RESUMO
Meningiomas are the most common primary brain tumors; they arise from the coverings of the brain. Although meningiomas are generally benign, some are more clinically aggressive, as reflected by their histopathological features or by their unexpected recurrence. We hypothesized that recurrent histologically benign meningiomas might have genetic features in common with those showing a more aggressive histology. By comparing gene expression profiles associated with meningioma progression and recurrence in 128 tumor samples (i.e. 83 benign World Health Organization [WHO] Grade I, 37 atypical WHO Grade II, and 8 anaplastic WHO Grade III) from 121 patients, we identified a 49-gene signature of meningioma aggressivity. This signature classified the tumors into 2 groups showing different clinical and pathological behaviors. The signature was composed of genes involved in the cell cycle (TMEM30B, CKS2, and UCHL1) and other pathways previously described as being altered in meningiomas, that is, WNT (SFRP1 and SFRP4) and transforming growth factor-ß pathways (LTBP2 and LMO4). Overall, gene downregulation was observed in advanced and recurrent samples versus benign and original ones. We propose that this gene repression may be caused by gene promoter hypermethylation, as in the case of UCHL1 and SFRP1, suggesting that this epigenetic event, together with loss of specific chromosomal regions, may play an important role in meningioma progression and recurrence.
Assuntos
Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Neoplasias Meníngeas/genética , Meningioma/genética , Recidiva Local de Neoplasia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Perfilação da Expressão Gênica/métodos , Humanos , Neoplasias Meníngeas/patologia , Meningioma/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Adulto JovemRESUMO
The majority of meningiomas are probably benign but a number of tumors display considerable histological and/or clinical aggressivity, sometimes with unexpectedly high recurrence rates after radical removal. Understanding the potential behavior of these tumors in individual patients is critical for rational therapeutic decision-making. This study aimed to identify gene expression profiles and candidate markers associated with original and recurrent meningiomas. Unsupervised hierarchical clustering of the samples confirmed 2 main groups of meningiomas with distinct clinical behaviors. The gene expression profiling study identified genes and pathways potentially associated with meningioma recurrence, revealing an overall lower level of gene expression. The differential gene expression profiling analyses of original and recurrent meningiomas identified 425 known genes and expressed sequence tags related to meningioma recurrence, with SFRP1 (8p12), TMEM30B (14q23), and CTGF (6q23) showing the most disparate expression. Most of the differentially expressed genes were located at 1p, 6q, and 14q and were underexpressed in recurrences. Loss of such chromosomal regions has previously been associated with a higher risk of meningioma recurrence or malignant progression. Thus, at these locations, we propose the existence of novel candidate genes that could be involved in meningioma recurrence. In addition, the overexpression of genes of histone cluster 1 (6p) in recurrent meningiomas is reported here for the first time. Finally, the altered genes related to meningioma recurrence are involved in pathways such as Notch, TGFß, and Wnt, as described previously, and in other pathways such as cell cycle, oxidative phosphorylation, PPAR, and PDGF, not related before to meningioma recurrence.
Assuntos
Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 6/genética , Histonas/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Recidiva Local de Neoplasia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Masculino , Neoplasias Meníngeas/metabolismo , Meningioma/metabolismo , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
Primary glioblastoma multiforme (GBM), in contrast with secondary GBM, has been associated with the presence of EGFR amplification and absence of p53 mutation. In this study, we analyzed relevant molecular and clinical variables in 194 primary GBMs and tested them for survival analysis. Although most of the tumors showed a mutually exclusive pattern, concurrent alterations of EGFR and p53 were detected. Survival analysis of CDK4 amplification revealed a highly significant association with a worse clinical outcome (P = .01), whereas MDM2, CDK6, PTEN, and p21 were not associated with patient survival. Multivariate analysis including the significant clinical and molecular variables revealed CDK4 amplification, age, and radiotherapy to be markers with independent prognostic value. In addition, the primary GBM tumors showing simultaneous EGFR and p53 alterations were significantly associated with worse survival (P < .01). These results highlight the prognostic value of CDK4 amplification and of simultaneous EGFR-p53 alterations in the clinical outcome of patients with primary GBM.
Assuntos
Neoplasias Encefálicas/genética , Quinase 4 Dependente de Ciclina/genética , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Terapia Combinada , Quinase 4 Dependente de Ciclina/metabolismo , Receptores ErbB/metabolismo , Feminino , Glioblastoma/mortalidade , Glioblastoma/terapia , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Análise Serial de Tecidos , Proteína Supressora de Tumor p53/metabolismo , Adulto JovemRESUMO
Pichia pastoris is a methylotrophic yeast of high biotechnological interest. The bioenergetic properties of mitochondria from Pichia pastoris have not yet been determined. We report on a protocol for the isolation of the mitochondria in a state that shows good energy coupling. Analysis of Pichia pastoris growth and bioenergetic properties of the isolated mitochondria reveals that glycerol is the carbon source that yields the best results. Under our growth conditions, mitochondria oxidize external NADH but do not possess an alternative oxidase. Finally, Pichia pastoris mitochondria also lack the nucleotide-stimulated uncoupling pathway previously identified in Saccharomyces cerevisiae.