The correlation between KRAS and TP53 gene mutations and early growth of pulmonary nodules.

PURPOSE: The purpose of this study is to investigate whether gene mutations can lead to the growth of malignant pulmonary nodules. METHODS: Retrospective analysis was conducted on patients with pulmonary nodules at Hebei Provincial People's Hospital, collecting basic clinical information such as gender, age, BMI, and hematological indicators. According to the inclusion and exclusion criteria, 85 patients with malignant pulmonary nodules were selected for screening, and gene mutation testing was performed on all patient tissues to explore the relationship between gene mutations and the growth of malignant pulmonary nodules. RESULTS: There is a correlation between KRAS and TP53 gene mutations and the growth of pulmonary nodules (P < 0.05), while there is a correlation between KRAS and TP53 gene mutations and the growth of pulmonary nodules in the subgroup of invasive malignant pulmonary nodules (P < 0.05). CONCLUSION: Mutations in the TP53 gene can lead to the growth of malignant pulmonary nodules and are correlated with the degree of invasion of malignant pulmonary nodules.

Cytogenetic abnormalities and TP53 and RAS gene profiles of childhood acute lymphoblastic leukemia in Morocco.

BACKGROUND: Recurrent genetic abnormalities affecting pivotal signaling pathways are the hallmark of childhood acute lymphoblastic leukemia (ALL). The identification of these aberrations remains clinically important. Therefore, we sought to determine the cytogenetic profile and the mutational status of TP53 and RAS genes among Moroccan childhood cases of ALL. METHODS: In total, 35 patients with childhood ALL were enrolled in the study. The diagnosis and treatment were established in the Pediatric Hematology and Oncology Center at the Children's Hospital of Rabat. Chromosome banding analysis and fluorescence in situ hybridization were used to detect genetic aberrations. Blood samples were screened for TP53 and RAS mutations using Sanger sequencing. RESULTS: Of the 35 cases, 30 were B-lineage ALL (85.7 %). Moreover, a male predominance was observed. Cytogenetic analysis revealed chromosomal anomalies in 27 cases (77.1 %). The most frequent aberrations were high hyperdiploidy and BCR/ABL rearrangement. Interestingly, we found the rare t(15;16) and the t(8;14), which are uncommon translocations in pediatric B-ALL. The mutational analysis revealed Pro72Arg (rs1042522:C > G) and Arg213Arg (rs1800372:A > G) in TP53. In correlation with cytogenetic data, rs1042522:C > G showed a significant association with the occurrence of chromosomal translocations (p = 0.04). However, no variant was detected in NRAS and KRAS genes. CONCLUSION: Our findings emphasize the significance of detecting chromosomal abnormalities as relevant prognostic markers. We also suggest a low occurrence of genetic variants among Moroccan children with ALL.

Cancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum.

PURPOSE: Establishing accurate age-related penetrance figures for the broad range of cancer types that occur in individuals harboring a pathogenic germline variant in the TP53 gene is essential to determine the most effective clinical management strategies. These figures also permit optimal use of cosegregation data for classification of TP53 variants of unknown significance. Penetrance estimation can easily be affected by bias from ascertainment criteria, an issue not commonly addressed by previous studies. MATERIALS AND METHODS: We performed a maximum likelihood penetrance estimation using full pedigree data from a multicenter study of 146 TP53-positive families, incorporating adjustment for the effect of ascertainment and population-specific background cancer risks. The analysis included pedigrees from Australia, Spain, and United States, with phenotypic information for 4,028 individuals. RESULTS: Core Li-Fraumeni syndrome (LFS) cancers (breast cancer, adrenocortical carcinoma, brain cancer, osteosarcoma, and soft tissue sarcoma) had the highest hazard ratios of all cancers analyzed in this study. The analysis also detected a significantly increased lifetime risk for a range of cancers not previously formally associated with TP53 pathogenic variant status, including colorectal, gastric, lung, pancreatic, and ovarian cancers. The cumulative risk of any cancer type by age 50 years was 92.4% (95% CI, 82.2 to 98.3) for females and 59.7% (95% CI, 39.9 to 81.3) for males. Females had a 63.3% (95% CI, 35.6 to 90.1) cumulative risk of developing breast cancer by age 50 years. CONCLUSION: The results from maximum likelihood analysis confirm the known high lifetime risk for the core LFS-associated cancer types providing new risk estimates and indicate significantly increased lifetime risks for several additional cancer types. Accurate cancer risk estimates will help refine clinical recommendations for TP53 pathogenic variant carriers and improve TP53 variant classification.

