Gene amplification in carcinogenesis

Gene amplification increases the number of genes in a genome and can give rise to karyotype abnormalities called double minutes (DM) and homogeneously staining regions (HSR), both of which have been widely observed in human tumors but are also known to play a major role during embryonic development due to the fact that they are responsible for the programmed increase of gene expression. The etiology of gene amplification during carcinogenesis is not yet completely understood but can be considered a result of genetic instability. Gene amplification leads to an increase in protein expression and provides a selective advantage during cell growth. Oncogenes such as CCND1, c-MET, c-MYC, ERBB2, EGFR and MDM2 are amplified in human tumors and can be associated with increased expression of their respective proteins or not. In general, gene amplification is associated with more aggressive tumors, metastases, resistance to chemotherapy and a decrease in the period during which the patient stays free of the disease. This review discusses the major role of gene amplification in the progression of carcinomas, formation of genetic markers and as possible therapeutic targets for the development of drugs for the treatment of some types of tumors.

Mutational analysis of the GAP-related domain of the neurofibromatosis type 1 gene in Brazilian NF1 patients

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder caused by mutations in the NF1 gene. In the present study, a total of 55 unrelated NF1 patients were screened for mutations in the GAP-related domain/GRD (exons 20-27a) by single-strand conformation polymorphism (SSCP). Four different mutations were identified and, taken together, they comprise one nonsense substitution (Q1189X), one deletion (3525-3526delAA), one missense substitution (E1356G) and one mutation in the splice acceptor site (c.4111-1G>A). One novel polymorphism (c.4514+11C>G) and other three putative polymorphisms were also found (c.3315-27G>A, V1146I and V1317A). Genotype-phenotype correlations were investigated, but no particular association was detected.

Identification and complete sequencing of novel human transcripts through the use of mouse orthologs and testis cDNA sequences

The correct identification of all human genes, and their derived transcripts, has not yet been achieved, and it remains one of the major aims of the worldwide genomics community. Computational programs suggest the existence of 30,000 to 40,000 human genes. However, definitive gene identification can only be achieved by experimental approaches. We used two distinct methodologies, one based on the alignment of mouse orthologous sequences to the human genome, and another based on the construction of a high-quality human testis cDNA library, in an attempt to identify new human transcripts within the human genome sequence. We generated 47 complete human transcript sequences, comprising 27 unannotated and 20 annotated sequences. Eight of these transcripts are variants of previously known genes. These transcripts were characterized according to size, number of exons, and chromosomal localization, and a search for protein domains was undertaken based on their putative open reading frames. In silico expression analysis suggests that some of these transcripts are expressed at low levels and in a restricted set of tissues.

Poliploidia em células cultivadas de lesões de próstata / Polyploidy in cultured cells of prostate lesions

O câncer prostático é uma das neoplasias mais frequentes em homens e, apesar da sua alta incidência na população, os dados citogenéticos são limitados quando comparados com outros tumores sólidos comuns. Esse fato provavelmente decorre das dificuldades referentes ao cultivo de suas células e, consequentente, da obtenção de boas preparações cromossômicas. O objetivo deste trabalho foi investigar com técnicas citogenéticas, após culturas de curta duração, quatro adenocarcinomas prostáticos, três hiperplasias nodulares da próstata e duas prostatites crônicas. Todas as amostras apresentaram células com número cromossômico próximo ao tetraplóide e, em alguns adenocarcinomas, foram observados cromossomos em anel, double minutes, figuras trirradiais e fragmentos acêntricos

Anomalias cromossômicas em tumores sólidos: aspectos biológicos e aplicaçöes diagnósticas + / Chromosome anomalies in solid tumores: biological aspects and diagnostic aplications

A análise citogenética de tumores sólidos tem sido amplamente estimulada pela escassez de informaçöes ora disponíveis e pela identificaçåo de certas aberraçöes cariotípicas que se associam a manifestaçöes citológicas e clínicas peculiares e com a resposta à terapia, em casos de neoplasias hematológicas, assim como pela necessidade de esclarecer aspectos da biologia a célula tumoral para propiciar o controle mais efetivo da malignidade. Neste artigo såo descritos os achados citogenéticos em 5 pacientes com neoplasias malignas, evidenciando a ocorrência de heterogeneidade genética inter e intratumoral, provavelmente decorrente de instabilidade genética. Tal fenômeno expressa-se, principalmente, pela presença de vários clones celulares nåo relacionados citogeneticamente, em um mesmo tumor e de fusöes teloméricas múltiplas, assim como pela alta freqüência de células com diversas aberraçöes cromossômicas raras de diferentes tipos. A contribuiçåo da citogenética ao diagnóstico diferencial entre tumores semelhantes histologicamente, como o ameloblastoma e o carcinoma adenocístico de glândula salivar, é também ilustrada