RESUMO
We have determined that PAX3 (found previously to be mutated in Waardenburg syndrome) is the chromosome 2 locus rearranged by the t(2;13)(q35;q14) translocation of the paediatric solid tumour alveolar rhabdomyosarcoma. The rearrangement breakpoints occur within an intron downstream of the paired box and homeodomain-encoding regions. Upstream PAX3 sequences hybridize to a novel transcript in t(2;13)-containing lines. Cloning and characterization of this novel transcript indicate that the translocation juxtaposes the PAX3 DNA binding elements with chromosome 13 sequences, suggesting formation of a hybrid transcription factor. Therefore, PAX3 gene alterations are associated with two completely unrelated human diseases.
Assuntos
Rearranjo Gênico , Genes Homeobox , Rabdomiossarcoma/genética , Sequência de Bases , Criança , Quimera , Mapeamento Cromossômico , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 2 , Clonagem Molecular , DNA de Neoplasias/genética , Humanos , Dados de Sequência Molecular , Transcrição Gênica , Translocação Genética , Células Tumorais CultivadasRESUMO
Two unrelated female infants presented at 9 days and 2 months, respectively, with apneic episodes in the former and gaze preference in the latter. MRI revealed enlargement of almost the entire right hemisphere, apparently smooth cortex, simplification of the gyral pattern, and expanded white matter with abnormal signal intensity containing multiple intraparenchymal cysts. Histologic examination of both cases revealed white matter infiltration by a hypocellular lesion composed of uniform, fibrillary astrocytes in a microcystic background. Multilocular tumor cysts were prominent, but Rosenthal fibers and eosinophilic granular bodies were absent. Very rare mitoses were seen in the absence of necrosis or vascular change. There was no convincing cortical infiltration, but the subpial zone was diffusely expanded by a band of astrocytes set in a dense fibrillar feltwork which opened out into numerous cystic spaces. No desmoplastic changes or associated atypical ganglion cells were identified. There was no evidence for a BRAFKIAA1549 fusion or BRAF mutation in one case tested. In conclusion, both lesions are not desmoplastic infantile astrocytoma/ganglioglioma, fibrillary astrocytoma, or typical for pilocytic astrocytoma. Such extreme subpial spread with cysts is most unusual and may suggest a novel variant of infantile astrocytoma.
Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Cistos/patologia , Astrocitoma/metabolismo , Neoplasias Encefálicas/metabolismo , Cistos/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Recém-NascidoRESUMO
BACKGROUND: The role of germline and somatic SMARCB1 gene mutations in malignant rhabdoid tumour (MRT) predisposition is well known. Germline SMARCB1 mutations have also recently been identified in a subset of individuals with schwannomatosis. Surprisingly, MRT predisposition and schwannomatosis have never been reported to co-occur in a family. The correlation between genotype and phenotype for mutations in SMARCB1 has not been determined. RESULTS: We have identified a germline 2631 bp duplication that includes exon 6 of SMARCB1 in a unique family with a four generation history of MRT predisposition and schwannomatosis. This duplication segregates with disease in individuals affected with both conditions, linking MRT predisposition and schwannomatosis as components of the same syndrome in this family. CONCLUSION: The unique combination of tumours that result from the duplication described in this report may provide important clues about the mechanisms that influence the phenotype associated with a given SMARCB1 mutation.
