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National Cancer Institute®
Ultima Vez Modificado: 1 de enero del 2002
UI - 11248063
AU - Sekiguchi J; Ferguson DO; Chen HT; Yang EM; Earle J; Frank K; Whitlow S;
TI - Gu Y; Xu Y; Nussenzweig A; Alt FW Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development.
SO - Proc Natl Acad Sci U S A 2001 Mar 13;98(6):3243-8
AD - The Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA.
DNA ligase IV (Lig4) and the DNA-dependent protein kinase (DNA-PK) function in nonhomologous end joining (NHEJ). However, although Lig4 deficiency causes late embryonic lethality, deficiency in DNA-PK subunits (Ku70, Ku80, and DNA-PKcs) does not. Here we demonstrate that, similar to p53 deficiency, ataxia-telangiectasia-mutated (ATM) gene deficiency rescues the embryonic lethality and neuronal apoptosis, but not impaired lymphocyte development, associated with Lig4 deficiency. However, in contrast to p53 deficiency, ATM deficiency enhances deleterious effects of Lig4 deficiency on growth potential of embryonic fibroblasts (MEFs) and genomic instability in both MEFs and cultured progenitor lymphocytes, demonstrating significant differences in the interplay of p53 vs. ATM with respect to NHEJ. Finally, in dramatic contrast to effects on Lig4 deficiency, ATM deficiency causes early embryonic lethality in Ku- or DNA-PKcs-deficient mice, providing evidence for an NHEJ-independent role for the DNA-PK holoenzyme.
UI - 11450971
AU - Tuteja N; Tuteja R
TI - Unraveling DNA repair in human: molecular mechanisms and consequences of repair defect.
SO - Crit Rev Biochem Mol Biol 2001;36(3):261-90
AD - International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India.
Cellular genomes are vulnerable to an array of DNA-damaging agents, of both endogenous and environmental origin. Such damage occurs at a frequency too high to be compatible with life. As a result cell death and tissue degeneration, aging and cancer are caused. To avoid this and in order for the genome to be reproduced, these damages must be corrected efficiently by DNA repair mechanisms. Eukaryotic cells have multiple mechanisms for the repair of damaged DNA. These repair systems in humans protect the genome by repairing modified bases, DNA adducts, crosslinks and double-strand breaks. The lesions in DNA are eliminated by mechanisms such as direct reversal, base excision and nucleotide excision. The base excision repair eliminates single damaged-base residues by the action of specialized DNA glycosylases and AP endonucleases. Nucleotide excision repair excises damage within oligomers that are 25 to 32 nucleotides long. This repair utilizes many proteins to remove the major UV-induced photoproducts from DNA, as well as other types of modified nucleotides. Different DNA polymerases and ligases are utilized to complete the separate pathways. The double-strand breaks in DNA are repaired by mechanisms that involve DNA protein kinase and recombination proteins. The defect in one of the repair protein results in three rare recessive syndromes: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. This review describes the biochemistry of various repair processes and summarizes the clinical features and molecular mechanisms underlying these disorders.
UI - 11606376
AU - Seker H; Butkiewicz D; Bowman ED; Rusin M; Hedayati M; Grossman L;
TI - Harris CC Functional significance of XPD polymorphic variants: attenuated apoptosis in human lymphoblastoid cells with the XPD 312 Asp/Asp genotype.
SO - Cancer Res 2001 Oct 15;61(20):7430-4
AD - Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA.
