RESUMO
Hemangioblastomas (HBs) of the central nervous system are benign tumors and occur as sporadic (sp) tumors (75%) or as a manifestation of the von Hippel-Lindau (VHL) disease (25%). VHL-disease is an autosomal dominant disorder characterized by HBs of the central nervous system and retina, renal cell carcinoma (RCC), phaeochromocytoma (PHEO), islet tumors of the pancreas, and endolympatic sac tumors as well as cysts and cystadenoma in the kidney, pancreas and epididymis. In VHL patients a large spectrum of germline mutations in the VHL gene has been detected. In spHBs VHL alleles are reported to be inactivated in up to 50% of the tumors. To our knowledge the involvement of other genes in spHBs has not been investigated. To elucidate the oncogenesis of spHBs, we performed CGH on 10 spHBs to screen for chromosomal imbalances throughout the entire tumor genome. Aberrations most frequently detected are losses of chromosomes 3 (70%), 6 (50%), 9 (30%), and 18q (30%) and a gain of chromosome 19 (30%). Based on these frequencies and the co-occurrence of these aberrations in the analyzed tumors we hypothesize that loss of chromosome 3 (harboring the VHL gene) is an early event in the oncogenesis of spHBs, followed by loss of 6, and then losses of chromosomes 9, 18q and gain of chromosome 19. Comparison of the chromosomal imbalances in spHBs to those previously reported in RCCs and PHEOs reveals that the pathway of spHBs shows similarities to both the RCCs and PHEOs.
Assuntos
Neoplasias Cerebelares/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 3/genética , Hemangioblastoma/genética , Hibridização de Ácido Nucleico , Proteínas Supressoras de Tumor , Ubiquitina-Proteína Ligases , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Idoso , Carcinoma de Células Renais/genética , Transformação Celular Neoplásica/genética , Cromossomos Humanos Par 18/ultraestrutura , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 9 , DNA de Neoplasias/genética , Humanos , Neoplasias Renais/genética , Ligases/deficiência , Ligases/genética , Perda de Heterozigosidade , Pessoa de Meia-Idade , Monossomia , Feocromocitoma/genética , Trissomia , Proteína Supressora de Tumor Von Hippel-Lindau , Doença de von Hippel-Lindau/genéticaRESUMO
Angiogenesis is of vital importance for the growth of solid tumors and constitutes a target for anti-cancer therapy. Glioblastomas (GBMs) are histologically characterized by striking microvascular proliferation. The identification of the mechanism of angiogenesis is of major importance for the further development of anti-angiogenic therapy. Tumor angiogenesis might be the result of a combination of local tissue conditions (especially hypoxia) and specific genetic alterations acquired during oncogenesis. In order to investigate the relationship between genetic aberrations and tumor angiogenesis in GBM xenograft lines, the genetic alterations were examined by Comparative Genomic Hybridization (CGH). Two vascular phenotypes of GBM xenografts could be identified: a well vascularized and a poorly vascularized type. In this model, the poorly vascularized type had a larger number of genetic alterations. However, there was no unequivocal correlation between angiogenesis, growth rate and patterns of genetic alterations as detected by CGH.
Assuntos
Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/genética , Aberrações Cromossômicas , DNA de Neoplasias/genética , Glioblastoma/irrigação sanguínea , Glioblastoma/genética , Neovascularização Patológica , Adulto , Idoso , Animais , Neoplasias Encefálicas/patologia , Mapeamento Cromossômico , Feminino , Glioblastoma/patologia , Humanos , Perda de Heterozigosidade , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Hibridização de Ácido Nucleico/métodos , Fenótipo , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
Oligo-astrocytic tumours (OAs) histologically show both oligodendroglial and astrocytic differentiation. Unequivocal criteria for delineation of OAs from pure oligodendroglial (Os) and astrocytic (As) tumours and for grading of OAs are lacking. Molecular genetic analysis may allow for a better characterization of OAs and thereby guide prognostic and therapeutic decisions. Comparative genomic hybridization (CGH) was performed on 39 gliomas with variable phenotypic expression of histological features characteristic of both astrocytic and oligodendroglial differentiation. The results show that OAs are genetically more heterogeneous than Os. In addition to the "-1p/-19q" and "+7/-10" subtypes that have been previously recognized, two additional genetic subtypes, "intermediate" and "other", were identified in the present study. "Intermediate" OAs likely represent progression from "-1p/-19q" tumours. The "other" subtype appears to represent an additional, heretofore unrecognized, genetic pathway(s). Application of rigorously "strict" histopathological criteria, as opposed to "relaxed" criteria, for the selection of oligo-astrocytic tumours resulted in a higher percentage of "-1p/-19q" tumours, but some "-1p/-19q" tumours might be missed. The results suggest that molecular genetic analysis is a useful and valid additional tool for the classification of gliomas, particularly for the significant subset of tumours in which subjective histopathological criteria are insufficient for an unequivocal distinction between Os, As, and mixed OAs.