Assuntos
Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Duplicação Gênica , Neurilemoma/genética , Tumor Rabdoide/genética , Fatores de Transcrição/genética , Sequência de Bases , Éxons , Família , Genótipo , Mutação em Linhagem Germinativa , Humanos , Dados de Sequência Molecular , Neurilemoma/patologia , Linhagem , Fenótipo , Tumor Rabdoide/patologia , Proteína SMARCB1RESUMO
OBJECTIVE: Atypical teratoid/rhabdoid tumors are aggressive neoplasms of the central nervous system occurring mainly in the early childhood and rarely in adults. We described a case of this tumor in an 18-year-old male patient without previous medical history. MATERIAL AND METHODS: The neoplasm was localized in the right frontotemporal area of the brain and was totally excised. The specimen was fixed in formalin and embedded in paraffin. The histological and immunohistochemical features of the neoplasm were assessed, while sequencing analysis as well as interphase fluorescence in situ hybridization (FISH) were performed. RESULTS: Histological and immunohistochemical analysis demonstrated atypical rhabdoid cells strongly and diffusely positive for EMA and Vimentin as well as focally immunoreactive for SMA and GFAP. Additionally, though no abnormalities detected in the coding sequence of the INI1 gene, interphase FISH studies were consistent with a homozygous deletion of the INI1 gene in the majority of examined nuclei. INI1 immunostaining demonstrated diffuse loss of nuclear INI1 expression in tumor cells. Taken together, the results were consistent with a diagnosis of atypical teratoid/rhabdoid tumor (ATRT). CONCLUSIONS: 26 previous cases of ATRT have been reported in adults, thus far. To our knowledge, this is the eighth case of an ATRT reported in an adult patient having genetic confirmation and the first one in which the tumor is, partly, localized in the right temporal area of the brain. This unusual presentation underlines the necessity of considering this devastating neoplasm in the differential diagnosis of malignant brain tumors of young adults.
Assuntos
Neoplasias Encefálicas/patologia , Tumor Rabdoide/patologia , Teratoma/patologia , Adolescente , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Masculino , Tumor Rabdoide/genética , Tumor Rabdoide/metabolismo , Proteína SMARCB1 , Teratoma/genética , Teratoma/metabolismo , Fatores de Transcrição/genéticaRESUMO
Among the small round cell tumors differential diagnosis is particularly difficult for their undifferentiated or primitive character. In this mixed group of tumors, only the primitive neuroectodermal tumors, which include Ewing's sarcoma (ES), show the unique and consistent feature of the (11;22)(q24;q12) translocation, which can therefore be considered a hallmark of these neoplasias. We analyzed four primitive neuroectodermal tumor cell lines, one osteosarcoma cell line, and 11 patients by fluorescent in situ hybridization with cosmid clones 23.2 and 5.8, bracketing the t(11;22) at 11q24. Metaphase spreads from tumor cell lines, and from biopsy specimens of three patients with ES were analyzed. In the remaining eight patients comprising five ES, two small cell osteosarcomas and one chronic osteomyelitis, only nuclei preparations were available for analysis. We detected the t(11;22) in interphase nuclei of the four primitive neuroectodermal tumor cell lines, of three patients in which the karyotype demonstrated the translocation and in five cases of ES in which cytogenetic analysis had not been possible. Two cases of small cell osteosarcoma and one chronic osteomyelitis were also analyzed and were both normal with respect to the t(11;22). By analyzing cell lines and small round cell tumor samples by fluorescent in situ hybridization, we established that interphase cytogenetics is a rapid alternative to chromosomal analysis for the detection of the t(11;22) and represents an invaluable tool for the differential diagnosis of small round cell tumors.
Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 22 , Interfase , Neoplasias/genética , Translocação Genética , Adolescente , Adulto , Criança , Feminino , Fluorescência , Humanos , Hibridização In Situ , Masculino , Células Tumorais CultivadasRESUMO
We have determined the frequency of EWS fusion transcripts in a series of primary Ewing's sarcomas and peripheral primitive neuroectodermal tumors and cells lines. Type 1 and 2 EWS-Fli1 fusions were demonstrated in 8 cell lines and 14 patient samples. Five patients with cytogenetically characterized rearrangements of chromosome 22 that did not involve chromosome 11 were included in these studies. A novel EWS-Fli1 in-frame isoform fusing EWS to exon 8 of Fli1 was isolated from a tumor with a variant t(12;22;22)(q14;p1;q12) translocation. Three in-frame isoforms of a novel hybrid transcript derived from the fusion of EWS with the ETS domain of the human erg gene were identified in patient samples and a cell line with cytogenetically unidentified or cryptic translocations involving chromosomes 21 and 22. Interphase analysis by fluorescent in situ suppression hybridization using two overlapping erg yeast artificial chromosome clones demonstrated disruption of the erg gene on chromosome 21 in a patient sample with monosomy 22. Our results provide new information about the involvement of EWS in small round cell tumors involving exchange of its putative RNA-binding domain with DNA-binding domains derived from different members of the ETS family of transcription factors. These studies emphasize the utility of reverse transcriptase PCR analysis and fluorescent in situ hybridization as additional diagnostic tools for differential diagnosis among small round cell tumors.