Recent molecular epidemiological studies have identified polymorphisms in the XPD gene that are associated with increased risk of brain gliomas and head, neck, lung, and skin cancers. However, the functional significance of these polymorphic variants in altering cell processes such as cell cycle checkpoints, DNA repair, and apoptosis is uncertain. We have cloned the XPD variants Lys751Gln, Asp312Asn, and Lys751Gln-Asp312Asn into a pcDNA-3.1-expression vector. Using these constructs, we did not find any detectable difference in either in vitro binding with wild-type p53 or in DNA repair proficiency as measured by host cell reactivation assay. We then genotyped 34 different lymphoblastoid cell lines from six Centre d'Etude du Polymorphisme Humaine (CEPH)/Utah pedigree families and a CEPH/French pedigree family for polymorphisms at codons 751 and 312 and assessed their apoptotic response after either UV or ionized radiation exposure. The lymphoblastoid cell lines with homozygous or heterozygous Asp at codon 312 have similar apoptotic rates, whereas cell lines with homozygous Asn at codon 312 showed a 2.5-fold increased response to UV (P = 0.005; Student's t test). This is the first report known to us of a functional polymorphism in a gene involved in DNA damage-induced apoptosis. However, the presence of Lys or Gln at codon 751 did not influence the apoptotic response to UV. The diminished apoptotic response of cells containing the 312 Asp allele could both allow the survival and selective clonal expansion of carcinogen-damaged cells and be a mechanistic explanation for the increased risk of cancer at diverse tissue sites.
UI - 11606401
AU - Dork T; Bendix R; Bremer M; Rades D; Klopper K; Nicke M; Skawran B;
TI - Hector A; Yamini P; Steinmann D; Weise S; Stuhrmann M; Karstens JH Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients.
SO - Cancer Res 2001 Oct 15;61(20):7608-15
AD - Department of Biochemistry and Tumour Biology, Clinic of Obstetrics and Gynecology, Medical School Hannover, D-30659 Hannover, Germany. firstname.lastname@example.org
Blood relatives of patients with the inherited disease ataxia telangiectasia (A-T) have an increased susceptibility for breast cancer. We therefore looked for sequence alterations of the ATM gene in a large hospital-based series of unselected breast cancer patients. The whole ATM coding sequence was analyzed in genomic DNA samples from a core group of 192 consecutive breast cancer cases to define the spectrum of ATM gene mutations. Common sequence alterations were then screened in the whole series of 1000 breast cancer patients and in 500 random individuals. In the core group, 21 distinct sequence alterations were identified throughout the ATM coding region, and 1 common splicing mutation was uncovered in intron 10. Almost half of the breast cancer patients (46%) were heterozygotes for 1 of 16 different amino acid substitutions, and three patients (1.6%) carried a truncating mutation. These data indicate that approximately 1 in 50 German breast cancer patients is heterozygous for an A-T-causing mutation. In our extended series, the most common A-T mutation 1066-6T-->G was disclosed in 7 of 1000 (0.7%) breast cancer patients. Transcript analyses indicated that the loss of exon 11 in the ATM mRNA was the pathogenic consequence of this splicing mutation, which produced a <10% of full-length ATM mRNA and ATM protein in a homozygous A-T patient. We also found an excess of rare missense substitutions in the breast cancer cohort compared with random individuals (7.9% versus 5.3% of alleles; odds ratio = 1.6; P < 0.01). One missense substitution, S707P in exon 15, was two times more frequent in breast cancer patients (odds ratio = 2.4; 95% confidence interval, 1.0-5.8) and five times more frequent in patients with bilateral disease than in random individuals (P < 0.001). We conclude that a large variety of distinct ATM mutations and variants exist among breast cancer patients, some of which can contribute to the etiology and progression of the malignancy. Screening for frequent A-T mutations such as the 1066-6-->G splice site substitution can be effective to prospectively identify A-T heterozygotes in an unselected cancer patient population.
UI - 11640873
AU - Taylor AM
TI - Chromosome instability syndromes.
SO - Best Pract Res Clin Haematol 2001 Sep;14(3):631-44
AD - CRC Institute for Cancer studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT, UK.