Biomarkers and intermediate-high risk non-muscle invasive bladder cancer: a multivariate analysis of three different cellular pathways with pronostic implications

Purpose To determine the presence of a group of mutations, and establish the prognostic value for recurrence and progression. Materials and methods Prospective observational study. Intermediate-to-high-risk non-muscle invasive bladder cancer (NMIBC) was evaluated. Data from genetic analyses were included in a database along with clinicopathological variables of interest. Results Seventy-four patients. Twenty-five (33.8%) recurred and 3 (4.1%) progressed. Median time to recurrence: 8 months (5.7–12.7). Median time to progression: 14 months (P75: 12). Mutation distribution: KRAS codon 12: one patient (1.4%), BAT25: five patients (6.8%), BAT-26: four patients (5.4%), and D2S123: 6 patients (8.1%). Arg72Pro polymorphism: 50 patients (67.6%) exhibited homozygous mutations, 23 (31.1%) were heterozygous, and 1 patient (1.4%) did not present the mutation. We found an association between presence of MSI at BAT26 and female sex (p < 0.05) and tumor stage and the TP53 Arg72Pro polymorphism. Recurrence-free survival (RFS) was significantly associated with presence of MSI at D2S123, with a HR of 5.44 for patients presenting the mutation (95% CI 1.83–16.16). On multivariate analysis, we found a statistically significant increase in risk of recurrence among patients with MSI at D2S123 (HR 5.15; p < 0.05) and more than 2 previous transurethral bladder resections (TURBs) (HR 5.07; p < 0.05) adjusted for tumor stage and grade. Harrell’s concordance index revealed an accuracy of 0.74 (p < 0.05). Conclusion An association was found between presence BAT26 MSI and female sex, Arg72Pro polymorphism with tumor stage and D2S123 and more than 2 TUR procedures were associated with RFS adjusted to tumor stage and grade (AU)

Adrenocortical tumors associated with the TP53 p. R337H germline mutation can be identified during child-care consultations / Tumores adrenocorticais associados à mutação germinativa TP53 p. R337H podem ser identificados durante as consultas de puericultura

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.

Exome sequence analysis of Kaposiform hemangioendothelioma: identification of putative driver mutations

Abstract BACKGROUND: Kaposiform hemangioendothelioma is a rare, intermediate, malignant tumor. The tumor's etiology remains unknown and there are no specific treatments. OBJECTIVE: In this study, we performed exome sequencing using DNA from a Kaposiform hemangioendothelioma patient, and found putative candidates for the responsible mutations. METHOD: The genomic DNA for exome sequencing was obtained from the tumor tissue and matched normal tissue from the same individual. Exome sequencing was performed on HiSeq2000 sequencer platform. RESULTS: Among oncogenes, germline missense single nucleotide variants were observed in the TP53 and APC genes in both the tumor and normal tissue. As tumor-specific somatic mutations, we identified 81 candidate genes, including 4 nonsense changes, 68 missense changes and 9 insertions/deletions. The mutations in ITGB2, IL-32 and DIDO1 were included in them. CONCLUSION: This is a pilot study, and future analysis with more patients is needed to clarify: the detailed pathogenesis of this tumor, the novel diagnostic methods by detecting specific mutations, and the new therapeutic strategies targeting the mutation.