Assuntos
Proteínas de Ligação a DNA/genética , Tumores Neuroectodérmicos/genética , Proteínas Proto-Oncogênicas , RNA Mensageiro/análise , Proteínas Recombinantes de Fusão/genética , Sarcoma de Ewing/genética , Transativadores/genética , Translocação Genética , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Cromossomos Artificiais de Levedura , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Proteína Proto-Oncogênica c-fli-1 , Células Tumorais CultivadasRESUMO
BACKGROUND AND PURPOSE: Primary atypical teratoid/rhabdoid tumors (AT/RTs) are rare malignant intracranial neoplasms, usually occurring in young children. The objectives of this study were to characterize the MR imaging features and locations of primary intracranial AT/RTs, to determine the frequency of disseminated disease in the central nervous system (CNS) at diagnosis and postoperatively, and to assess patient outcomes. METHODS: The preoperative cranial MR images of 13 patients with AT/RTs were retrospectively reviewed for evaluation of lesion location, size, MR signal intensity and enhancement characteristics, and the presence of disseminated intracranial tumor. Postoperative MR images of the head and spine for 17 patients were reviewed for the presence of locally recurrent or residual tumor and disseminated neoplasm. Imaging data were correlated with patient outcomes. RESULTS: Patients ranged in age from 4 months to 15 years (median age, 2.9 years). Primary AT/RTs were intra-axial in 94% of patients. The single primary extra-axial lesion was located in the cerebellopontine angle cistern. AT/RTs were infratentorial in 47%, supratentorial in 41%, and both infra- and supratentorial in 12%. A germ-line mutation of the hSNF5/INI1 tumor-suppressor gene was responsible for the simultaneous occurrence of an intracranial AT/RT and a malignant renal rhabdoid tumor in a 4-month-old patient. Mean tumor sizes were 3.6 x 3.8 x 3.9 cm. On short TR images, AT/RTs typically had heterogeneous intermediate signal intensity, as well as zones of low (54%), high (8%), or both low and high (31%) signal intensity from cystic and/or necrotic regions, hemorrhage, or both, respectively. On long TR/long TE images, solid portions of AT/RTs typically had heterogeneous intermediate-to-slightly-high signal intensity with additional zones of high (54%) or both high and low signal intensity (38%), secondary to cystic and/or necrotic regions, edema, prior hemorrhage, and/or calcifications. AT/RT had isointense and/or slightly hyperintense signal intensity relative to gray matter on fluid-attenuated inversion-recovery (FLAIR) and long TR/long TE images, and showed restricted diffusion. All except 1 AT/RT showed contrast enhancement. The fraction of tumor volume showing enhancement was greater than two thirds in 58%, between one third and two thirds in 33%, and less than one third in 9%. Disseminated tumor in the leptomeninges was seen with MR imaging in 24% of patients at diagnosis/initial staging and occurred in another 35% from 4 months to 2.8 years (mean, 1.1 years) after surgery and earlier imaging examinations with negative findings. The overall 1-year and 5-year survival probabilities were 71% and 28%, respectively. Patients with MR imaging evidence of disseminated leptomeningeal tumor had a median survival rate of 16 months compared with 149 months for those without disseminated tumor (P < .004, logrank test). CONCLUSION: AT/RTs are typically intra-axial lesions, which can be infra- and/or supratentorial. The unenhanced and enhanced MR imaging features of AT/RT are often variable secondary to cystic/necrotic changes, hemorrhage, and/or calcifications. Poor prognosis is associated with MR imaging evidence of disseminated leptomeningeal tumor.
