RESUMEN
Hepatocellular Carcinoma (HCC) is a leading cause of cancer-related death worldwide. Globally, the most important HCC risk factors are Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV), chronic alcoholism, and dietary exposure to aflatoxins. We have described the epidemiological pattern of 202 HCC samples obtained from Colombian patients. Additionally we investigated HBV/HCV infections and TP53 mutations in 49 of these HCC cases. HBV biomarkers were detected in 58.1% of the cases; HBV genotypes F and D were characterized in three of the samples. The HCV biomarker was detected in 37% of the samples while HBV/HCV coinfection was found in 19.2%. Among TP53 mutations, 10.5% occur at the common aflatoxin mutation hotspot, codon 249. No data regarding chronic alcoholism was available from the cases. In conclusion, in this first study of HCC and biomarkers in a Colombian population, the main HCC risk factor was HBV infection.
RESUMEN
Hepatocellular carcinoma (HCC) may develop according to two major pathways, one involving HBV infection and TP53 mutation and the other characterized by HCV infection and CTNNB1 mutation. We have investigated HBV/HCV infections and TP53/CTNNB1 mutations in 26 HCC patients from Thailand. HBV DNA (genotype B or C) was detected in 19 (73%) of the cases, including 5 occult infections and 3 coinfections with HCV. TP53 and CTNNB1 mutations were not mutually exclusive, and most of TP53 mutations were R249S, suggesting a significant impact of aflatoxin-induced mutagenesis in HCC development.
RESUMEN
Introducción. La mutación E280A en el gen de presenilina 1 se encuentra asociada al grupo familiar más grande del mundo con enfermedad de Alzheimer. La presenilina 1 es un componente esencial del complejo g-secretasa, responsable de la producción del péptido beta-amiloide, considerado clave en la fisiopatogenia de la enfermedad. Objetivo. Determinar si la mutación E280A en presenilina 1 incrementa la producción de beta-amiloide, como reflejo de la ganancia de función g-secretasa. Materiales y métodos. Se evaluaron, por la tinción con rojo congo e inmunohistoquímica, depósitos sistémicos de beta-amiloide en tejidos de cadáveres afectados, portadores de la mutación E280A en la presenilina 1 y cadáveres de no afectados. Se cuantificó por la técnica de ELISA el beta-amiloide de 40 y 42 aminoácidos en cultivos de células CHO que expresan la proteína precursora de amiloide, transfectadas con los cADN de presenilina 1 portando las mutaciones M146L, E280A, DE9 y L392V. Resultados. Se encontraron depósitos proteicos en todos los tejidos estudiados y escasos depósitos de beta-amiloide. No se encontró diferencia en la cantidad de depósitos, ni en su localización. No se observó incremento en la producción de beta-amiloide en las células transfectadas con los cADN de presenilina 1 con las mutaciones comparadas con los controles. Conclusiones. La mutación E280A en presenilina 1 no aumentó la producción de beta-amiloide en tejidos periféricos no neuronales o en el modelo in vitro, contrario a lo que sucede en una ganancia de función de g-secretasa.
Introduction. The E280A mutation of the presenilin 1 gene has been found to be the most common associate in Alzheimers patients with a family history of this disease. Presenilin 1 is a critical component of the g-secretase complex and plays an essential role in the production of amyloid-b peptide. This peptide has been strongly associated with the physiopathology of the disease. Objective. The E280A mutation in the presenilin 1 was investigated for increased production of amyloid-b, as a response to gain in g-secretase function. Materials and methods. Levels of systemic amyloid-b were measured with congo red staining and immuno-histochemistry of the tissues of affected cadavers, compared with non-affected cadavers. The 40 and 42 amino acid amyloid-b levels were quantified by ELISA assay in CHO cell cultures. The amyloid precursor protein expressed by the cultures was detected by transfection with the cDNAs of presenilin 1 carrying the M146L, E280A, DE9 y L392V mutations. Results. Protein deposits were found in all tissues investigatged, but only a few with b-amyloid deposition. No differences were observed in the amount or location of amyloid-b between affected and unaffected cadavers. Not increase was noted in the production of amyloid-b from the CHO cells transfected with cDNA from any of the mutations of presenilin 1. Conclusions. The E280A mutation in the presenilin 1 gene was not associated with the increased production of amyloid-b in non-neuronal peripheral tissues, or in the in vitro model. This is in contrast to the expectation in a g-secretase gain of function.
Asunto(s)
Enfermedad de Alzheimer , Rojo Congo , Mutación , Péptidos beta-AmiloidesRESUMEN
INTRODUCTION: The E280A mutation of the presenilin 1 gene has been found to be the most common associate in Alzheimers patients with a family history of this disease. Presenilin 1 is a critical component of the g-secretase complex and plays an essential role in the production of amyloid-beta peptide. This peptide has been strongly associated with the physiopathology of the disease. OBJECTIVE: The E280A mutation in the presenilin 1 was investigated for increased production of amyloid-beta , as a response to gain in gamma-secretase function. MATERIALS AND METHODS: Levels of systemic amyloid-beta were measured with congo red staining and immuno-histochemistry of the tissues of affected cadavers, compared with non-affected cadavers. The 40 and 42 amino acid amyloid-beta levels were quantified by ELISA assay in CHO cell cultures. The amyloid precursor protein expressed by the cultures was detected by transfection with the cDNAs of presenilin 1 carrying the M146L, E280A, DE9 y L392V mutations. RESULTS: Protein deposits were found in all tissues investigatged, but only a few with beta -amyloid deposition. No differences were observed in the amount or location of amyloid-beta between affected and unaffected cadavers. Not increase was noted in the production of amyloid-beta from the CHO cells transfected with cDNA from any of the mutations of presenilin 1. CONCLUSIONS: The E280A mutation in the presenilin 1 gene was not associated with the increased production of amyloid-beta in non-neuronal peripheral tissues, or in the in vitro model. This is in contrast to the expectation in a gamma-secretase gain of function.