Glioblastoma multiforme congénito infratentorial. Un tumor excepcional con una biología aún desconocid / Infratentorial congenital glioblastoma multiforme. A rare tumour with a still unknown biology

Introducción. El glioblastoma multiforme congénito representa sólo el 3% de los tumores congénitos del sistema nervioso central, y su ubicación infrantentorial es excepcional. Caso clínico. Recién nacido con un glioblastoma multiforme congénito sin mutación en el gen TP53 ni inmunorreactividad nuclear p53, que infiltraba prácticamente todo el tronco cerebral e invadía también estructuras supratentoriales. Conclusiones. Hasta donde sabemos, sólo se han referido previamente cuatro casos de localización infratentorial, tres en el cerebelo y uno en el tronco del encéfalo. La biología del glioblastoma multiforme congénito no se conoce bien y, a diferencia del glioblastoma multiforme en la edad adulta, las mutaciones en el gen TP53 son poco frecuentes, sin que eso parezca implicar un mejor pronóstico. Estas observaciones sugieren que el glioblastoma multiforme con origen en la vida fetal tiene una biología diferente del que se presenta en otras etapas de la vida (AU)

Introduction. Congenital glioblastoma multiforme represents only 3% of congenital central nervous system tumours and an infratentorial location is unusual. Case report. A newborn with congenital glioblastoma multiforme with no mutation in the TP53 gene or p53 nuclear immunoreactivity that infiltrated practically the whole brainstem and also invaded supratentorial structures. Conclusions. As far as we know, only four cases with an infratentorial location have been reported previously, three in the cerebellum and one in the brainstem. The biology of congenital glioblastoma multiforme is not well known and, unlike glioblastoma multiforme in adults and children, mutations in the TP53 gene are uncommon. However, this is not associated with a more favourable prognosis. These observations suggest that specific biological processes underlie fetal glioblastoma multiforme development (AU)

P53 gene codon 72 polymorphism in patients with oral squamous cell carcinoma in the population of northern Iran

OBJECTIVES: Squamous cell carcinoma is the most common cancer of the oral cavity, and several etiologic factors are involved in its development. Single nucleotide polymorphism (SNP) of the P53 gene codon 72 (P53c72) changes the structure of the protein and affects its activity. The prevalence of P53c72 different genotypes, which seems to vary with race and geographic location, has shown a strong correlation with many types of human cancers. The aim of this study was to investigate the correlation between P53c72 polymorphism and risk of oral squamous cell carcinoma (OSCC) in the heavily populated Gilan Province in northern Iran. Design of Study: This case-control study was done on 55 paraffin-embedded samples from OSCC patients and 100 samples of non-dysplastic oral cavity lesions. The P53c72 genotypes were determined using the ARMS-PCR method. SPSS-15 software was used for statistical analysis. RESULTS: There were no significant statistical differences found between the prevalence of different P53c72 genotypes in the OSCC group vs. the control. However, the Pro/Pro genotype in OSCC samples showed a strong correlation with age, as 70% of such patients were below 50 years old. Interestingly, a large portion (40%) of the patients with the Pro/Pro genotype had the tumor in the lip area. CONCLUSIONS: Although P53c72 polymorphism does not appear to be a predisposing factor for OSCC in the population of Northern Iran, the Pro/Pro genotype could be considered as a risk factor for OSCC in adults below 50 years old and the anatomical location of the tumor