Assuntos
Neoplasias Encefálicas/diagnóstico , Imageamento por Ressonância Magnética , Tumor Rabdoide/diagnóstico , Teratoma/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos RetrospectivosRESUMO
The recent development of an AKR(Rb6.15)1Ald lymphoma model in our laboratory presents a unique means of comparing sister chromatid exchange (SCE) frequencies and cellular replication kinetics of normal and lymphoma cells in the same host environment. Lymphoma cells, distinguished from normal cells by the presence of two metacentric chromosomes, had an average cell cycle time of 8 hr compared to 11 hr for normal cells. Normal bone marrow cells from nonleukemic AKR/J, nonleukemic AKR(Rb6.15) Ald, and tumor passage recipients had similar baseline and 1,3-bis(2-chloroethyl)-1-nitrosourea-induced SCE frequencies following exposure to 4.4 mg 1,3-bis(2-chloroethyl)-1-nitrosourea per kg and 19 hr 5-bromo-2-deoxyuridine. While baseline SCE frequencies were only slightly higher, 1,3-bis(2-chloroethyl)-1-introsourea-induced lymphoma cell SCE frequencies were 3 times higher than normal induced SCE frequencies [34.06 +/- 6.6 (S.E.) versus 11.0 +/- 0.6 SCEs/cell].
Assuntos
Medula Óssea/ultraestrutura , Ciclo Celular , Troca Genética , Linfoma/ultraestrutura , Troca de Cromátide Irmã , Animais , Medula Óssea/fisiopatologia , Células da Medula Óssea , Carmustina/farmacologia , Linhagem Celular , Feminino , Linfoma/fisiopatologia , Camundongos , Camundongos Endogâmicos AKR , Transplante de Neoplasias , Troca de Cromátide Irmã/efeitos dos fármacosRESUMO
The present studies were designed to evaluate the role of cell cycle time and time of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) administration on the persistence of sister chromatid exchange (SCE)-inducing lesions in normal and lymphoma second- and third-division AKR bone marrow cells. Normal second-division cells harvested from mice given injections of BCNU at the start of an 18-, 24-, or 28-hr 5-bromo-2-deoxyuridine (BrdUrd) infusion exhibited similar linear dose-dependent increases in SCE frequencies (p greater than 0.05). The faster-cycling lymphoma cells, harvested after 18-hr BrdUrd infusion, had significantly higher baseline (p less than 0.05) and BCNU-induced increases (p less than 0.001) in SCE frequencies than did normal cells. Dose-dependent increases in SCE frequencies were demonstrated in third-division normal and lymphoma cells from mice infused with BrdUrd for 24 or 28 hr. Whereas lymphoma cells from mice treated with 3.3 mg BCNU per kg exhibited 31.2 +/- 3.9 (S.E.) SCEs in second-division cells and 4.7 +/- 0.4 reciprocal and 22.9 +/- 2.0 nonreciprocal SCEs in third-division cells, a 5 times higher dose of BCNU was required to induce similar levels of 30.0 +/- 0.8 SCEs in second-division cells and 4.4 +/- 0.6 reciprocal and 22.6 +/- 1.2 nonreciprocal SCEs in third-division normal cells. BCNU dose-dependent increases in SCE frequencies were also observed following injection of BCNU 8 hr after the start of BrdUrd infusion. The unexpectedly higher levels of SCEs for both normal and lymphoma cells by this treatment protocol may be due to SCEs occurring at the same site in successive divisions in BrdUrd. Regardless of the protocol used, lower nonreciprocal SCE frequencies were observed in third-division cells relative to SCE frequencies in second-division cells; a possible consequence of the cytotoxicity of BCNU. Injection of BCNU produced significant changes in the proportions of normal and lymphoma cells completing one, two, and three or more divisions in BrdUrd. Lymphoma cells were consistently more sensitive to the specific type(s) of BCNU-induced damage leading to SCEs and cell death than were normal cells. These studies indicated that differences in SCE response were not due to cell cycle time, time of drug administration, or potential for repair. It is therefore suggested that increased sensitivity of lymphoma versus normal cells may be due to increased cellular uptake of BCNU.