The chromosome instability syndromes, ataxia telangiectasia (A-T), Fanconi anaemia (FA) and Bloom syndrome (BS) have been known for many years. More recently Nijmegen breakage syndrome (NBS) and ataxia telangiectasia-like disorder (ATLD) have been identified. A-T, ATLD and NBS form a group of disorders all of which show very similar cellular features that result from the consequences of increased sensitivity to ionizing radiation (IR). They also share some clinical features, particularly A-T and ATLD, and all show an immunodeficiency. A-T and NBS both show a predisposition to lymphoid tumours. Fanconi anaemia can be caused by mutations in eight different genes, although the majority of mutations are accounted for by FANCA and FANCC. The very rare Bloom syndrome is caused by mutation in a single gene, BLM. An important feature which all of these disorders have in common is that the genes identified are involved in aspects of recombination repair of DNA damage. Copyright 2001 Harcourt Publishers Ltd.
UI - 11677656
AU - Sarkaria JN; Eshleman JS
TI - ATM as a target for novel radiosensitizers.
SO - Semin Radiat Oncol 2001 Oct;11(4):316-27
AD - Department of Oncology, Mayo Foundation, Rochester, MN 55905, USA.
DNA damage checkpoints are complex signal transduction pathways that are critical for normal cellular recovery following potentially lethal genotoxic insults. The ataxia-telangiectasia mutated (ATM) protein kinase is a critical component in these pathways and integrates the cellular response to damage by phosphorylating key proteins involved in cell cycle regulation and DNA repair. Lack of normal ATM function in the inherited ataxia-telangiectasia (A-T) syndrome results in a pleiotropic clinical syndrome characterized by a marked increased risk of cancer and profound hypersensitivity to ionizing radiation. Cells derived from patients with A-T share some of these attributes with genomic instability, loss of normal cell cycle arrest pathways, defects in DNA repair and increased radiation sensitivity. The radiosensitivity of A-T cells suggests that pharmacological inhibitors of the ATM kinase should be effective radiosensitizing agents. In fact, caffeine inhibits ATM kinase activity at concentrations that result in an A-T-like phenotype with loss of cell cycle checkpoints and hypersensitivity to ionizing radiation. Although the clinical use of caffeine as a radiosensitizer is limited by potentially lethal systemic toxicities, more potent methyl xanthines may selectively inhibit the ATM pathway at clinically achievable levels. Interestingly, caffeine and other methyl xanthines preferentially radiosensitize cells that lack normal p53 function. Because p53 is commonly inactivated in epithelial malignancies, this suggests that small molecule inhibitors of ATM might selectively sensitize the majority of tumors to the lethal effects of ionizing radiation while sparing normal tissues. Copyright 2001 by W.B. Saunders Company
UI - 11765061
AU - Kastan MB; Lim DS; Kim ST; Yang D
TI - ATM--a key determinant of multiple cellular responses to irradiation.
SO - Acta Oncol 2001;40(6):686-8
AD - Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105-2794, USA. email@example.com
Ataxia-telangiectasia is a rare clinical disorder manifesting a variety of different abnormalities, including progressive neurodegeneration, increased cancer incidence, immune deficiency, sterility, and extreme radiosensitivity. Recent studies have demonstrated that the defective gene product in this disease, ATM, is a protein kinase. The identification of several different substrates for this kinase is beginning to explain the wide array of different physiologic abnormalities that occur when this gene product is dysfunctional. Since the ATM protein is a critical signaling molecule in the cellular response to ionizing irradiation, the identification of these substrates also results in elucidation of the steps involved in a number of different cellular signaling pathways initiated by irradiation. Such insights also result in the identification of potential new targets for enhancing the efficacy of radiation therapy.
UI - 11765064
AU - Gatti RA
TI - The inherited basis of human radiosensitivity.
SO - Acta Oncol 2001;40(6):702-11
AD - Department of Pathology, UCLA School of Medicine, Los Angeles, CA 90095-1732, USA. firstname.lastname@example.org
Certain individuals cannot tolerate 'conventional' doses of radiation therapy. This is known to be true of patients with ataxia-telangiectasia and ligase IV deficiency. Although in vitro testing may not correlate completely with clinical radiosensitivity, fibroblasts and lymphoblasts from patients with both of these disorders have been clearly shown to be radiosensitive. Using a colony survival assay (CSA) to test lymphoblastoid cells after irradiation with 1 Gy, a variety of other genetic disorders have been identified as strong candidates for clinical radiosensitivity, such as Nijmegen breakage syndrome, Mre 11 deficiency, and Fanconi's anemia. These data are presented and considered as a starting-point for the inherited basis of human radiosensitivity.
