[Promoter hypermethylation gene patterns in gynecological tumors]. / Patrones de hipermetilación génica en tumores ginecológicos.

BACKGROUND AND OBJECTIVE: Gene silencing mediated by the aberrant methylation of the promoter region of DNA is involved in the inactivation of genes implicated in various metabolic pathways. Such a gene hypermethylation has become a useful molecular marker for the diagnosis, treatment and follow-up of cancer patients. Our objective is to analyze the patterns of gene hypermethylation in patients with gynecological tumors. PATIENTS AND METHODS: We selected 115 patients with gynecological cancers: 22 ovarian; 13 endometrial, 11 cervical-uterine and 69 breast cancers. By testing methylation-specific PCR, we studied the methylation status of genes CDNK2A (p16), APC1A, FHIT, CDH1 and hMLH1. RESULTS: The frequencies of gene methylation in genes p16, APC1A, FHIT, hMLH1 and CDH1 were 29.2%, 34%, 60.4%, 10.9% and 79.8%, respectively. 70% of cases showed at least two methylated genes, which means a rate of methylation >0.4. The lowest frequency of methylation was seen in ovarian cancer, while the highest one was observed in endometrial cancer. CONCLUSIONS: The results indicate that the aberrant methylation of the promoter region is an important event in carcinogenesis of gynecological tumors and that the pattern of gene methylation is associated with the nature of the tumor. These particular characteristics can deliver relevant information on the major metabolic pathways altered in each tumor type. In addition to complementary studies (ie, loss of expression and/or function), this represents a clinical tool for the proper management of the disease.

Patrones de hipermetilación génica en tumores ginecológicos / Promoter Hypermethylation gene patterns in gynecological tumors

Fundamento y objetivo: El silenciamiento génico mediado por la metilación aberrante de la región promotora del ácido desoxirribonucleico está implicado en la inactivación de genes involucrados en diversas vías metabólicas y se ha constituido en un marcador molecular útil en el diagnóstico, tratamiento y seguimiento de sujetos oncológicos. El objetivo de este trabajo es analizar los patrones de hipermetilación génica en mujeres con tumores ginecológicos. Sujetos y método: Se seleccionaron 115 mujeres con cánceres ginecológicos: 22 mujeres con cáncer de ovario (CO), 13 mujeres con cáncer de endometrio (CE), 11 mujeres con cáncer de cuello uterino y 69 mujeres con cáncer de mama. Mediante prueba de metilación específica por reacción en cadena de la polimerasa, se estudió el estado de metilación de los genes CDNK2A (p16), APC1A, FHIT, CDH1 y hMLH1.ResultadosLas frecuencias de metilación génica para los genes CDNK2A (p16), APC1A, FHIT, CDH1 y hMLH1 fueron del 29,2; 34; 60,4; 10,9, y 79,8%, respectivamente. El 70% de los casos presentó al menos 2 genes metilados, es decir, un índice de metilación superior a 0,4. La frecuencia de metilación más baja se observó en el CO, mientras que la frecuencia de metilación más alta se presentó en el CE. Conclusiones: Los resultados indican que la metilación aberrante de la región promotora es un acontecimiento importante en la carcinogénesis de los tumores ginecológicos y que el patrón de metilación génica se asocia a la naturaleza tumoral. Estas características particulares pueden entregar información relevante acerca de las principales vías metabólicas alteradas en cada tipo tumoral, información que sumada a estudios complementarios de pérdida de expresión o de función representa una herramienta clínica para el tratamiento adecuado de la enfermedad (AU)

Background and objective: Gene silencing mediated by the aberrant methylation of the promoter region of DNA is involved in the inactivation of genes implicated in various metabolic pathways. Such a gene hypermethylation has become a useful molecular marker for the diagnosis, treatment and follow-up of cancer patients. Our objective is to analyze the patterns of gene hypermethylation in patients with gynecological tumors. Patients and methods: We selected 115 patients with gynecological cancers: 22 ovarian; 13 endometrial, 11 cervical-uterine and 69 breast cancers. By testing methylation-specific PCR, we studied the methylation status of genes CDNK2A (p16), APC1A, FHIT, CDH1 and hMLH1.ResultsThe frequencies of gene methylation in genes p16, APC1A, FHIT, hMLH1 and CDH1 were 29.2%, 34%, 60.4%, 10.9% and 79.8%, respectively. 70% of cases showed at least two methylated genes, which means a rate of methylation >0.4. The lowest frequency of methylation was seen in ovarian cancer, while the highest one was observed in endometrial cancer. Conclusions: The results indicate that the aberrant methylation of the promoter region is an important event in carcinogenesis of gynecological tumors and that the pattern of gene methylation is associated with the nature of the tumor. These particular characteristics can deliver relevant information on the major metabolic pathways altered in each tumor type. In addition to complementary studies (ie, loss of expression and/or function), this represents a clinical tool for the proper management of the disease (AU)