Assuntos
Carmustina/farmacologia , Ciclo Celular/efeitos dos fármacos , Troca Genética/efeitos dos fármacos , Linfoma/ultraestrutura , Troca de Cromátide Irmã/efeitos dos fármacos , Animais , Medula Óssea/patologia , Medula Óssea/ultraestrutura , Bromodesoxiuridina/farmacologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Linfoma/patologia , Camundongos , Camundongos Endogâmicos AKR , Transplante de NeoplasiasRESUMO
Primitive neuroectodermal tumors of the central nervous system are the most common malignant brain tumors in children. Cytogenetic analysis of these tumors has demonstrated alterations of chromosome 17, in particular isochromosome 17q, as the most frequent chromosomal abnormality detected. Since the consistent loss of a specific chromosomal region in a given tumor type most likely indicates the presence of a tumor related gene in that region, we undertook a combined molecular and cytogenetic approach to examine alterations of chromosome 17 in primitive neuroectodermal tumors. Seven of 14 tumors analyzed demonstrated loss of alleles for loci on 17p. In three of the seven tumors tested, a loss in copy number was observed for only the most telomeric locus on 17p13.3, D17S34. Limited sequence analysis of the same seven tumors did not reveal mutations in four highly conserved coding regions of the p53 gene. These data suggest a new tumor associated locus on 17p distinct from and distal to TP53, which is involved in the initiation or progression of at least a subset of primitive neuroectodermal tumors.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 17 , Genes p53/genética , Meduloblastoma/genética , Sequência de Aminoácidos , Southern Blotting , Criança , Pré-Escolar , Bandeamento Cromossômico , Feminino , Humanos , Lactente , Cariotipagem , Masculino , Dados de Sequência MolecularRESUMO
Although the t(2;13)(q35;q14) translocation has been found in most cases of the pediatric cancer alveolar rhabdomyosarcoma, several cases have been reported with a variant t(1;13)(p36;q14) translocation. Our findings indicate that this t(1;13) rearranges PAX7 on chromosome 1 and fuses it to FKHR on chromosome 13. This fusion results in a chimeric transcript consisting of 5' PAX7 and 3' FKHR regions, which is similar to the 5' PAX3-3' FKHR transcript formed by the t(2;13). The 5' PAX3 and PAX7 regions encode related DNA binding domains, and therefore we postulate that these translocations create similar chimeric transcription factors that alter expression of a common group of target genes.
Assuntos
Cromossomos Humanos Par 13 , Cromossomos Humanos Par 1 , Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio , Proteínas Musculares/genética , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Rabdomiossarcoma Alveolar/genética , Fatores de Transcrição/genética , Translocação Genética/genética , Sequência de Aminoácidos , Sequência de Bases , Proteínas de Ligação a DNA/química , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Proteínas Musculares/química , Proteínas de Neoplasias/química , Proteínas do Tecido Nervoso/química , Fator de Transcrição PAX7 , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Rabdomiossarcoma Alveolar/química , Fatores de Transcrição/químicaRESUMO
We examined 18 atypical teratoid and rhabdoid tumors of the brain and 7 renal and 4 extrarenal rhabdoid tumors for mutations in the candidate rhabdoid tumor suppressor gene, INI1. Fifteen tumors had homozygous deletions of one or more exons of the INI1 gene, and the other 14 tumors demonstrated mutations. Germ-line mutations of INI1 were identified in four children, one with an atypical teratoid tumor of the brain and three with renal rhabdoid tumors. These studies suggest that INI1 is a tumor suppressor gene involved in rhabdoid tumors of the brain, kidney, and other extrarenal sites.