Malignancy risk models for oral lesions

OBJECTIVES: The aim of this work was to assess risk habits, clinical and cellular phenotypes and TP53 DNA changes in oral mucosa samples from patients with Oral Potentially Malignant Disorders (OPMD), in order to create models that enable genotypic and phenotypic patterns to be obtained that determine the risk of lesions becoming malignant. STUDY DESIGN: Clinical phenotypes, family history of cancer and risk habits were collected in clinical histories. TP53 gene mutation and morphometric-morphological features were studied, and multivariate models were applied. Three groups were estabished: a) oral cancer (OC) group (n=10), b) oral potentially malignant disorders group (n=10), and c) control group (n=8).RESULTS: An average of 50% of patients with malignancy were found to have smoking and drinking habits. A high percentage of TP53 mutations were observed in OC (30%) and OPMD (average 20%) lesions (p=0.000). The majority of these mutations were GC TA transversion mutations (60%). However, patients with OC presented mutations in all the exons and introns studied. Highest diagnostic accuracy (p=0.0001) was observed when incorporating alcohol and tobacco habits variables with TP3 mutations. CONCLUSIONS: Our results prove to be statistically reliable, with parameter estimates that are nearly unbiased even for small sample sizes. Models 2 and 3 were the most accurate for assessing the risk of an OPMD becoming cancerous. However, in a public health context, model 3 is the most recommended because the characteristics considered are easier and less costly to evaluate (AU)

The role of p21Waf1/CIP1 as a Cip/Kip type cell-cycle regulator in oral squamous cell carcinoma (Review)

Oral Squamous Cell Carcinoma (OSCC) is biologically characterized by the accumulation of multiple genetic and molecular alterations that end up clinically characterized as a malignant neoplasm through a phenomenon known as multistep. The members of the Cip/Kip family, specifically p21Waf1/CIP1, are responsible for cell cycle control, blocking the transition from phase G1 to phase S. We made a search of articles of peer-reviewed Journals in PubMed/ Medline, crossing the keywords. The goal of this paper is to determine the relationship between p21Waf1/CIP1 expression and several clinical and pathological aspects of OSCC, their relationship with p53 and HPV, as well as genetic alterations in their expression pattern, their use as a prognosis market in the evolution of precancerous lesions and their roles in anticancer treatments. The results of p21WAF1/CIP1 expression in OSCC showed mixed results in terms of positivity/negativity throughout different studies. It seems that, although p21Waf1/CIP1 expression is controlled in a p53-dependent manner, coexpression of both in OSCC is not intrinsically related. Although the presence of HPV viral oncoproteins increases p21Waf1/CIP1 levels, the small number of studies, have forced us to (..) (AU)

Cáncer de mama asociado a síndrome de Li-Fraumeni en dos hermanas / No disponible

Se presenta a dos hermanas diagnosticadas de un carcinoma de mama (CM), con el antecedente de que su madre fue diagnosticada de carcinoma de mama a los treinta y cuatro años y falleció cuatro años después. Consecuentemente, se hizo un estudio genético descartándose una mutación de los oncogenes BRCA1 y BRCA2. Sin embargo, sí se evidenció una alteración a nivel del gen supresor p53, característico del síndrome de Li-Fraumeni (SLF). El SLF es una rara enfermedad autosómica dominante que afecta fundamentalmente a pacientes jóvenes y que consiste en una predisposición a desarrollar una amplia variedad de tumores, entre ellos el CM(AU)

We present two sisters who were diagnosed as having breast cancer; being their mother diagnosed as having breast cancer when she was thirty-four years old, and having died four years later. Hence, we decided to make a genetic testing, which was negative in BRCA1 and BRCA2 mutation. However, a mutation in p53 tumor suppressor gene was detected in the genetic study, which is characteristic of Li-Fraumeni syndrome (LFS). LFS is a rare autosomal dominant hereditary disorder that frequently appears in young patients. Patients with LFS are at risk for a wide range of malignancies, being breast cancer particularly frequent(AU)

Proyectos de investigación concedidos dpto. de salud. Valoración de las alteraciones genéticas de p53, p14 y MSI, y de los niveles de Topoisomerasa I, Topors y Carboxilesterasa CES2 como factores predictivos de respuesta tumoral al tratamiento con Irinotecán en pacientes con cáncer colorrectal avanzado / No disponible

No disponible

Identificación de alteraciones genéticas en oligodendrogliomas mediante amplificacióndependiente de ligasa de múltiples sondas (MLPA) (multiple ligationdependentprobe amplification) / Identification of genetic alterations by multiple ligation- dependent probe amplification (MLPA) analysis in oligodendrogliomas