UI - 11746754
AU - Mirzayans R; Paterson MC
TI - Correction of radioresistant DNA synthesis in ataxia telangiectasia fibroblasts by prostaglandin E2 treatment.
SO - Environ Mol Mutagen 2001;38(2-3):191-9
AD - Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada.
Cultured cells from patients inheriting the rare cancer-prone and radiotherapy-sensitive disorder ataxia telangiectasia (AT) exhibit defects in the activation of cell-cycle checkpoints after exposure to ionizing radiation. In particular, the failure of AT cells to arrest transiently the DNA de novo replication machinery immediately after irradiation--so-called radioresistant DNA synthesis (RDS)--is often taken as a molecular hallmark of the disease. Recently we reported that: (i) the radiation-responsive S-phase checkpoint operating in normal human cells is mediated by a signal transduction pathway involving Ca2+/calmodulin-dependent protein kinase II (CaMKII); and (ii) the RDS phenotype of AT cells is associated with failure to mobilize Ca2+ from intracellular stores, which is required for activation of the CaMKII-dependent S-phase arrest. In the present study, we demonstrate that the RDS phenotype of AT dermal fibroblasts can be rectified in the absence of ectopic expression of functional ATM, the 350-kDa protein kinase encoded by the gene mutated in AT. Correction of RDS was observed when AT fibroblasts were coincubated with normal fibroblasts under conditions in which the 2 different cell cultures shared the same medium but were completely separated physically. The RDS trait was also rectified when AT fibroblasts were briefly incubated with prostaglandin E2 in the absence of normal feeder cells, signifying that this ubiquitous eicosanoid can serve as the diffusible "RDS-correction factor" for AT cells in the aforementioned cocultivation studies. It would therefore appear that prostaglandin E2 can assume the role of an extracellular signaling modulator of the S-phase checkpoint in AT cells exposed to ionizing radiation, inducing DNA synthesis shutdown via an alternative, ATM-independent signal transduction pathway. Copyright 2001 Wiley-Liss, Inc.
UI - 2344249
AU - Deschildre A; Vallee L; Croquette MF; Nelken B; Nuyts JP
TI - [Oncologic complications and cytogenetic features of ataxia telangiectasia]
SO - Arch Fr Pediatr 1990 Mar;47(3):203-5
AD - Service des Maladies infectieuses et de Neurologie infantile, CHR Lille.
A very high incidence of cancers (10%) is recorded in patients homozygous for ataxia telangiectasia (AT). From 1970 to 1987, 35 children were investigated in the department of pediatric neurology in Lille. Three developed a malignancy (one hepatic tumor, one Hodgkin's disease and one non Hodgkin's lymphoma). Constitutional chromosome fragility and immune deficiency are the main features of AT. The first one is probably linked to the pathogenesis of malignancies. Moreover, cancer therapy has to take these features into account.
UI - 2366819
AU - Lee KH; Abe S; Yanabe Y; Matsuda I; Yoshida MC
TI - Superoxide dismutase activity and chromosome damage in cultured chromosome instability syndrome cells.
SO - Mutat Res 1990 Jul;244(3):251-6
AD - Department of Biology, Korea University, Seoul.