Assuntos
Proteínas de Ligação a DNA/genética , Genes Supressores de Tumor , Mutação em Linhagem Germinativa , Tumor Rabdoide/genética , Teratoma/genética , Criança , Pré-Escolar , Proteínas Cromossômicas não Histona , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Proteína SMARCB1 , Fatores de TranscriçãoRESUMO
The epidermal growth factor receptor has received much interest as a target for various antineoplastic agents, but a complication is that many normal tissues also express this receptor. We have previously identified in human glial tumors an 801-bp in-frame deletion within the epidermal growth factor receptor gene that created a novel epitope at the junction. By using Western blot assays with a mutant-specific antibody as a rapid and sensitive means for detecting this alteration in primary human tumors, it was found that 57% (26 of 46) of high-grade and 86% (6 of 7) of low-grade glial tumors, but not normal brain, express this protein. This altered receptor was also present in 66% (4 of 6) of pediatric gliomas and 86% (6 of 7) of medulloblastomas, 78% (21 of 27) of breast carcinomas, and 73% (24 of 32) of ovarian carcinomas. The fact that this receptor is frequently found in tumors but not in normal tissue makes it an attractive candidate for various antitumor strategies.
Assuntos
Receptores ErbB/genética , Proteínas de Neoplasias/genética , Neoplasias/química , Anticorpos Monoclonais , Sequência de Bases , Western Blotting , Neoplasias Encefálicas/química , Neoplasias da Mama/química , Receptores ErbB/análise , Feminino , Humanos , Dados de Sequência Molecular , Proteínas de Neoplasias/análise , Neoplasias Ovarianas/química , Células Tumorais CultivadasRESUMO
Familial predisposition to neuroblastoma, a common embryonal cancer of childhood, segregates as an autosomal dominant trait with high penetrance. It is therefore likely that neuroblastoma susceptibility is due to germ line mutations in a tumor suppressor gene. Cytogenetic, functional, and molecular studies have implicated chromosome band 1p36 as the most likely region to contain a suppressor gene involved in sporadic neuroblastoma tumorigenesis. We now demonstrate that neuroblastoma predisposition does not map to any of eight polymorphic markers spanning 1p36 by linkage analysis in three families. In addition, there is no loss of heterozygosity at any of these markers in tumors from affected members of these kindreds. Furthermore, there is strong evidence against linkage to two Hirschsprung disease (a condition that can cosegregate with neuroblastoma) susceptibility genes, RET and EDNRB. We conclude that the neuroblastoma susceptibility gene is distinct from the 1p36 tumor suppressor and the currently identified Hirschsprung disease susceptibility genes.
Assuntos
Bandeamento Cromossômico , Cromossomos Humanos Par 1 , Neuroblastoma/genética , Adolescente , Criança , Pré-Escolar , Mapeamento Cromossômico , Suscetibilidade a Doenças , Saúde da Família , Feminino , Deleção de Genes , Ligação Genética , Genótipo , Mutação em Linhagem Germinativa , Heterozigoto , Doença de Hirschsprung/genética , Humanos , Lactente , Recém-Nascido , Masculino , LinhagemRESUMO
A polymorphism at codon 36 in exon 4 of the p53 gene was identified by single strand conformation polymorphism (SSCP) analysis and direct sequencing of genomic DNA PCR products. The polymorphic allele, present in the heterozygous state in genomic DNAs of four of 100 individuals (4%), changes the codon 36 CCG to CCA, eliminates a FinI restriction site and creates a BccI site. Including this polymorphism there are four known polymorphisms in the p53 coding sequence.