Assuntos
Astrocitoma/genética , Adulto , Idoso , Astrocitoma/classificação , Astrocitoma/patologia , Aberrações Cromossômicas , Diagnóstico Diferencial , Feminino , Genótipo , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Oligodendroglioma/genética , Oligodendroglioma/patologiaRESUMO
We identified a novel familial case of clear-cell renal cancer and a t(3;6)(q12;q15). Subsequent cytogenetic and molecular analyses showed the presence of several abnormalities within tumour samples obtained from different patients. Loss of the der(3) chromosome was noted in some, but not all, of the samples. A concomitant VHL gene mutation was found in one of the samples. In addition, cytogenetic and molecular evidence for heterogeneity was obtained through analysis of several biopsy samples from one of the tumours. Based on these results and those reported in the literature, we conclude that loss of der(3) and subsequent VHL gene mutation may represent critical steps in the development of renal cell cancers in persons carrying the chromosome 3 translocation. Moreover, preliminary data suggest that other (epi)genetic changes may be related to tumour initiation.
Assuntos
Carcinoma de Células Renais/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 6/genética , Neoplasias Renais/genética , Translocação Genética/genética , Adulto , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem/métodos , Perda de Heterozigosidade/genética , Masculino , Pessoa de Meia-Idade , Hibridização de Ácido Nucleico/métodos , Linhagem , Células Tumorais CultivadasRESUMO
OBJECT: Human tumors implanted as subcutaneous xenografts in nude mice are widely used for the study of tumor biology and therapy. Validation of these models requires knowledge of the genetic makeup of the xenografts. The aim of this study was to establish whether chromosomal imbalances in 11 xenograft lines derived from human glioblastomas multiforme (x-GBMs) are similar to those found in GBM biopsy samples. The authors also studied genetic stability during serial passaging of three xenograft lines. METHODS: Chromosomal imbalances in x-GBMs were detected using comparative genomic hybridization (CGH). The authors compared the CGH results in x-GBMs with those in the original GBMs (o-GBMs) that were used to establish three of the xenograft lines and with the GBM biopsy results reported in the literature (1-GBMs). In three xenograft lines two different passages were analyzed. CONCLUSIONS: The results show that the chromosomal imbalances in x-GBMs are similar to those in o-GBMs and 1-GBMs, indicating that the GBM xenograft lines used were valid models from a genetic point of view. The CGH analysis of two different passages of three xenograft lines indicates that x-GBMs (like 1-GBMs) show intratumoral genetic heterogeneity and do not acquire chromosomal imbalances as a result of serial passaging.
Assuntos
Glioblastoma/genética , Transplante de Neoplasias , Hibridização de Ácido Nucleico , Neoplasias Cutâneas/genética , Transplante Heterólogo , Animais , Biópsia , Aberrações Cromossômicas/genética , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 9/genética , DNA de Neoplasias/genética , Modelos Animais de Doenças , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Cutâneas/patologia , Translocação Genética/genética , Células Tumorais CultivadasRESUMO
In contrast to astrocytic tumors, approximately two thirds of anaplastic oligodendrogliomas are reported to be chemosensitive. Relatively little is known about the genetic aberrations in oligodendroglial tumors (OTs). In order to elucidate oligodendroglial oncogenesis and to find specific genetic aberrations that may have prognostic and therapeutic implications, we performed comparative genomic hybridization (CGH) to detect chromosomal copy number changes in 17 low-grade OTs (LG-OTs) and 12 high-grade OTs (HG-OTs) lacking a prominent astrocytic component. Loss of chromosome 1p (79%) and 19q (76%) were most frequently detected by CGH, all LG-OTs and 50% of the HG-OTs contained -1p (including 1p36-32), -19q (including 19q13.3), or both, and the rest of the HG-OTs showed +7, -10, or both. Since losses of 1p36-32 and 19q13.3 were mutually exclusive with +7 or -10, the HG-OTs could be divided in -1p/-19q and +7/-10 tumors. While the -1p/-19q tumors can be considered as pure anaplastic oligodendrogliomas, the +7/-10 tumors may rather be glioblastomas with prominent oligodendroglial differentiation. We conclude that CGH is a powerful tool to assist in the identification of 2 major subgroups of HG-OTs with prognostic and possibly therapeutic relevance.