Mutación puntual del gen supresor de tumores TP53 en lesiones preneoplásicas y neoplásicas del estómago / Mutations of TP53 suppressor gene in pre-neoplastic and neoplastic lesions of the stomach: cross-sectional study in a high risk region

Background: In the current model for the development of gastric cancer, regions of multifocal atrophic gastritis give rise to intestinal metaplasia, dysplasia and finally, adenocarcinoma. Aim: To study the frequency and characteristics of TP53 gene mutations in preneoplastic and neoplastic lesions of the stomach. Material and methods: DNA sequencing of the TP53 gene was performed in 46 patients with gastric carcinoma. Normal mucosa, intestinal metaplasia and invasive adenocarcinoma tissues were obtained by scraping 6-Ám histological sections from formalin-fixed and paraffin-embedded tissue. Results: DNA sequencing of exons 5-9 of the TP53 gene demonstrated a mutation in 31 percent of patients. These findings were seen both in tumoral tissue (13 cases) and in intestinal metaplasia (2 cases). Most mutations were found in exons 5 and 8, and the majority of them were transitions (10 out of 19 mutations). Discussion: Patients with gastric cancer showed a frequency of TP53 mutations similar to that previously communicated in populations with low gastric cancer risk. Moreover, there was a predominance of transitions, genetic alterations that are identified with carcinogenesis associated with N-nitrosamine compounds. Finally, mutations of TP53 gene were detected in areas of intestinal metaplasia

¿Es el cáncer de la vesícula biliar una enfermedad de mal pronóstico en Chile? / Is galbladder cancer a tumor with bad prognosis?

Gallbladder cancer is frequent in Chile, but it is not uniformly mortal. The diagnosis is usually made after a cholecystectomy. indicated for a symptomatic cholelithiasis. Global survival of gallbladder cancer can be as high as 40 percent at five years. In 69 percent of women of less than 30 years old, the tumor is detected in early stages. In these cases, cholecystectomy is the curative procedure, with a 90 percent survival at five years. According to our experience, cholecystectomies should be performed between 40 and 50 years of age in men and between 30 and 40 years in women. The prognostic factors that should be considered are symptoms associated to lithiasis, age, parity, obesity, size of stones and the size of the gallbladder. If the tumor is detected in early stages, the survival is good. The natural history of the disease would change significantly if all women with symptomatic stones were operated

Elementos morfológicos pronósticos en el cáncer de la vesícula biliar / Morphological prognostic factors in gallbladder cancer

Background: The exact survival rates and prognostic factors of gallbladder cancer are still incompletely known. Aim: To report the actuarial survival of patients with gallbladder cancer. Material and methods: Six hundred thirty seven women, aged 59 years old as a mean and 108 men, aged 64 years old as a mean, with gallbladder cancer are reported. Patients were followed for up to 150 months. Results: Two hundred twenty four patients had an early and 521 had an advanced carcinoma. Overall survival was 38 percent at ten years. Sex or ethnic origin did not influence survival. Early tumors had a 92 percent survival at 10 years whereas the survival of advanced tumors was 16 percent at 5 years. Subserous tumors had a 5 years survival of 32 percent whereas serous tumors had a 5 years survival of 11 percent. Well-differentiated advanced tumors had a significantly better survival than moderately or poorly differentiated tumors. Vascular or lymphatic infiltration was also associated to a lower survival. All patients with advanced tumors and vascular infiltration died before 5 years. Conclusions: Tumor infiltration and differentiation degree were the most important prognostic independent factors in gallbladder cancer

Carcinoma incipiente de la vesícula biliar: estudio clínico patológico y pronóstico de 196 casos / Clinical and pathological features of early gallbladder carcinoma

