Asunto(s)
Antineoplásicos/farmacología , Regulación Neoplásica de la Expresión Génica , FN-kappa B/genética , Nitrilos/farmacología , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Sulfonas/farmacología , Adolescente , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Niño , Técnicas de Cocultivo , Supervivencia de Injerto , Humanos , Ratones , Ratones SCID , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Fenotipo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Pronóstico , Transducción de Señal , Células del Estroma/citología , Células del Estroma/metabolismo , Linfocitos T/metabolismo , Linfocitos T/patología , Trasplante Heterólogo , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto JovenRESUMEN
Translocations and deletions involving chromosomal band 22q11 are common genetic aberrations in malignant rhabdoid tumors. Previous molecular analyses of a t(11;22) in the malignant rhabdoid tumor cell line TM87-16 localized the breakpoint distal to BCR on 22q11. In the present report, we have further refined the map position of this breakpoint between CRYBB2 and D22S258. Moreover, the D22S258, CRYBA4, D22S300, D22S1, and D22S310 loci, which lie between CRYBB2 and D22S42, were found to be deleted, presumably as a result of the translocation event. The identification of this deletion of at least 2 Mb on the long arm of chromosome 22 should be helpful for mapping the gene(s) in the region involved in the development of malignant rhabdoid tumors as well as providing insights into the mechanisms of chromosomal translocation in human solid tumors.
Asunto(s)
Cromosomas Humanos Par 11 , Cromosomas Humanos Par 12 , Eliminación de Gen , Neoplasias Retroperitoneales/genética , Tumor Rabdoide/genética , Translocación Genética , Mapeo Cromosómico , Sondas de ADN , Humanos , Lactante , Masculino , Reacción en Cadena de la Polimerasa , Células Tumorales CultivadasRESUMEN
We have isolated a new marker (cos11-5TH) that detects an MspI restriction fragment length polymorphism in the 5' region of the human tyrosine hydroxylase gene (TH) on chromosome band 11p15.5. This region of human chromosome 11 contains several important loci for disease phenotypes including Beckwith-Wiedemann syndrome (BWS), Wilms' tumor, and embryonal rhabdomyosarcoma. Thus, identification of new polymorphic markers in this region are important for future gene mapping and linkage analyses. To better define the region of 11p15.5 deleted in embryonal rhabdomyosarcoma, this new marker was used to investigate allelic losses in embryonal rhabdomyosarcoma tumors.
Asunto(s)
Polimorfismo de Longitud del Fragmento de Restricción , Rabdomiosarcoma Embrionario/genética , Tirosina 3-Monooxigenasa/genética , Secuencia de Bases , Cromosomas Humanos Par 11 , ADN de Neoplasias , Desoxirribonucleasa HpaII , Desoxirribonucleasas de Localización Especificada Tipo II/metabolismo , Femenino , Eliminación de Gen , Frecuencia de los Genes , Marcadores Genéticos , Heterocigoto , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Rabdomiosarcoma Embrionario/enzimologíaRESUMEN
Malignant rhabdoid tumors are extremely aggressive soft-tissue sarcomas that tend to be widely metastatic at diagnosis. These tumors were first described as variants of the kidney neoplasm Wilms' tumor, although tumors of similar clinicopathologic features have been cited in a variety of extrarenal sites. Here, we have characterized the chromosomal translocation t(11;22)(p15.5;q11.23) from a retroperitoneal rhabdoid tumor. Somatic cell hybrids with segregated copies of the derivative 11 and derivative 22 chromosomes allowed sublocalization of the chromosome 11 breakpoint to a 1- to 2-Mb region between the proximal marker D11S12 and the distal locus tyrosine hydroxylase (TH). Translocation-associated aberrant fragments were identified by pulsed-field gel electrophoresis, with the smallest resulting from BssHII digestion as detected with a probe for TH. These data indicate that the locus or loci disrupted by this genetic abnormality might lie less than 60 kb proximal to this marker and place it in the chromosomal vicinity of genes involved in the etiologies of rhabdomyosarcoma, Wilms' tumor, and the congenital overgrowth disorder, Beckwith-Wiedemann syndrome. Analysis of two other tumor-associated loci, EWS1 and NF2, that have been mapped to the general region of 22q11.2 indicated that they were not involved in this translocation breakpoint. Isolation of the genes present at this translocation junction on both chromosomes 11 and 22 may yield important clinicopathologic and genetic markers for this enigmatic tumor as well as other pediatric diseases.