La alteración genética más frecuente en oligodendrogliomases la pérdida conjunta de lp/19q. Este eventoya acontece en etapas primarias del desarrollo deestos tumores. Es de gran valor clínico conocersi dichos tumores poseen esta deleción ya que seha correlacionado con un mejor pronóstico de lospacientes. Además de esta alteración. también se haobservado la deleción de CDKN2A y PTEN y la amplificaciónde EGFR; estos cambios parecen asociarse auna mayor agresividad tumoral. Mediante la técnicade MLPA en una misma reacción podemos determinarsi existe pérdida de lp/19q y deleciones/amplificacionesde los genes anteriormente mencionados en el ADNprocedente de muestras tumorales. En este trabajohemos analizado 40 oligodendrogliomas y el kit MLPAP088 para determinar el estado alélico de lp/19q, asícomo el kit MLPA P105 para observar la amplificación/deleción de los genes CDKN2A, PTEN, ERBB2, TP53 yEGFR. Mostraron pérdida de 1p el 45% de los tumores(18/40) y el 65% (26/40) de los oligodendrogliomaspresentaron deleción de las sondas que hibridan en lasregiones de 19q. Para el kit MLPA P105, mostraronduplicación/deleción de EGFR en el 7,5% (3/41) y 35%(14/40) de las muestras, respectivamente. El 60% de loscasos (24/40) mostraron deleción de CDKN2 y ningunamuestra presentó duplicación de las sondas para estegen. El gen ERBB2 se presentó duplicado en el 12,5%de los tumores (5/40) y un único tumor mostró pérdidasde dicho gen. El 30% (12/40) de las muestras presentódeleción para PTEN y el 12,5% (5/40) mostró duplicaciónde dicho gen y, por último, 12,5% de los casos(5/40) presentaron duplicaciones de TP53. Estos resultadosindican que la técnica de MLPA es idónea para laidentificación de las alteraciones moleculares característicasde oligodendrogliomas. Estas alteraciones estaríancontribuyendo a la formación del tumor, siendola anomalía más significativa en oligodendrogliomas la (...) (AU)

Concurrent deletion at 1p/19q is a common signatureof oligodendrogliomas, and it may be identified inlow-grade tumours (grade II) suggesting it representsan early event in the development of these brain neoplasms.Additional non-random changes primarilyinvolve CDKN2A, PTEN and EGFR. Identification ofall of these genetic changes has become an additionalparameter in the evaluation of the clinical patients' prognosis, including good response to conventional chemotherapy.Multiple ligation-dependent probe amplification(MLPA) analysis is a new methodology thatallows an easy identification of the oligodendrogliomas'abnormalities in a single step. No need of the respectiveconstitutional DNA from each patient is anotheradvantage of this method. We used MLPA kits P088and P105 to determine the molecular characteristics ofa series of 40 oligodendrogliomas. Deletions at l p and19q were identified in 45% and 65% of cases, respectively.Alterations of EGFR, CDKN2A, ERBB2, PTENand TP53 were also identified in variable frequenciesamong 7% to 35% of tumours. These findings demonstratethat MLPA is a reliable technique to the detectionof molecular genetic changes in oligodendrogliomas (AU)

Alteraciones genéticas de los adenocarcinomas del aparato digestivo y su correlación con la secuencia de su gestación / Genetic abnormalities of digestive tract adenocarcinomas and correlation with the histologic sequence of their development