Background: There is little information about the behavior of early gallbladder carcinoma. Aim: To report the clinical and pathological features of 196 patients with early gallbladder carcinoma. Material and methods: All patients with gallbladder cancer diagnosed between 1988 and 1997 were reviewed. In 703 of 829 patients, there was information about clinical features and follow up, and were included in this study. All gallbladders were subjected to a complete mapping. When neoplastic cells involved only the mucosa or muscular layer, the tumors were considered as early. Results: One hundred ninety six patients had an early carcinoma (161 women, aged 57.5 years and 35 male, aged 63.4 years). One hundred twenty eight tumors were located in the mucosa and 68 in the muscular layer. Patients with tumors involving the mucosa were younger than those with tumors involving the muscular layer. All tumors were adenocarcinomas, 66 per cent were well differentiated and 32 per cent moderately differentiated. Tumors were not visible macroscopically in 132 cases. Five and 10 years survival was 92 per cent. Subjects of less than 40 years old had a 100 per cent survival at 5 years. A hepatic and lymph node resection was done in 12 patients with tumors infiltrating the muscular layer but in only one, the tumor infiltrated the liver. No difference in survival was observed when a simple cholecystectomy or radical surgery was done. Conclusions: Nearly 25 per cent of gallbladder carcinomas can be classified as early and its diagnosis requires a directed study. Simple cholecystectomy is curative for this type of gallbladder cancer

Hallazgos en reintervenciones quirúrgicas por cáncer de la vesícula biliar en pacientes con y sin quimio-radiación preoperatoria / Pathological findings in surgical reinterventions for gallbladder cancer in patients with and without preoperative chemo and radiotherapy

Background: The usefulness of surgery in the treatment of gallbladder cancer has not been clearly established. The benefits of chemo and radiotherapy are similarly dubious. Aim: To report the pathological findings in patients subjected to surgical reinterventions for gallbladder cancer. Patients and methods: We report 54 patients with gallbladder cancer that were subjected to a second surgical intervention for resection of liver segments IVb and V and lymph nodes corresponding to the liver hilar, portal, peripancreatic, celiac artery and periaortic territories. Thirteen of these patients were subjected to preoperative chemo-radiotherapy (4500 Gy and 5-fluouracil 500 mg/m2). Results: Lymph node metastases were found in 25 and 38 percent, and liver metastases in 25 and 28 percent of patients with or without chemo-radiotherapy respectively. The most frequent pathological findings attributed to radiation in the liver were fatty infiltration in 75 percent of cases, vascular transformation in 83 percent of cases and minimal periportal lymphocyte infiltration in 40 percent of cases. Lymph nodes were atrophic in 67 percent of cases and had foci of cortical necrosis in 46 percent of cases. Three cases had regional lymph node and liver metastases. Most tumor cells were viable. Conclusions: No differences in the number of lymph node or liver metastases were observed between patients with and without chemo-radiotherapy. No effect of the treatment on residual tumor was observed either

Expresión de CD44 HCAM en el carcinoma subseroso de la vesícula biliar / CD44 HCAM expression in subserous gallbladder carcinoma

Background: HCAM or CD44 is a multifunctional cell adhesion molecule, related to cell-cell, cell-extracellular matrix interactions and involved in tumor invasion. Aim: To study the importance of CD44 expression in subserous gallbladder carcinoma. Material and methods: One hundred five samples (93 female) of subserous gallbladder carcinoma and 33 non tumoral gallbladder were studied. CD44 was stained using the streptavidine-biotin technique, using human anti CD44 antibodies. Eighty subjects with carcinoma were followed for a period up to 105 months. Results: Mean age of patients was 62,6 years old, all tumors were adenocarcinoma, all were silent and 13 percent were well differentiated. CD44 was expressed in all controls and in 91 percent, the expression was normal. In 57 percent of cancer samples, CD44 expression was abnormal, in 50 percent it was less expressed and in 24 percent, it was not expressed. No differences in CD44 expression was observed between mucosa from control samples and mucosa adjacent to the tumor or superficial or deep tumoral areas. Global five years survival was 40 percent. No significant differences in survival were observed in those tumors with a lower of absent CD44 expression. Six patients with a higher expression died before 18 months of follow up. Conclusions: Nearly 50 percent of subserous gallbladder carcinomas show an abnormal CD44 expression

Efectos de paratión sobre la síntesis proteica testicular / Parathion effects in testicular protein synthesis

