Three-hit hypothesis in astrocytoma: tracing the polymorphism D1853N in ATM gene through a pedigree of the proband affected with primary brain tumor

Mehdipour, Parvin; Habibi, Laleh; Mohammadi-Asl, Javad; Kamalian, Naser; Azin, Masoud Mehr

doi:10.1007/s00432-008-0404-4

Cited by 19 publications

(18 citation statements)

References 15 publications

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“…By considering the importance of protein-and mRNA-expression of ATM gene in brain tumors [15,20], and due to the common involvement of the D1853N polymorphism of ATM gene in brain tumors [15,20], expression assay might be also included as part of the complementary investigation in the patients affected with primary breast cancer in the future studies as well.…”

Section: Discussionmentioning

confidence: 99%

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Importance of ATM gene as a susceptible trait: predisposition role of D1853N polymorphism in breast cancer

et al. 2010

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The involvement of ATM gene and specifically, the important role of D1853N polymorphism, as a three-hit hypothesis has been previously reported in an Iranian proband affected with brain tumor and this polymorphism could be screened in her relatives as well. The aim of present study was to investigate the involvement of D1853N polymorphism as a predisposition factor in 129 Iranian patients affected with primary breast cancer and 248 sex- and age-matched healthy controls. Mutant allele-specific PCR amplification (MASA) assay was performed to analyze the D1853N polymorphism in the ATM gene. The frequency of D1853N polymorphism in cases, internal and external controls was 31.0% (40/129), 26.9% (28/104) and 12.5% (18/144), respectively. The frequency of D1853N in total control groups, including normal external control and pedigree internal control, was 18.6% (46/248). The odds ratio was calculated with the logistic regression test, with an estimated relative risk of 2.579 (P=0.005). The significant difference was observed between the patient-carriers of this alteration and external controls (P=0.001). The number of controls harboring D1853N polymorphism was higher in internal control compared to external controls, and the difference was statistically significant (P=0.004). The significant difference was observed between the patient-carriers and external controls and could be considered as a predisposing and diagnostic marker in the population and specifically in the cancer-prone pedigrees.

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Section: Discussionmentioning

confidence: 99%

“…The involvement of ATM gene and specifically, the important role of D1853N polymorphism, as a three-hit hypothesis has been previously reported in an Iranian proband affected with brain tumor [15].…”

Section: Introductionmentioning

confidence: 92%

Importance of ATM gene as a susceptible trait: predisposition role of D1853N polymorphism in breast cancer

et al. 2010

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“…According to this study, p53 and ATM are the major checkpoint genes in response to DNA damage [57]. Of course, we have reported ATM variations and three-hit hypothesis for this gene in one case affected with astrocytoma in another study [58]. According to present study, ATM expression did not correlate with P53 and Rb expression in grade II of these tumors and relatively has an expression similar to grade I.…”

Section: Discussionmentioning

confidence: 62%

Expression of cyclin D2, P53, Rb and ATM cell cycle genes in brain tumors

et al. 2010

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Cyclin D2, P53, Rb and ATM as cell cycle genes regulate cell growth and proliferation. Considering their roles, we assumed that they have different level of mRNA expression in different grades of brain tumors. To determine this point, we investigated the mRNA expression in two types of brain tumors, including astrocytoma and meningioma. The mRNA of 52 brain tumor samples were extracted; cyclin D2, P53, Rb and ATM mRNA expression was quantified using the real-time quantitative reverse-transcription polymerase chain reaction. We compared mRNA expression of these genes between astrocytoma and meningioma tumors and also between different grades of them. Cyclin D2, P53, Rb and ATM had higher expression in astrocytoma than meningioma tumors. Higher grade (III and IV) of astrocytoma tumors had up-regulation for cyclin D2 and ATM genes, but higher grades of these tumors showed down-regulation of P53 and Rb genes. Analysis of relative expression between two grades of meningioma tumors showed a high down-regulation in grade II related to grade I. Also, cyclin D2, P53, Rb and ATM mRNA expression in each group of tumors (meningioma and astrocytoma) showed a highly positive correlation in lower grades. Considering this fact and also different templates of up- and down-regulation for these genes' interaction in different types of brain tumors, it seems that these genes do not have a unique model of interaction.