Más del 90% de los tumores malignos del aparato digestivo pertenecen a la familia de los adenocarcinomas (ADC) y casi el 95% de éstos presentan localizaciones gástricas (G), colorrectales (CR) o pancreáticas(P). Revisar las alteraciones genéticas que protagonizan los ADC de estas localizaciones y sus posibles coincidencias, junto a la correlación histogénica de su gestación, es el motivo de este trabajo. Lasalteraciones genéticas que afectan a más del 50% de los casos son: en los ADC-G, la inactivación de los genes supresores de tumor p53, APC y DCC, en su variante «intestinal», la hipoexpresión de la caderinaE en la variante «difusa» y la hiperexpresión de la ciclooxigenasa- 2 y la ciclina D en la forma «intestinal»; en los ADC-CR, la inactivaciónde los genes p53, APC y DCC, junto a la activación mutacional del oncogén k-ras y, por último, en los ADC-P, la inactivación de los genes supresores p53, p16 y DPC4 junto a la activación mutacional del oncogén k-ras. El ADC-P es el que muestra una marca genéticamás característica y exclusiva, seguido del ADC-CR. Por último, la correlación histogénica en la secuencia tumorígena es más evidente en los ADC-CR, seguidos de los ADC-P. La compleja realidad biológica de los ADC-G hace más difícil dibujar tanto su perfil genético comosu correlación histogénica. Para comprender mejor los argumentos de este trabajo, los autores recuerdan las bases genéticas y moleculares que regulan la vida y muerte de las células somáticas normales y elperfil biológico de las familias de genes principalmente involucrados en la carcinogenia

Over 90% of digestive tract malignancies are adenocarcinomas (ADC) and almost 95% of them have gastric (G), colorectal (CR) or pancreatic(P) localizations. The objectives of this work are to review the genetic abnormalities of ADC in these locations and their potential coincidences,along with the histogenetic correlation of their emergence. Genetic abnormalities affecting over 50% of cases include: in G-ADC, inactivation of suppressor genes of p53, APC and DCC tumor in its intestinalvariant, hypoexpression of of caderine E in the diffuse variant and hyperexpression of cyclooxygenase-2 and cyclyn D in the intestinal form; in in CR-ADC, inactivation of of genes p53, APC and DCC togetherwith mutational activation of k-ras oncogen, and in P-ADC, the inactivation of suppressor genes p53, p16 and DPC4 along with mutational activation of k-ras oncogen. P-ADC is the one showing a more characteristicand exclusive genetic mark, followed by CR-ADC. Finally, the histogenetic correlation in the tumorigenic sequence is more evident in CR-ADC, followed by P-ADC. The complex biologic reality of G-ADC makes it more difficult to draw its genetic profile and its histogenetic correlation. In order to understand better the arguments of this work, the authors comment on the genetic-molecular basis governing the lifeand death of normal somatic cells and the biologic profile of the groups of genes mainly involved in tumorigenesis

Caracterización bioquímica del nervio óptico en el ratón que sobreexpresa el gen p53. Análisis de estrés oxidativo / Biochemical characterization of the optic nerve in mice overexpressing the P53 gen. Oxidative stress assays

Objetivos: El gen supresor tumoral p53 detiene la proliferación y la muerte celular por apoptosis subsecuente a la acción de diversos factores, entre ellos el estrés oxidativo. La proteína p53 es fundamentalmente un regulador de la expresión génica. Utilizando ratones genéticamente manipulados para presentar una copia extra del gen p53 (transgénicos super p53) frente a ratones controles, hemos investigado el estado oxidativo y antioxidante en los nervios ópticos, en relación a p53. Método: Se han utilizado ratones de la cepa C57BL/6 de 12 meses de edad en dos grupos: 1) grupo super p53 (Sp53) y 2) grupo de controles wild-type (GC). Los ratones fueron anestesiados en atmósfera de éter, extrayendo los globos oculares y nervios ópticos que se lavaron en PBS, manteniendo las muestras en nitrógeno líquido y en congelador de –85ºC hasta su procesamiento. Se homogeneizaron 3-4 nervios ópticos por cada eppendorf, clasificando por grupos y determinando mediante métodos enzimático-colorimétricos la actividad traperoxidativa y actividad antioxidante total y la concentración de oxido nítrico. Resultados: Existe aumento significativo en la formación de radicales libres via peroxidación lipídica (p<0,001), de la actividad antioxidante (p<0,001) y síntesis de óxido nítrico (p<0,05) en los nervios ópticos de los ratones transgénicos super p53, frente a los ratones controles. Conclusiones: La presencia de una copia extra del gen p53 está ligada a modificaciones de la actividad redox en el nervio óptico del ratón, sugiriendo que p53 otorga una mayor resistencia a la agresión oxidativa. Valoramos la utilización de este modelo de ratón transgénico en procesos neurodegenerativos relacionados con el estrés oxidativo y la inducción de la apoptosis, como la neuropatía óptica glaucomatosa o la degeneración macular asociada a la edad