El paratión como insecticida de uso masivo en la agricultura, puede afectar el potencial reproductivo de la población humana y animal expuesta. Sus propiedades bioquímicas potencialmente alteral los mecanismos de síntesis proteica testicular, afectando la morfofuncionalidad del aparato reproductor. El objetivo del presente trabajo, es cuantificar la síntesis de proteínas testicular, bajo la presencia de paratión, en ratón CF1, in vitro. Se cultivaron túbulos seminífero de ratones CF-1 e incubaron con concentraciones decrecientes (0,4; 0,04 y 0,004 mM) de paratión (PT) por 4 horas. Leucina tritiada (2 µ Ci) fue agregada después de una hora. Posteriormente se evaluó la síntesis proteica como actividad específica (cpm/µgr proteínas). Los resultados mostraron que el paration induce inhibición significativa de la síntesis proteica en la concentración 0,4 mM, mientras que a dosis menores de paratión disminuye el efecto sobre la inhibición de la síntesis de proteínas

Carbunco meníngeo y cutáneo en una región agrícola / Meningeal and cutaneous carbuncle in an agricultural region

Se presentan 5 casos de ántrax (carbunco) con inoculación cutánea. Todos tenían el antecedente epidemiológico de haber trabajo reciente en un vacuno muerto por causa desconocida, con el objeto de quitar y preservar el cuero animal. En el primer caso de los dos descritos con detalles, el paciente ingresó con un síndrome infeccioso grave y severo compromiso de conciencia. A pesar que los signos meníngeos eran negativos, se demostró una meningitis hemorrágica, con grandes bacilos visibles aun sin tinciones en el examen citoquímico del LCR. La tinción de Gram y las características de cultivo fueron compatibles con B. anthracis. A su ingreso, el paciente tenía sólo dos pequeñas lesiones de la piel, lo que contrastaba con la gravedad del cuadro clínico. Todos los demás casos presentaban lesiones de la piel más notables, pero cerradas, lo que no permitió tomar muestras bacteriológicas. A su ingreso estaban afebriles, pero dos pacientes presentaron un compromiso sistémico progresivo en los primeros días, a pesar del tratamiento antibiótico adecuado, y uno de ellos falleció. El examen postmortem fue enteramente compatible con ántrax diseminado, pero no se encontraron bacilos. Se atribuye esta progresión inicial de los síntomas a la acción de la toxina del agente infeccioso

Gen supresor de tumores p53 en neoplasias digestivas / p53 tumor supresor gene in digestive cancer

Malignant diseases of the digestive tract cause more than 50 percent of deaths due to cancer in Chile. There is a high incidence of gastric and gallbladder cancer and an increasing frequency of colorectal cancer. P53 tumor suppressor gene has a great importance in carcinogenesis and its alterations are specially important in digestive tract tumors such as colorectal cancer. There is contradictory evidence about the frequency of p53 gene or protein alterations or their biological significance. There is little information about p53 in Chile and it is mostly limited to immunohistochemical studies. This revision analyzes the frequency of p53 alterations in digestive tract tumors in Chile, using immunohistochemical and molecular biology methods. A special emphasis is given to the prognostic importance of this gene

Expresión de oncoproteína inhibidora de apoptosis de bcl-2 y de antígeno de proliferación celular ki-67 en cáncer gástrico / Apoptosis inhibiting oncoprotein bcl-2 and celular proliferation antigen ki-67 in gastric cancer

El objetivo de este trabajo fue determinar la expresión de oncoproteína bloqueadora de apoptosis bcl-2 en carcinomas gástricos, comparándola con la tasa de proliferación celular. Se utilizó método inmunohistoquímico para estudiar la expresión oncoproteína bcl-2 y de antígeno de proliferación celular Ki-67 en 35 carcinomas gástricos. Se observó inmunoreactividad para bcl-2 en nueve casos (26 por ciento). La sobreexpresión de bcl-2 se correlacionó significativamente con el grado histológico y la localización del tumor, con mayor expresión en tumores bien y moderadamente diferenciados y en lesiones cardiales. En promedio, un 32,4 por ciento de las células tumorales mostró expresión del antígeno de proliferación celular Ki-67, con mayor expresión en los pacientes de edad más avanzada. La expresión del antígeno Ki-67 en pacientes menores de 50 años de edad fue 21,5 por ciento, mientras que en pacientes de 50 años o más fue 34,9 por ciento. No se observó correlación entre sobreexpresión de proteína bcl-2 e índice de expresión del antígeno Ki-67. La sobreexpresión de bcl-2 en los tumores mejor diferenciados y en lesiones cardiales puede causar una ventaja proliferativa debido al aumento de la vida media de las células tumorales por bloqueo de la apoptosis, no asociada a aumento de la proporción de células en fases activas del ciclo celular