Assuntos
Códon , Genes p53 , Polimorfismo Genético , Sequência de Bases , Humanos , Dados de Sequência Molecular , MutaçãoRESUMO
PURPOSE: To identify biologic prognostic factors in childhood primitive neuroectodermal tumors (PNET), including medulloblastoma, that accurately define patient groups with sufficiently good prognosis to permit a reduction in treatment intensity. PATIENTS AND METHODS: We determined expression levels of the neurotrophin receptor TrkC mRNA in formalin-fixed tumor samples from 87 well characterized PNET patients using in situ hybridization. Comparison of TrkC mRNA expression levels with clinical and other laboratory variables was performed using univariate and multivariate Cox regression analysis. RESULTS: High TrkC mRNA expression was found to be associated more with higher 5-year cumulative survival rate than was low TrkC mRNA expression (89% v 46%, respectively). When compared with established clinical prognostic factors and laboratory variables of potential prognostic significance, TrkC mRNA expression, by univariate analysis, was found to be the single most powerful predictor of outcome (hazards ratio, 4.81; P <.00005), exceeding all clinical prognostic factors. In multivariate analysis, the hazards ratio remained significant (P <.00005). CONCLUSION: High TrkC mRNA expression in PNET is a powerful independent predictor of favorable clinical outcome. Assessment of TrkC mRNA levels may aid in treatment planning for patients with PNETs and should be incorporated prospectively into PNET clinical trials.
Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias Encefálicas/metabolismo , Tumores Neuroectodérmicos Primitivos/metabolismo , Receptor trkC/biossíntese , Adolescente , Adulto , Fatores Etários , Antígenos de Diferenciação/análise , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 17 , Feminino , Humanos , Imuno-Histoquímica , Lactente , Masculino , Tumores Neuroectodérmicos Primitivos/diagnóstico , Tumores Neuroectodérmicos Primitivos/genética , Tumores Neuroectodérmicos Primitivos/mortalidade , Prognóstico , RNA Mensageiro/biossíntese , Fatores Sexuais , Análise de SobrevidaRESUMO
Germ-line and somatic mutations of the hSNF5/INI1 gene have been reported in atypical teratoid/rhabdoid tumors (AT/RTs) of the brain, consistent with its role as a tumor suppressor gene. In the present study, we determined the frequency of deletions and mutations of INI1 in 52 children whose original diagnosis was medulloblastoma (MB) or primitive neuroectodermal tumor (PNET) of the central nervous system. Mutations were detected in DNA isolated from four tumors, all from children less than 3 years of age at diagnosis. Two of the four were reviewed and reclassified as atypical teratoid tumor, whereas there was insufficient material to establish this diagnosis in the two remaining cases. The relatively low frequency of mutations, even in a large series of infants, suggests that loss of sequences from chromosome 22 and/or mutations of INI1 do not account for the poor prognosis of children with MB or PNET who are less than 3 years of age at diagnosis. Nevertheless, chromosome 22 deletion and INI1-mutation analysis of infants with MB/PNET should be considered for all children who are less than 1 year of age. Detection of these mutations suggests that the child has an AT/RT, rather than a MB/PNET, a finding with important prognostic value.
Assuntos
Neoplasias Encefálicas/genética , Cromossomos Humanos Par 22 , Proteínas de Ligação a DNA/genética , Genes Supressores de Tumor , Meduloblastoma/genética , Mutação , Tumores Neuroectodérmicos Primitivos/genética , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Neoplasias Encefálicas/cirurgia , Criança , Pré-Escolar , Proteínas Cromossômicas não Histona , Mapeamento Cromossômico , Proteínas de Ligação a DNA/química , Mutação da Fase de Leitura , Humanos , Lactente , Recém-Nascido , Cariotipagem , Perda de Heterozigosidade , Meduloblastoma/cirurgia , Monossomia , Tumores Neuroectodérmicos Primitivos/cirurgia , Proteína SMARCB1 , Deleção de Sequência , Fatores de TranscriçãoRESUMO
Deletions in the short arm of chromosome 17 (17p) are the most common genetic abnormality in primitive neuroectodermal tumors of the posterior fossa/medulloblastoma (PNET/Mb). The biological consequences of these deletions are not known for children with PNET/Mb; however, the presence of a tumor suppressor gene located in 17p, distinct from p53, has been implicated in tumorigenesis. Two recent studies suggest that 17p deletions in PNET/Mb are associated with a poor prognosis. To address this question, we identified deletions of chromosome 17p by cytogenetic and/or molecular biology methods in tumor biopsy samples from 56 patients with PNET/Mb. Associations between clinical characteristics or survival outcomes and 17p status were examined by multivariate analysis. Forty-one percent of PNET/Mb cases had a deletion of 17p. No significant association was found between 17p deletion and shorter survival duration or higher metastatic stage. Multivariate analysis did not find independent prognostic significance for 17p deletions after accounting for the effects of significant clinical variables. A larger study of the prognostic value of 17p deletion should be considered; however, clinical use of this factor to distinguish high-risk from standard-risk PNET/Mb populations is not warranted at this time.