Purpose: The tumour inhibitor p53 gene has the ability of triggering proliferation arrest and cellular death by apoptosis subsequent to several factors, among them oxidative stress. The p53 protein is a major regulator of gene expression. Using genetically manipulated mice carrying an extra copy of gene p53 (transgenic mice super p53) versus control mice, we have investigated the generation of reactive oxygen species and antioxidant activity in the optic nerve of mice in relation to p53 availability. Methods: We studied two groups of 12-month-old mice of the strain C57BL/6: 1) super p53 group (Sp53) and 2) wild-type control group (CG). Mice were anesthetized in ether atmosphere and the eyeball and retrobulbar optic nerves were excised, washed, soaked in PBS, and stored in liquid nitrogen at –85ºC until processing. Three-four optic nerves from the same group were placed in an eppendorf tube, homogenized and enzymatic-colorimetric methods used to determine oxidative and antioxidant activities and the nitric oxide synthesis. Results: A significant increase in free radical formation (via lipid peroxidation; p<0.001), antioxidant activity (p<0.001) and nitric oxide synthesis (p<0.001) was found in the optic nerves from transgenic super p53 mice compared to respective controls. Conclusion: The presence of an extra copy of the p53 gene correlated with redox status in the mouse optic nerve. This transgenic mouse could be useful as an experimental model to study cell resistance to neurodegenerative processes in relation to oxidative stress and to apoptosis induction, such as glaucomatous optic neuropathy or age-related macular degeneration

Sarcoma de estroma endometrial. Estudio clinicopatológico e inmunofenotípico de 5 casos / Endometrial stromal sarcoma. Clinicopathologic and immunophenotypic study of 5 cases

Introducción: El sarcoma de estroma endometrial uterino es un tumor muy poco frecuente con una incidencia de 0,4 -3,4 por 100.000 mujeres, comprende menos del 1% de tumores malignos ginecológicos y el 2-5% de tumores malignos uterinos, siendo el tercer sarcoma en frecuencia después del carcinosarcoma y el leiomiosarcoma. Material y métodos: Presentamos cinco casos de sarcoma de estroma endometrial diagnosticados en un periodo de siete años con la evolución clínica de las pacientes. Resultados: Immunohistoquímicamente, estos tumores expresaban vimentina, receptores hormonales, CD10 y p53 (sarcomas de alto grado), siendo los marcadores musculares, la CK, el c-kit y ALK negativos. De estos cinco sarcomas dos de ellos eran de alto grado y tres de bajo grado (uno con diferenciación miogénica y otro combinado con áreas tipo «cordones sexuales», áreas miogénicas y áreas estromales puras). Discusión: Asimismo se plantean una serie de diagnósticos diferenciales con metodología práctica para poder caracterizar estos tumores

Introduction: Endometrial stromal sarcoma (ESS) is an infrequent neoplasm with an incidence of 0,4-3,4 cases/100.000 woman. This tumor represents less than 1% of the gynecologic malignancies as well as the 2,5% of the uterine malignant tumors being the third malignancy after carcinosarcoma and leiomyosarcoma. Patients and methods: We present five cases of endometrial sarcoma, diagnosed in a period of seven years. This study includes a complete immunohistochemical analysis as well as the follow-up of the patients. Results: Immunohistochemically, these tumors expressed vimentin, hormone receptors, CD10 and p53 (high grade sarcomas), whereas muscle markers, CK, c-Kit and ALK resulted negative. Two of the ESS were high grade tumors whereas the other three were considered low grade tumors (one with myogenic differentiation and the other combining sex cord areas, myogenic foci and pure stromal areas). Discussion: We discuss their differential diagnosis with other uterine malignant tumors

