Edwards MSB, Sheffield VC. Involvement of multiple chromosome 17p loci in medulloblastoma tumorigenesis

Department of Neurological Surgery, School of Medicine, University of California, San Francisco.
The American Journal of Human Genetics (Impact Factor: 10.93). 04/1992; 50(3):584-9.
Source: PubMed


Loss of heterozygosity for sequences located on chromosome 17p in several tumor types is often associated with mutations in the tumor suppressor gene p53. We previously showed consistent deletion of chromosome 17p12-13.1 in medulloblastoma, a common childhood brain tumor. Using denaturing gradient gel electrophoresis and direct sequencing, we have detected p53 mutations in only two of 20 medulloblastoma specimens. Moreover, additional RFLP studies of these 20 specimens showed loss of heterozygosity at a more distal and distinct site, 17p13.3. Deletion of 17p almost invariably signified a negative prognosis. Our results suggest that p53 mutations may contribute to the pathogenesis of medulloblastoma in relatively few cases. The consistent deletion of other discrete loci on 17p suggests that additional or alternative tumor suppressor genes may contribute to the tumor's phenotype.

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    • "An alternative explanation is that other gene(s) may be the target of these allelic deletions. Evidence of a second gene at 17p has been found in other neoplasias (Casey et al, 1993; Cogen et al, 1992; Cornelis et al, 1994; Makos Wales et al, 1995). Further studies combining the analysis of p53 mutations and loss of heterozygosity along the 17p region in sequential tumour samples may help to clarify this issue. "
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    ABSTRACT: To determine the role of the p53 gene in chronic lymphocytic leukaemia (CLL) and its possible involvement in the pathogenesis of a progressive form of CLL characterized by > 10% prolymphocytes (CLL/PL), we selected 32 cases, 17 with typical morphology and 15 CLL/PL. The extent of inactivation of p53 was examined by assessing loss of heterozygosity (LOH) at 17p13.3, by sequencing the highly conserved region (exons 5–9) of the p53 gene and by analysing p53 protein expression. LOH was detected in 8/28 (29%) cases, p53 mutations in 5/32 (16%) cases and p53 expression in 5/27 (19%) cases. Overall 11 cases (30%) had p53 abnormalities of which eight cases had CLL/PL. There was a significant association between CLL/PL and p53 abnormalities (P = 0.05); 75% of cases with LOH, 80% of p53 mutations and 80% of cases positive for p53 protein had CLL/PL. Thus, p53 inactivation is the first gene abnormality identified so far to be involved in the development of CLL/PL. All the cases with typical CLL and p53 abnormalities had only one allele affected whereas 4/6 CLL/PL had both alleles inactivated. This difference in the extent of p53 inactivation suggests that accumulation of p53 abnormalities may be associated with progression of CLL to CLL/PL. CLL cases with p53 abnormalities were characterized by a higher incidence of stage C (P < 0.025), a higher proliferative rate (P = 0.05), short survival (P < 0.005) and resistance to first-line therapy (P < 0.02) but not to nucleoside analogues. Analysis of the correlation between p53 status and incidence of trisomy 12 by fluorescence in situ hybridization (FISH) showed that trisomy 12 was more frequent in cases without p53 abnormalities, suggesting that trisomy 12 and p53 may represent different pathways of transformation in CLL.
    British Journal of Haematology 12/1997; 99(4):848-57. DOI:10.1046/j.1365-2141.1997.4723278.x · 4.71 Impact Factor
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    • "The ABR gene, which is expressed in brain, has been favoured as a candidate. However, specific mutations have not yet been found (Cogen et al, 1992). The race for a specific medulloblastoma gene has not come to an end. "
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    ABSTRACT: Medulloblastoma is the most frequent paediatric brain tumour. Because of the uniform histology, a common genetic mechanism has been postulated. Loss of heterozygosity (LOH) studies support evidence that a candidate gene, which functions as a tumour-suppressor gene, is located in 17p13. Eighteen tumours were examined for loss of heterozygosity at 15 different loci at chromosome 17p. Nine of 18 (50%) tumours had allelic loss in 17p 13.3-13.2. The smallest region of overlap, which harbours the disease gene, includes markers from UT222 (D17S675) to UT49 (D17S731) and spans a region of less than 6 cM. Candidate genes within this region are HIC-1, a potential tumour-suppressor gene, and DPH2L, a gene that has been cloned from the ovarian critical region. The putative region excludes the p53 gene and the ABR gene, which have been favoured by others. LOH of chromosome 17p may be used as a new prognostic biological marker. Children with an allelic loss had a poorer prognosis than those patients without loss of heterozygosity (P<0.05). Images Figure 1
    British Journal of Cancer 11/1997; 76(10):1284-7. DOI:10.1038/bjc.1997.549 · 4.84 Impact Factor
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    • "Analysis of the various neuroblast markers reveals that these tumor cell types exhibit phenotypes of immature neurons, similar to those expressed by granule cells during maturation. ~53 is rarely mutated in these tumors (Saylors et al., 1991; Biegel et al., 1992; Cogen et al., 1992) and the majority of these tumors respond well to x-ray therapy (Slagel et al., 1982). Our results suggest that medulloblastoma cells undergo apoptosis in response to radiation therapy. "
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    ABSTRACT: Apoptosis is a mechanism of cell death operative in the normal development and regulation of vertebrate tissues and organ cellularity. During the postnatal development of the mouse cerebellum, extensive granule neuron apoptosis occurs that may regulate the final granule cell to Purkinje cell stoichiometry observed in the adult. Cerebellar granule cells are highly sensitive to genotoxic agents such as gamma-irradiation and methylazoxymethanol during the first 2 weeks of postnatal development. We demonstrate that ionizing radiation induces extensive cerebellar granule cell death via apoptosis in vivo. In p53 null mice, however, the cerebellar granule cells do not undergo apoptosis in response to gamma-irradiation. In mice heterozygous for the p53 allele, the granule cells apoptosis is delayed, indicating an intermediate response. The developmental apoptosis of cerebellar granule cells, however, occurs similarly in wild-type and p53 null mice. Therefore, neurons undergo p53-dependent and p53-independent apoptosis, depending upon the initiating stimulus that triggers DNA fragmentation. In contrast to x-ray damage, the extensive death of cerebellar granule cells induced by methylazoxymethanol was found to be independent of the DNA fragmentation characteristic of apoptosis, and was also independent of expression of p53. Ablation of neuron progenitor cells with genotoxic agents may occur by p53-dependent apoptosis or by p53-independent mechanisms not associated with DNA fragmentation.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 09/1995; 15(8):5851-7. · 6.34 Impact Factor
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