The basal levels of superoxide dismutase (SOD) activity and chromosome aberration (CA) and sister-chromatid exchange (SCE) frequencies were examined in cultured fibroblasts or Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs). These cells were derived from patients with chromosome instability syndromes (CISs) including Bloom's syndrome (BS), Fanconi's anemia (FA) and ataxia telangiectasia (AT). Embryonal fibroblasts and LCLs from normal subjects served as controls. Although LCLs tended to exhibit a higher SOD level than fibroblasts due to an elevation of Cu/Zn-SOD activity, BS and FA fibroblasts with increased frequencies of CAs and/or SCEs showed abnormally elevated SOD activity due to the manifold increase of Mn-SOD levels compared with control cells. However, BS and AT LCLs with almost control levels of CA and SCE frequencies showed no, or a slightly elevated, SOD activity, suggesting a possible selection of such cells during EBV transformation. The observed parallelism between the SOD activity and the cytogenetic manifestation may imply an involvement of active oxygen species, especially superoxide radicals, in the increased chromosome damage of CIS cells.
UI - 1876866
AU - Llerena JC Jr; Murer-Orlando M
TI - Bloom syndrome and ataxia telangiectasia.
SO - Semin Hematol 1991 Apr;28(2):95-103
AD - Unidade de Citogenetica Humana, Instituto de Biofisica, Rio de Janeiro, Brazil.
UI - 1885492
AU - Paruthi SC; Singh H; Singh H
TI - Ataxia telangiectasia.
SO - J Assoc Physicians India 1991 Feb;39(2):215-6
AD - Medical College, Patiala.
UI - 1913594
AU - Brito-Babapulle V; Catovsky D
TI - Inversions and tandem translocations involving chromosome 14q11 and 14q32 in T-prolymphocytic leukemia and T-cell leukemias in patients with ataxia telangiectasia.
SO - Cancer Genet Cytogenet 1991 Aug;55(1):1-9
AD - Academic Department of Haematology and Cytogenetics, Royal Marsden Hospital, London, U.K.
Ataxia telangiectasia (AT) and T-prolymphocytic leukemia (T-PLL) have similar chromosome abnormalities. Cytogenetic findings reported in 5 patients with AT who developed T-cell leukemia revealed: inv(14)(q11q32) (1 case), tandem translocations of chromosome 14 with breakpoints at q11 and q32 (3 cases), and int. del(14)(q11q32) (1 case). Additional abnormalities were present in 4 patients of whom two had trisomy for 8q. Of 27 patients with T-PLL but without AT, investigated by us, 17 had inv(14)(q11q32) and 3 had tandem rearrangement of chromosome 14 with breaks at 14q11 and q32; 15 of them also had rearrangements resulting in trisomy 8q. Two of the leukemias supervening on AT had morphology and clinical course suggestive of T-PLL. Two other cases of AT studied by us developed typical T-PLL at a young age (18 and 39 years). T-cell clones carrying an inv(14), tandem t(14;14) and t(X;14) can be present in AT for long periods of time without evolving into leukemia. In T-PLL, inv(14) and t(14;14) always occurs with other chromosome abnormalities. We suggest that these additional chromosome abnormalities may be required for the leukemic transformation of AT. This is supported by one of the two AT cases studied by us in which a long-standing t(X;14) clone evolved with the formation of t(1;14)(p21;q11), t(8;22)(q24;q11) at the time of the development of T-PLL.
UI - 1375558
AU - Lanzi G; Balottin U; Franciotta D; Maserati E; Ottolini A; Pasquali F;
TI - Veggiotti P Clinical, cytogenetic and immunological aspects in 4 cases resembling ataxia telangiectasia.
SO - Eur Neurol 1992;32(3):121-5
AD - Fondazione Istituto Neurologico C. Mondino, Universita di Pavia, Italy.
Four cases resembling ataxia telangiectasia, all characterized by the absence of telangiectasias, are presented. Two are sisters while the other 2 are sporadic cases. The 2 sisters, aged 14 and 12 years, present a progressive neurological disease similar to that characterizing the Louis-Bar syndrome. The clinical picture in 1 of the sporadic cases, a girl aged 13 years, differs from the typical ataxia telangiectasia in having bilateral pyramidal signs in the lower limbs. The last case, a girl aged 8 years, presents an atypical clinical pattern characterized by a severe mental retardation, quite modest cerebellar signs and absence of involuntary movements. The results of the immunological and cytogenetic investigations are presented and discussed.
