Squamous metaplasia was observed in the S. haematobium eggs+NDMA group at week 12 but not in other groups. Immunohistochemistry revealed significantly high expression of Ki-67 in urothelial epithelial cells of the S. haematobium eggs+BBN group at week 20. The qRT-PCR showed high expression of p53 gene in S. haematobium eggs group at week 4 and S. haematobium eggs+BBN group at week 20. E-cadherin and vimentin showed contrasting expression in S. haematobium eggs+BBN group. Such inverse expression of E-cadherin and vimentin may indicate epithelial mesenchymal transition in the UB tissue. In conclusion, S. haematobium eggs and nitrosamines may transform UB cells into squamous metaplasia and dysplasia in correlation with increased expression of Ki-67. Marked decrease in E-cadherin and increase in p53 and vimentin expressions may support the transformation. The present study introduces a promising modified animal model for UB cancer study using S. haematobium eggs.


Subject(s)
Animals , Cadherins , Carcinogens , Dimethylnitrosamine , Eggs , Epithelial Cells , Epithelial-Mesenchymal Transition , Genes, p53 , Humans , Hyperplasia , Immunohistochemistry , Metaplasia , Mice , Models, Animal , Nitrosamines , Ovum , Schistosoma haematobium , Schistosoma , Urinary Bladder Neoplasms , Urinary Bladder , Vimentin
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