Hemizygous or homozygous deletion of the chromosomal region containing thep16INK4a gene is associated with amplification of the EGF receptor gene in glioblastomas

Hegi, Monika E.; Hausen, Axel zur; Rüedi, Daniela; Malin, Gerhard; Kleihues, Paul

doi:10.1002/(sici)1097-0215(19970926)73:1<57::aid-ijc10>3.0.co;2-2

Cited by 53 publications

(43 citation statements)

References 21 publications

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“…Deletion of INK4a locus [26,27] along with activation of Ras and Akt pathways can be responsible for oncogenic/mitogenic signals that lead to the dedifferentiation of the mature astroglial cells to astrocytoma [28]. Our results demonstrated that 4-HPR induced astrocytic differentiation with the down regulation of key signaling molecules to orchestrate prolongation of cell cycle arrest.…”

Section: Discussionmentioning

confidence: 66%

N-(4-Hydroxyphenyl)retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-γ sensitivity for apoptosis in human glioblastoma cells

2008

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Glioblastoma is the most malignant and prevalent brain tumor in humans. It is composed of heterogenic abnormal astroglial cells that avoid differentiation, maintain proliferation, and reluctant to apoptosis. N-(4-Hydroxyphenyl) retinamide (4-HPR) induced astrocytic differentiation and increased sensitivity to interferon-gamma (IFN-γ) for apoptosis in human glioblastoma A172, LN18, and SNB19 cells. Combination of 4-HPR and IFN-γ significantly inhibited human telomerase reverse transcriptase (hTERT), cyclin dependent kinase 2 (CDK2), and survivin to upregulate caspase-8, caspase-9, and caspase-3 for increasing apoptosis in all glioblastoma cell lines. Hence, combination of 4-HPR and IFN-γ should be considered for controlling growth of different human glioblastoma cells.

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Section: Discussionmentioning

confidence: 66%

N-(4-Hydroxyphenyl)retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-γ sensitivity for apoptosis in human glioblastoma cells

2008

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“…In an attempt to evaluate whether genetic alterations observed in human astrocytomas were also present in the murine tumors obtained in this study, genetic regions homologous to human genes, including EGFR, PTEN, DMBT1, Rb-1, and p16/p14ARF were analysed for LOH (Ekstrand et al, 1991;Fulci et al, 2000;Hegi et al, 1997;Ichimura et al, 1996;Maier et al, 1998;Mollenhauer et al, 1997;Steck et al, 1997). Deletion of the chromosomal region containing the pten gene was lost in two brain tumors (25%) and might indicate mutational inactivation of pten on the retained allele.…”

Section: Cooperating Genetic Alterationsmentioning

confidence: 99%

Reduced latency but no increased brain tumor penetrance in mice with astrocyte specific expression of a human p53 mutant

Klein

Rüedi

Nozaki³

et al. 2000

Oncogene

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p53-germline mutations located in the core DNA-binding domain have been associated with a more dominant tumor penetrance especially for breast cancer and brain tumors. We previously reported an unusual accumulation of CNS tumors associated with a unique p53 germline mutation, Y236D (deletion of codon 236). To test whether this tissue-speci®c tumor predisposition re¯ects a gain-of-function activity of Y236D, we generated transgenic mice expressing Y236D in astrocytes using the regulatory elements of the glial ®brillary acidic protein (GFAP) gene. After transplacental exposure to N-ethyl-N-nitrosourea (25 mg/kg BW) brain tumors developed in 18% (7/39) of GFAP-Y236D transgenic p53 +/7 mice, while in p53 +/7 mice the incidence was 28% (11/40) (P40.3). However, the mean tumor latency for GFAP-Y236D/p53 +/7 mice was signi®cantly shorter than for p53 +/7 mice, with 19.9 weeks vs 31.6 weeks (P=0.039), respectively. Taken together, cell speci®c expression of Y236D results in an acceleration of tumor progression but does not confer a higher tumor penetrance. Conceivably, the transdominant e ect of Y236D provided a growth advantage early in the progression of neoplastic cells, since the endogenous p53 wild-type allele was lost in all brain tumors independent of the genotype. This re¯ects well observations from human astrocytic neoplasms with p53 mutations. Oncogene (2000) 19, 5329 ± 5337.

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“…In primary human tumor tissue, however, precise assessment of the genomic status of both INK4A products has been dicult due to technical limitations and the presence of non-neoplastic DNA (Cairns et al, 1994(Cairns et al, , 1995Hegi et al, 1997;Merlo et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Quantitative real-time PCR does not show selective targeting of p14ARF but concomitant inactivation of both p16INK4A and p14ARF in 105 human primary gliomas

et al. 2001

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In many human cancers, the INK4A locus is frequently mutated by homozygous deletions. By alternative splicing this locus encodes two non-related tumor suppressor genes, p16INK4A and p14 ARF (p19 ARF in mice), which regulate cell cycle and cell survival in the retinoblastoma protein (pRb) and p53 pathways, respectively. In mice, the role of p16 INK4A as the critical tumor suppressor gene at the INK4A locus was challenged when it was found that p19 ARF only knock-out mice developed tumors, including gliomas. We have analysed the genetic status of the INK4A locus in 105 primary gliomas using both microsatellite mapping (MSM) and quantitative realtime PCR (QRT ± PCR). Comparison of the results of the two methods revealed agreement in 67% of the tumors examined. In discordant cases,¯uorescence in situ hybridization (FISH) analysis was always found to support QRT ± PCR classi®cation. Direct assessment of p14 ARF exon 1b, p16 INK4A exon 1a and exon 2 by QRT ± PCR revealed 43 (41%) homozygous and eight (7%) hemizygous deletions at the INK4A locus. In 49 (47%) gliomas, both alleles were retained. In addition, QRT ± PCR, but not MSM, detected hyperploidy in ®ve (5%) tumors. Deletion of p14 ARF was always associated with co-deletion of p16 INK4A and increased in frequency upon progression from low to high grade gliomas. Shorter survival was associated with homozygous deletions of INK4A in the subgroup of glioblastoma patients older than 50 years of age (P=0.025, Anova test single factor, a=0.05). Oncogene (2001) 20, 1103 ± 1109.

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Hemizygous or homozygous deletion of the chromosomal region containing thep16INK4a gene is associated with amplification of the EGF receptor gene in glioblastomas

Cited by 53 publications

References 21 publications

N-(4-Hydroxyphenyl)retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-γ sensitivity for apoptosis in human glioblastoma cells

N-(4-Hydroxyphenyl)retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-γ sensitivity for apoptosis in human glioblastoma cells

Reduced latency but no increased brain tumor penetrance in mice with astrocyte specific expression of a human p53 mutant

Quantitative real-time PCR does not show selective targeting of p14ARF but concomitant inactivation of both p16INK4A and p14ARF in 105 human primary gliomas

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