RESUMO
BACKGROUND: Platelet derived growth factor receptor alpha (PDGFRalpha) expression is typical for a variety of brain tumours, while in normal adult brain PDGFRalpha expression is limited to a small number of neural progenitor cells. The molecular mechanisms responsible for the PDGFRalpha expression in tumours are not known, but in the absence of amplification, changes in transcriptional regulation might be an important factor in this process. METHODS AND RESULTS: We have investigated the link between single nucleotide polymorphisms (SNPs) within the PDGFRalpha gene promoter and the occurrence of brain tumours (medulloblastomas, supratentorial primitive neuroectodermal tumours (PNETs), ependymal tumours, astrocytomas, oligodendrogliomas, and mixed gliomas). These SNPs give rise to five different promoter haplotypes named H1 and H2alpha-delta. It is apparent from the haplotype frequency distribution that both PNET (10-fold) and ependymoma (6.5-fold) patient groups display a significant over-representation of the H2delta haplotype. The precise functional role in PDGFRalpha gene transcription for the H2delta haplotype is not known yet, but we can show that the H2delta haplotype specifically disrupts binding of the transcription factor ZNF148 as compared to the other promoter haplotypes. CONCLUSIONS: The specific over-representation of the H2delta haplotype in both patients with PNETs and ependymomas suggests a functional role for the ZNF148/PDGFRalpha pathway in the pathogenesis of these tumours.
Assuntos
Neoplasias Encefálicas/genética , Proteínas de Ligação a DNA/metabolismo , Ependimoma/genética , Tumores Neuroectodérmicos/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fatores de Transcrição/metabolismo , Sequência de Bases , Neoplasias Encefálicas/classificação , Primers do DNA , Humanos , Reação em Cadeia da Polimerase , Valores de Referência , Transcrição GênicaRESUMO
Eighty-seven precancerous lesions of the larynx were studied; 46 showed keratosis, 31 slight dysplasias, five severe dysplasias, and five carcinomas in situ. The average follow-up was 3.8 years per patient, and malignant degeneration was observed in nine of them (10.3%). This arose on a pre-existing dysplasia in eight cases, and in the other on a hyperkeratosis. Dyskeratosis was observed in 12 cases, half of which degenerated, this being the group of worst prognosis.