Assuntos
Neoplasias Encefálicas/genética , Deleção Cromossômica , Cromossomos Humanos Par 17 , Meduloblastoma/genética , Tumores Neuroectodérmicos Primitivos/genética , Fatores Etários , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/patologia , Neoplasias Cerebelares/cirurgia , Pré-Escolar , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Meduloblastoma/mortalidade , Meduloblastoma/patologia , Meduloblastoma/cirurgia , Análise Multivariada , Estadiamento de Neoplasias , Tumores Neuroectodérmicos Primitivos/mortalidade , Tumores Neuroectodérmicos Primitivos/patologia , Tumores Neuroectodérmicos Primitivos/cirurgia , Prognóstico , Análise de SobrevidaRESUMO
Controversial issues relating to the pathobiology and classification of central nervous system primitive neuroectodermal tumors (PNETs) have plagued neuropathologists for more than 70 years. Hypotheses advanced in the mid-1920's have remained as fixed concepts in contemporary literature, largely consequent to repetitious support by a small number of neuropathologists despite a growing body of information discrediting these ideas from neuroembryologists, oncologists, neuroscientists and pathologists. Attention has largely focused upon PNETs arising in the cerebellum (commonly known as medulloblastomas ([MBs]), because about 80% of central nervous system (CNS) PNETs originate in this site. It has been asserted that the 20% which do not are biologically different, although most individuals agree that the histological features of PNETs that occur in different sites throughout the CNS are indistinguishable from those growing in the cerebellum. The historical aspects of this controversy are examined in the face of evidence that there is, in fact, a unique class of CNS tumors which should appropriately be regarded as primitive neuroectodermal in nature. Specifically, a number of different approaches to the problem have yielded data supporting this hypothesis. These approaches include the identification of patterns of expression among a variety of cellular antigens (demonstrated by the use of immunopathological techniques), molecular analyses of cell lines derived from these tumors, experimental production of PNETs and molecular genetic analyses. Differences of opinion among surgeons, oncologists and radiotherapists are typically resolved by conducting cooperative studies of patients with these tumors who are diagnosed and treated at multiple centers.
Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Tumores Neuroectodérmicos/patologia , Humanos , Oncologia/tendências , Tumores Neuroectodérmicos/diagnóstico , Tumores Neuroectodérmicos/terapia , Neurologia/tendências , PesquisaRESUMO
We employed exon trapping and large-scale genomic sequence analysis of two bacterial artificial chromosome clones to isolate genes from the region between the IGLC and BCR in chromosome 22q11.2. At the time these studies were initiated, one previously identified gene, GNAZ, was known to map to this region. Two genes, RTDR1 and RAB36, were cloned from this portion of 22q11, which is heterozygously or homozygously deleted in pediatric rhabdoid tumors of the brain, kidney and soft tissues. RTDR1 is a novel gene with a slight homology to a yeast vacuolar protein. RAB36 is a member of the Rab family of proteins. A series of primary rhabdoid tumors with chromosome 22q11 deletions were screened for mutations in the coding sequences of RTDR1, GNAZ and RAB36, but did not demonstrate any disease-specific alterations. Recently, INI1, which maps to the distal portion of the deletion region in 22q11, was identified as the candidate rhabdoid tumor suppressor gene. Further studies of RTDR1 and RAB36 are required to determine whether their absence contributes to the progression of rhabdoid tumors. Alternatively, these genes may be candidates for other diseases that map to human chromosome 22.