Astrocytoma linked to familial ataxia-telangiectasia

Miyagi, Koichi; Mukawa, Jiro; Kinjo, Noriko; Horikawa, Kyoi; Mekaru, Shunei; Nakasone, Satoshi; Koga, Hisamitsu; Higa, Yasutoshi; Naito, Masafumi

doi:10.1007/bf02307420

Cited by 27 publications

(7 citation statements)

References 31 publications

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“…In addition, a child's developing central nervous system may provide an environment that promotes tumorigenesis, especially in combination with the abnormal AT host environment characterized by deranged cellular responses to stress. Cases of astrocytoma have been reported in children with AT [34]. …”

Section: Discussionmentioning

confidence: 99%

Donor-Derived Brain Tumor Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient

et al. 2009

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BackgroundNeural stem cells are currently being investigated as potential therapies for neurodegenerative diseases, stroke, and trauma. However, concerns have been raised over the safety of this experimental therapeutic approach, including, for example, whether there is the potential for tumors to develop from transplanted stem cells.Methods and FindingsA boy with ataxia telangiectasia (AT) was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm. We compared the tumor cells and the patient's peripheral blood cells by fluorescent in situ hybridization using X and Y chromosome probes, by PCR for the amelogenin gene X- and Y-specific alleles, by MassArray for the ATM patient specific mutation and for several SNPs, by PCR for polymorphic microsatellites, and by human leukocyte antigen (HLA) typing. Molecular and cytogenetic studies showed that the tumor was of nonhost origin suggesting it was derived from the transplanted neural stem cells. Microsatellite and HLA analysis demonstrated that the tumor is derived from at least two donors.ConclusionsThis is the first report of a human brain tumor complicating neural stem cell therapy. The findings here suggest that neuronal stem/progenitor cells may be involved in gliomagenesis and provide the first example of a donor-derived brain tumor. Further work is urgently needed to assess the safety of these therapies.

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Section: Discussionmentioning

confidence: 99%

Donor-Derived Brain Tumor Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient

et al. 2009

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“…With regard to the central nervous system tumors, some cases of primary brain tumors, including gliomas, have also been reported in A-T patients (Miyagi et al, 1995). CHEK2, one of the main ATM downstream effectors, has been proposed to act as a multiorgan cancer susceptibility gene (Cybulski et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Loss of ATM/Chk2/p53 Pathway Components Accelerates Tumor Development and Contributes to Radiation Resistance in Gliomas

et al. 2010

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Maintenance of genomic integrity is essential for adult tissue homeostasis and defects in the DNA-damage response (DDR) machinery are linked to numerous pathologies including, cancer. Here we present evidence that the DDR exerts tumor suppressor activity in gliomas. We show that genes encoding components of the DDR pathway are frequently altered in human gliomas and that loss of elements of the ATM/Chk2/p53 cascade accelerates tumor formation in a glioma mouse model. We demonstrate that Chk2 is required for glioma response to ionizing radiation in vivo and is necessary for DNA-damage checkpoints in the neuronal stem cell compartment. Finally, we observed that the DDR is constitutively activated in a subset of human GBMs, and such activation correlates with regions of hypoxia.

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“…This was likely radiation-induced, and had a fatal outcome. While medulloblastomas 41,46,47 , astrocytomas 9,46,[48][49][50][51] , craniopharyngiomas 52 , and primary central nervous system (CNS) lymphomas 53 have been described in individuals with A-T, supratentorial PNET's have not. Also of note is that ATM gene mutations do not appear to play a role in the pathogenesis of medulloblastoma in children who do not have A-T 54 .…”

Section: Discussionmentioning

confidence: 99%

Ataxia-Telangiectasia: Atypical Presentation and Toxicity of Cancer Treatment

Yanofsky

Seshia

Dawson

et al. 2009

Can. j. neurol. sci.

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462Ataxia-telangiectasia (A-T) is an autosomal recessive genomic instability syndrome characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, hypersensitivity to ionizing radiation, and cancer predisposition, with lymphoid malignancies predominating in the first two decades of life [1][2][3][4][5][6][7][8][9][10] . Mutations in the Ataxiatelangiectasia mutated (ATM) gene result in markedly decreased or absent levels of ATM kinase, a protein that phosphorylates many downstream targets. A deficiency of ATM kinase leads to cell cycle defects, faulty repair of DNA damage, defective apoptosis, and poor responses to oxidative stress 1,3,11 .ABSTRACT: Background: The onset of progressive cerebellar ataxia in early childhood is considered a key feature of ataxiatelangiectasia (A-T), accompanied by ocular apraxia, telangiectasias, immunodeficiency, cancer susceptibility and hypersensitivity to ionizing radiation. Methods: We describe the clinical features and course of three Mennonite children who were diagnosed with A-T following the completion of therapy for lymphoid malignancies. Results: Prior to cancer therapy, all had non-progressive atypical neurological abnormalities, with onset by age 30 months, including dysarthria, dyskinesia, hypotonia and/or dystonia, without telangiectasias. Cerebellar ataxia was noted in only one of the children and was mild until his death at age eight years. None had severe infections. All three children were "cured" of their lymphoid malignancies, but experienced severe adverse effects from the treatments administered. The two children who received cranial irradiation developed supratentorial primitive neuroectodermal tumors of the brain, an association not previously described, with fatal outcomes. Conclusions: The range of neurological presentations of A-T is broad. Ataxia and telangiectasias may be minimal or absent and the course seemingly non-progressive. The diagnosis of A-T should be considered in all children with neuromotor dysfunction or peripheral neuropathy, particularly those who develop lymphoid malignancies. The consequences of missing the diagnosis may be dire. Radiation therapy and radiomimetic drugs should be avoided in individuals with A-T. RÉSUMÉ: Mode de présentation atypique et toxicité du traitement anticancéreux chez les patients atteints d'ataxie-télangiectasie. Contexte :L'apparition d'une ataxie cérébelleuse progressive dans la petite enfance est considérée comme une manifestation clé de l'ataxie-télangiectasie (A-T), accompagnée d'apraxie oculaire, de télangiectasies, d'un déficit immunitaire, de susceptibilité au cancer et d'hypersensibilité aux radiations ionisantes. Méthodes : Nous décrivons les manifestations cliniques et l'évolution chez trois enfants mennonites chez qui un diagnostic d'A-T a été posé après un traitement pour cancer lymphoïde. Résultats : Avant le traitement anticancéreux, tous présentaient des anomalies neurologiques atypiques non évolutives, dont l'âge de début se situait vers 30 mois, soit de ...

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Astrocytoma linked to familial ataxia-telangiectasia

Cited by 27 publications

References 31 publications

Donor-Derived Brain Tumor Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient

Donor-Derived Brain Tumor Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient

Loss of ATM/Chk2/p53 Pathway Components Accelerates Tumor Development and Contributes to Radiation Resistance in Gliomas

Ataxia-Telangiectasia: Atypical Presentation and Toxicity of Cancer Treatment

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