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“…By focusing on the normal brain tissue in an autopsy sample from healthy decease individual, ATM and RB were characterized with low and high protein expression (Figs. 4 and 5), which is expected for ATM due to its involvement as a frequent alteration within our normal population as well [18]. Moreover, in meningioma, a heterogenic pattern of protein expression including high and low could be detected in both ATM, RB, and KI-67 (Fig.…”

Section: Discussionmentioning

confidence: 90%

“…We previously investigated the role of this polymorphism in breast cancer and brain tumor patients through amplification refractory mutation system-polymerization chain reaction (ARMS-PCR) and sequencing [17]. Besides, the three-hit hypothesis has been proposed in which D1853N polymorphism and two novel splice site IVS 38-63T>A and IVS38-30 A>G polymorphisms comprise the germ line and somatic hits required for astrocytoma development, respectively [18].…”

Section: Introductionmentioning

confidence: 99%

Linking ATM Promoter Methylation to Cell Cycle Protein Expression in Brain Tumor Patients: Cellular Molecular Triangle Correlation in ATM Territory

et al. 2014

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Ataxia telangiectasia mutated (ATM) is a key gene in DNA double-strand break (DSB), and therefore, most of its disabling genetic alterations play an important initiative role in many types of cancer. However, the exact role of ATM gene and its epigenetic alterations, especially promoter methylation in different grades of brain tumors, remains elusive. The current study was conducted to query possible correlations among methylation statue of ATM gene, ATM/ retinoblastoma (RB) protein expression, D1853N ATM polymorphism, telomere length (TL), and clinicopathological characteristics of various types of brain tumors. Isolated DNA from 30 fresh tissues was extracted from different types of brain tumors and two brain tissues from deceased normal healthy individuals. DNAs were treated with bisulfate sodium using DNA modification kit (Qiagen). Methylation-specific polymerase chain reaction (MSP-PCR) was implicated to determine the methylation status of treated DNA templates confirmed by promoter sequencing. Besides, the ATM and RB protein levels were determined by immunofluorescence (IF) assay using monoclonal mouse antihuman against ATM, P53, and RB proteins. To achieve an interactive correlation, the methylation data were statistically analyzed by considering TL and D1853N ATM polymorphism. More than 73% of the brain tumors were methylated in ATM gene promoter. There was strong correlation between ATM promoter methylation and its protein expression (p < 0.001). As a triangle, meaningful correlation was also found between methylated ATM promoter and ATM protein expression with D1853N ATM polymorphism (p = 0.01). ATM protein expression was not in line with RB protein expression while it was found to be significantly correlated with ATM promoter methylation (p = 0.01). There was significant correlation between TL neither with ATM promoter methylation nor with ATM protein expression nor with D1853N polymorphism. However, TL has shown strong correlation with patient's age and tumor grade (p = 0.01). Given the important role of cell cycle checkpoint proteins as well as RB and ATM in TL and cancer evolution, further assessment is warranted to shed more light on the pathway linking the telomere instability to tumor progression. High ATM methylation rate in brain tumor patients could open a new avenue toward early screening and cancer therapy.

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Three-hit hypothesis in astrocytoma: tracing the polymorphism D1853N in ATM gene through a pedigree of the proband affected with primary brain tumor

Cited by 19 publications

References 15 publications

Importance of ATM gene as a susceptible trait: predisposition role of D1853N polymorphism in breast cancer

Importance of ATM gene as a susceptible trait: predisposition role of D1853N polymorphism in breast cancer

Expression of cyclin D2, P53, Rb and ATM cell cycle genes in brain tumors

Linking ATM Promoter Methylation to Cell Cycle Protein Expression in Brain Tumor Patients: Cellular Molecular Triangle Correlation in ATM Territory

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