Expresión de pRb, p53 y bcl-2 en el carcinoma de células transicionales de bajo grado no infiltrante (pTa) de la vejiga urinaria / Rb, p53 and bcl-2 expression in non-infiltrating (pTa) low grade transitional cell carcinomas of the urinary bladder

Antecedentes: En la actualidad, el carcinoma urotelial superficial es la forma más frecuente de cáncer vesical, pero su evolución clínica es difícil de prever. Teniendo en cuenta que una parte de estos tumores evolucionan a enfermedad infiltrante, el patólogo se encuentra a menudo ante el dilema irresoluble de anunciar cuales son los casos que van a ir mal. En este trabajo se intenta identificar qué carcinomas pTa de vejiga se van a comportar agresivamente en base a la expresión de marcadores inmunohistoquímicos de uso común. Métodos: Se analiza un total de 27 carcinomas vesicales pTa que fueron seleccionados de manera estricta y con más de 5 años de seguimiento. Se valoran los datos clínicos, los criterios histológicos clásicos y el patrón de tinción con anticuerpos para Rb, p53 y bcl-2. Resultados: La media de edad fue de 64,3 años y el ratio varón/mujer de 4,5:1. La mayoría de los casos fueron G1 (22 casos, 81%). Se detectó recurrencia en 18 casos (67%) y progresión a pT1 en 8 (30%). En 10 casos (37%) la expresión de p53 fue positiva y en 11 (40,7%) hubo pérdida de la expresión de proteína Rb. El marcaje con bcl-2 fue focalmente positivo en 5 casos (18,5%). La expresión de bcl-2 se asoció a progresión del tumor hacia pT1 (test de Fisher, p=0,02). El intervalo libre de recurrencia en los casos con pérdida de Rb fue significativamente menor que en los que la expresión se mantuvo (log-rank, p=0,036). La expresión de p53 no resultó significativa ni para la recurrencia ni para la progresión. Discusión: La pérdida en la expresión de Rb y la expresión de bcl-2 pueden ayudar a discernir qué grupo de carcinomas uroteliales pTa van a van a recurrir más precozmente o van a progresar en estadio. Dicha información puede ser útil para el urólogo a la hora de tratar de manera adecuada e individualizada a estos pacientes

Background: Superficial carcinoma is nowadays the most frequent form of bladder cancer, but its clinical evolution is difficult to predict. The prediction of which of these cases will behave bad is a continuous challenge for the pathologist. The present paper tries to identify the subset of pTa carcinomas that will pursue a bad clinical course by analysing the expression of several immunohistochemical routine markers. Methods: Twenty seven pTa carcinomas with more than 5 years of follow up were analysed. Aside from clinical and classical histopathological criteria, Rb, p53, and bcl-2 expression was studied. Results: Average age was 64.3 years and male/female ratio 4.5/1. Most cases were G1 (22 cases, 81%). Tumour recurrence was detected in 18 cases (67%) and progression to pT1 in 8 cases (30%). Ten cases (37%) showed positive immunostaining for p53 and 11 cases (40.7%) had loss for Rb expression. The immunostaining with bcl-2 was focally positive in 5 cases (18.5%). Bcl-2 expression was associated with tumour progression to pT1 (Fisher’s test, p=0.02). Recurrence-free interval in Rb negative cases was shorter than in Rb positive ones (log rank, p=0.036). p53 had not significant associations. Discussion: Loss of Rb expression and bcl-2 expression may help to predict which pTa carcinomas will behave aggressively. This information is crucial for choosing the best treatment modality in every patient