KUB3 amplification and overexpression in human gliomas.

Gene amplification is known to occur frequently in human glioma. Recently we reported cloning of a novel gene termed glioma-amplified sequence 16 (GAS16) by microdissection-mediated cDNA capture. In this article, we demonstrate that GAS16 results from an alternative splicing process of the Ku70 binding protein 3 (KUB3) that is essential for DNA double-strand break repair. The alternative splice product was found in glioblastoma and in normal fetal brain. We determined the amplification frequency of KUB3 in glioma with different grading. We analyzed a total of 102 glioma primary tumors and found KUB3 to be amplified in 12/82 (14%) glioblastomas, 4/13 anaplastic astrocytomas (30%), and 2/4 astrocytomas, but in none of three pilocytic astrocytomas. Northern blot analysis of glioblastoma shows a strong correlation between KUB3 amplification and overexpression. Amplification of KUB3 appears to be independent of other genetic changes frequently associated with the development of gliomas, including EGFR amplification, LOH of TP53, and LOH of chromosome 10. The KUB3 amplification and overexpression may interfere with the function of KUB3 in the DNA-PK complex involved in the maintenance of genome stability and reduction of mutation frequency.

Adolescente con Tetrasomía del X e inversión del cromosoma 9: reporte de un caso / Adolescent with X Tretrasomies inversion of the chromosome 9: report a case

Las terasomías del cromosoma X son complementos cromosómicos raros no asociados a un cuadro clínico específico pero la mayoría de los pacientes con esta polisomía del X presentan retardo en el aprendizaje, inmadurez emocional y disfunción gonadal. En el presente trabajo, se describen los hallazgos clínicos y citogenéticos en una paciente con amenorrea primaria, retardo psicomotor, inmadurez emocional y cariotipo 48, XXXX, inv (9). Aunque es difícil correlacionar los cromosomas X supernumerarios en esta paciente con la inversión del cromosoma 9 heredada del padre, el presente caso parece ser, hasta donde sabemos, la primera tetrasomía del X asociada a una inversión pericentromérica del cromosoma 9. Las tetrasomías del X podrían originarse por dos errores no-disyuncionales sucesivos ocurridos posiblemente en la gametogénesis materna

MRI findings in a patient with partial monosomy 10p.

Partial monosomy 10p is a rare chromosomal disorder characterised by frontal bossing, micrognathia, congenital heart defects, vesicoureteral abnormalities, and developmental delay. This is the first report to describe seizures not associated with hypocalcaemia, as well as cortical atrophy and decreased white matter volume on magnetic resonance imaging, in a patient with documented partial monosomy 10p. The neuroradiographic abnormalities found in this patient provide a first step towards understanding the aetiology of the developmental delay and ventriculomegaly associated with this chromosomal abnormality.

Adrenoleucodistrofia ligada al cromosoma X: informe de dos casos clínicos / Adrenoleukodystrophy linked with chromosome X. Report of two clinical cases

La adrenoleucodistrofia infantil es un trastorno peroxisomal caracterizado por una falla en la función de la lignoceroil CoA sintetasa, se transmite en forma reseciva ligada al cromosoma X, con localización el locus 28 (q28). La deficiencia enximática condiciona una degradación imcompleta de los ácidos grasos de cadena larga, acumulándose en consecuencia en el tejido cerebral y adrenal. El motivo del presente trabajo es identificar los hallazgos clínicos encontrados en estos casos donde incluímos la presencia del asma bronquial, manifestaciones endocrinológicas y neurológicas. Los pacientes fueron tratados en el servicio a partir de 1990. Se describen los métodos utilizados para el diagnóstico, desde las alteraciones tempranas de los potenciales evocados de tallo, hasta las imágenes de tomografía computarizada de cráneo con doble cantidad de medio de contraste, y cortes tardíos

Loss of heterozygosity for loci on chromosome 10 is associated with morphologically malignant meningioma progression.

Meningioma is a common tumor of the central nervous system which displays morphological heterogeneity. In order to determine whether this phenotypic variability is associated with distinct or overlapping genetic lesions, we compared genotypes at several loci defined by allele length polymorphism in tumor and normal tissues from patients with meningioma. In particular, we concentrated on loci on chromosomes 22 and 10 because these genomic regions have previously been shown to be altered in the former in sporadic and familial meningiomas and in the latter as a late stage event in progression of another common brain tumor, astrocytoma. We examined 38 tumors which were classified as benign, atypical, or malignant by morphological criteria, invasive characteristics, or both. We found that loss of heterozygosity (LOH) for loci on chromosome 22 occurred in 5 of 15 benign, 2 of 2 atypical, and 5 of 10 malignant meningiomas. Similar alterations of chromosome 10 were found in 0 of 20 benign, 1 of 2 atypical, and 4 of 13 malignant meningiomas. Among the malignant tumors, LOH for loci on chromosome 10 occurred in 2 of 4 morphologically malignant tumors and in 2 of 4 morphologically and invasively malignant tumors. In contrast, LOH was not observed for any of the 5 informative tumors classified as malignant by invasive characteristics only. LOH for loci on chromosome 22 accompanied (but was not restricted to) allelic loss of loci on chromosome 10. These data suggest that the progression of meningiomas from arachnoidal cells to the morphologically malignant phenotype may, in part, entail the loss of a tumor suppressor gene(s) on chromosome 22 early in the process and that this may be compounded by alterations of chromosome 10, the LOH of which is associated with morphological signs of malignancy.

Genetic mechanisms of neoplasia in MEN 2.

Several possible mechanisms for the initiation and progression of tumors in multiple endocrine neoplasia type 2 (MEN 2) merit consideration. Localization of MEN2A to the pericentromeric area of chromosome 10 indicates the site of the initial mutagenic event but does not explain the tissue specificity observed. The consistency of tissue involvement within families, despite the variability between families, suggests that the tumors result from separate but contiguous tissue-specific genes arranged in a particular linear order. Linkage studies in MEN 2A and 2B families are compatible with this contiguous gene theory. Data suggest that Knudson's two-mutational-event theory is applicable in MEN 2, with cellular hyperplasia resulting from the initial heritable mutation. The second event could be a homozygous allelic mutation, but the lack of consistent loss of heterozygosity of chromosome 10 markers in tumors suggests other mechanisms. Observations in MEN 2 may be explained by the heritable chromosome 10 mutation causing hyperplasia, with the hyperplastic cells being converted to cancer cells by second mutations at any of many possible sites. Tumor progression probably involves subsequent events at other loci. These hypotheses may have important clinical implications.