Asunto(s)
Cromosomas Humanos Par 11/ultraestructura , Cromosomas Humanos Par 22/ultraestructura , Rabdomiosarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Translocación Genética , Animales , Secuencia de Bases , Células CHO , Preescolar , Mapeo Cromosómico , Cricetinae , Electroforesis en Gel de Campo Pulsado , Genes Supresores de Tumor , Humanos , Células Híbridas , Masculino , Datos de Secuencia Molecular , Oncogenes , Neoplasias Retroperitoneales/genéticaRESUMEN
The development of Wilms' tumor has been associated with two genetic loci on chromosome 11: WT1 in 11p13 and WT2 in 11p15.5. Here, we have used loss of heterozygosity (LOH) in Wilms' tumors to narrow the WT2 locus distal to the D11S988 locus. A similar region was apparent for the clinically associated tumor, embryonal rhabdomyosarcoma. We have also demonstrated that a constitutional chromosome translocation breakpoint associated with Beckwith-Wiedemann syndrome and an acquired somatic chromosome translocation breakpoint in a rhabdoid tumor each occur in the same chromosomal interval as the smallest region of LOH in Wilms' tumors and embryonal rhabdomyosarcoma. Finally, we report the first Wilms' tumor without a cytogenetic deletion that shows targeted LOH for 11p15 and 11p13 while maintaining germline status for 11p14.
Asunto(s)
Cromosomas Humanos Par 11 , Eliminación de Gen , Genes del Tumor de Wilms/genética , Neoplasias Renales/genética , Rabdomiosarcoma Embrionario/genética , Tumor de Wilms/genética , Secuencia de Bases , Síndrome de Beckwith-Wiedemann/genética , Línea Celular , Niño , Marcadores Genéticos , Heterocigoto , Humanos , Células Híbridas , Datos de Secuencia Molecular , Translocación GenéticaRESUMEN
We examined 63 unrelated individuals from the United States for the Apa-LI polymorphism in intron 5 of the WT1 gene. Allele frequencies of 0.13 and 0.87 for the A and B alleles, respectively, and a heterozygosity index of 24% contrast sharply with previous data obtained in the Japanese population where allele frequencies of 0.55 and 0.45 for the A and B alleles and a heterozygosity index of 59% were reported. These data suggest genetic heterogeneity at the WT1 locus, which may contribute to the differences in the incidence of Wilms tumor between the two population groups.
Asunto(s)
Genes del Tumor de Wilms , Variación Genética , Intrones/genética , Polimorfismo de Longitud del Fragmento de Restricción , Alelos , Proteínas de Unión al ADN/genética , Epistasis Genética , Frecuencia de los Genes , Heterocigoto , Humanos , Incidencia , Japón/epidemiología , Neoplasias Renales/epidemiología , Neoplasias Renales/genética , Eliminación de Secuencia , Factores de Transcripción/genética , Estados Unidos/epidemiología , Proteínas WT1 , Tumor de Wilms/epidemiología , Tumor de Wilms/genéticaRESUMEN
Medulloblastomas are primitive neuroectodermal tumors (PNETs) of the cerebellum with poorly understood pathogenesis. Previous molecular studies suggested a role for loci on chromosome 11 in the development of medulloblastomas-PNETs. In order to identify the frequency of loss and eventually the extent of allelic loss on chromosome 11, we have examined 23 pediatric medulloblastomas for loss of heterozygosity (LOH) with 16 polymorphic microsatellites. Our data reveal that LOH on 11p or 11q occurs rarely (13%) suggesting the unlikely involvement of chromosome 11 in most cases of medulloblastomas. The same frequency of LOH in medulloblastomas was detected using 8 microsatellites on 22q. Alterations of microsatellite length were found in only 4/594 PCR analyses using 28 markers located on chromosomes 2, 9, 11, 18, and 22, demonstrating that genomic instability is uncommon in medulloblastomas.