Molecular analysis of two putative tumour suppressor genes, PTEN and DMBT, which have been implicated in glioblastoma multiforme disease progression

Somerville, Robert; Shoshan, Yigal; Eng, Charis; Barnett, Gillian C.; Miller, David W.; Cowell, John K.

doi:10.1038/sj.onc.1202066

Cited by 74 publications

(48 citation statements)

References 15 publications

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“…Somatic alterations in genome structure affecting the DMBT1 gene region and loss of DMBT1 gene expression have been observed in glioblastomas, medulloblastomas (Mollenhauer et al, 1997) and in non-CNS tumors such as lung cancers (Takeshita et al, 1999;Wu et al, 1999) and GI tumors (Mori et al, 1999). In malignant astrocytic tumors further studies confirmed either hemizygous or homozygous alterations (Fujisawa et al, 1999;Sasaki et al, 2001;Somerville et al, 1998;Steck et al, 1999). So far, systematic analysis of the entire coding region of DMBT1 in tumors has not yet been performed since either distinct regions could not be amplified (Petersen et al, 2000), major portions of the gene were not included (Takeshita et al, 1999) or the primer design allowed simultaneous amplification of multiple amplicons in the highly repetitive regions of DMBT1 (Wu et al, 1999).…”

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confidence: 55%

Rare mutations of the DMBT1 gene in human astrocytic gliomas

et al. 2002

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The Deleted in Malignant Brain Tumors 1 gene (DMBT1) has been proposed as a tumor suppressor gene candidate in human brain tumors, based on the observation of homozygous deletions affecting the DMBT1 region or part of the gene. In order to support this hypothesis, we performed a mutational analysis of the entire coding region of DMBT1, employing SSCP analysis and direct DNA sequencing in a series of 79 astrocytic gliomas. Five somatic mutations were detected. Two mutations, one of which resulted in an amino acid exchange, occurred in glioblastomas. One pilocytic astrocytoma carried two missense mutations and another pilocytic astrocytoma contained a somatic mutation, not affecting the presumed protein. In addition, 21 of the 27 single nucleotide polymorphisms identified in this study have not been recognized previously. The data indicate, that small mutations are not a frequent finding in gliomas.

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confidence: 55%

Rare mutations of the DMBT1 gene in human astrocytic gliomas

et al. 2002

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“…25 The possible factors that cause lack of DMBT1 expression are still unclear. Somerville et al 22 suggested that homozygous loss at 74k STS, located at the N-terminal position of DMBT1, can be related with lack of DMBT1 expression because of its putative vicinity with the promoter. By contrast, Sasaki et al 41 have recently reported that homozygous lack at 74k may not be a real loss of DMBT1 sequence, but also an artifact generated by a sequence polymorphism at that region.…”

Section: Discussionmentioning

confidence: 99%

“…The sequence-tagged site (STS) c12 (190 bp) located on chromosome 8 was chosen as an internal control. 22 H4 cell line DNA, homozygously deleted at the DMBT1 STS g14, was used as a positive control for differential PCR. We could not find any other positive controls for the rest of the DMBT1 STSs.…”

Section: Pten and Dmbt1 Homozygous Deletionsmentioning

confidence: 99%

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Homozygous deletion and expression of PTEN and DMBT1 in human primary neuroblastoma and cell lines

Muñoz

Lázcoz

Inda

et al. 2004

Intl Journal of Cancer

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Neuroblastoma is the most common pediatric solid tumor. Although many allelic imbalances have been described, a bona fide tumor suppressor gene for this disease has not been found yet. In our study, we analyzed 2 genes, PTEN and DMBT1, mapping 10q23.31 and 10q25.3-26.1, respectively, which have been found frequently altered in other kinds of neoplasms. We screened both genes for homozygous deletions in 45 primary neuroblastic tumors and 12 neuroblastoma cell lines. Expression of these genes in cell lines was assessed by RT-PCR analysis. We could detect 2 of 41 (5%) primary tumors harboring PTEN homozygous deletions. Three of 41 (7%) primary tumors and 2 of 12 cell lines presented homozygous losses at the g14 STS on the DMBT1 locus. All cell lines analyzed expressed PTEN, but lack of DMBT1 mRNA expression was detected in 2 of them. We tried to see whether epigenetic mechanisms, such as aberrant promoter hypermethylation, had any role in DMBT1 silencing. The 2 cell lines lacking DMBT1 expression were treated with 5-aza-2-deoxycytidine; DMBT1 expression was restored in only one of them (MC-IXC). From our work, we can conclude that PTEN and DMBT1 seem to contribute to the development of a small fraction of neuroblastomas, and that promoter hypermethylation might have a role in DMBT1 gene silencing.

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“…We previously reported that mutations in the PTEN gene, which is located on 10q23, are common (32%) in primary but rare (4%) in secondary glioblastomas (Tohma et al, 1998). DMBT1 is deleted frequently in glioblastomas (Mollenhauer et al, 1997;Somerville et al, 1998) but DMBT1 mutations have not yet been identified. Although growth suppression has been observed after microcell-mediated transfer of chromosome fragments from 10p14 -15 into T98G glioblastoma cells (Kon et al, 1998), the putative tumor suppressor gene at this locus has not yet been identified.…”

Section: Fujisawa Et Almentioning

confidence: 99%

Loss of Heterozygosity on Chromosome 10 Is More Extensive in Primary (De Novo) Than in Secondary Glioblastomas

Fujisawa

Reis

Nakamura

et al. 2000

Laboratory Investigation

151

104

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SUMMARY:Glioblastomas develop de novo (primary glioblastomas) or through progression from low-grade or anaplastic astrocytoma (secondary glioblastomas). There is increasing evidence that these glioblastoma subtypes develop through different genetic pathways. Primary glioblastomas are characterized by EGFR and MDM2 amplification/overexpression, PTEN mutations, and p16 deletions, whereas secondary glioblastomas frequently contain p53 mutations. Loss of heterozygosity (LOH) on chromosome 10 (LOH#10) is the most frequent genetic alteration in glioblastomas; the involvement of tumor suppressor genes, other than PTEN, has been suggested. We carried out deletion mappings on chromosome 10, using PCR-based microsatellite analysis. LOH#10 was detected at similar frequencies in primary (8/17; 47%) and secondary glioblastomas (7/13; 54%). The majority (88%) of primary glioblastomas with LOH#10 showed LOH at all informative markers, suggesting loss of the entire chromosome 10. In contrast, secondary glioblastomas with LOH#10 showed partial or complete loss of chromosome 10q but no loss of 10p. These results are in accordance with the view that LOH on 10q is a major factor in the evolution of glioblastoma multiform as the common phenotypic end point of both genetic pathways, whereas LOH on 10p is largely restricted to the primary (de novo) glioblastoma. (Lab Invest 2000, 80:65-72).

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Molecular analysis of two putative tumour suppressor genes, PTEN and DMBT, which have been implicated in glioblastoma multiforme disease progression

Cited by 74 publications

References 15 publications

Rare mutations of the DMBT1 gene in human astrocytic gliomas

Rare mutations of the DMBT1 gene in human astrocytic gliomas

Homozygous deletion and expression of PTEN and DMBT1 in human primary neuroblastoma and cell lines

Loss of Heterozygosity on Chromosome 10 Is More Extensive in Primary (De Novo) Than in Secondary Glioblastomas

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