UI - 1603308
AU - Demaerel P; Kendall BE; Kingsley D
TI - Cranial CT and MRI in diseases with DNA repair defects.
SO - Neuroradiology 1992;34(2):117-21
AD - Department of Neuroradiology, Hospital for Sick Children, London, UK.
The CT and MRI appearances of 5 patients with Cockayne's syndrome, 5 with ataxia telangiectasia and 1 with Fanconi's anaemia are reported. These conditions, together with Bloom's syndrome and xeroderma pigmentosum are regarded as disorders of DNA repair. Characteristic CT and MRI features of Cockayne's syndrome include generalised atrophy, calcification in basal ganglia and dentate nuclei and white matter low density. Neuroradiological findings in the other DNA repair disorders are nonspecific.
UI - 1610280
AU - Avet-Loiseau H; Mechinaud-Lacroix F; Harousseau JL
TI - [Ataxia telangiectasia]
SO - Arch Fr Pediatr 1992 Mar;49(3):205-10
AD - Service d'Hemato-Oncologie Pediatrique, Pavillon de la Mere et l'Enfant, Nantes.
UI - 1632451
AU - Chessa L; Petrinelli P; Antonelli A; Fiorilli M; Elli R; Marcucci L;
TI - Federico A; Gandini E Heterogeneity in ataxia-telangiectasia: classical phenotype associated with intermediate cellular radiosensitivity.
SO - Am J Med Genet 1992 Mar 1;42(5):741-6
AD - Dipartimento di Medicina Sperimentale, Universita La Sapienza, Roma, Italy.
We identified a subgroup of ataxia-telangiectasia (AT) patients (2 sibs and 1 unrelated case) characterized by typical clinical manifestations of the disease and cellular radiosensitivity intermediate between classical AT and normal subjects. Our data and a literature review of the intermediate radiosensitivity AT cases show that radioresistant DNA synthesis, cellular radiosensitivity (measured in terms of survival and chromosome breakage), and the clinical hallmarks behave independently. This raises a number of interesting questions about the correlation between radiobiological and clinical features, and about the nature of the AT gene(s).
UI - 3983641
AU - Isobe M; Erikson J; Emanuel BS; Nowell PC; Croce CM
TI - Location of gene for beta subunit of human T-cell receptor at band 7q35, a region prone to rearrangements in T cells.
SO - Science 1985 May 3;228(4699):580-2
The T-cell receptor is formed by two chains, alpha and beta, for which specific clones were recently obtained. In this report the gene for the beta chain of the human T-cell receptor was located on the long arm of chromosome 7, band q35, by means of in situ hybridization. This chromosome region in T cells is unusually prone to develop breaks in vivo, perhaps reflecting instability generated by somatic rearrangement of T-cell receptor genes during normal differentiation in this cell lineage.
UI - 3983642
AU - Morton CC; Duby AD; Eddy RL; Shows TB; Seidman JG
TI - Genes for beta chain of human T-cell antigen receptor map to regions of chromosomal rearrangement in T cells.
SO - Science 1985 May 3;228(4699):582-5
The T-cell antigen receptor is a cell-surface molecule that participates in the immune response. In the present experiments the genes encoding the beta chain of the T-cell receptor were found to reside on the long arm of human chromosome 7 at or near band q32. Related sequences were found on the short arm of chromosome 7 in bands p15-21 in some experiments. Chromosomal rearrangements in T-cells from normal individuals and patients with ataxia telangiectasia have previously been observed at and near these map assignments for the beta-chain genes.
UI - 7116322
AU - Kohn PH; Whang-Peng J; Levis WR
TI - Chromosomal instability in ataxia telangiectasia.
SO - Cancer Genet Cytogenet 1982 Aug;6(4):289-302
We have examined various aspects of lymphocyte chromosomal instability in three families comprised of five individuals affected with ataxiatelangiectasia (AT), their obligate heterozygous parents, and their unaffected sibs. We found that neither baseline sister chromatid exchanges (SCEs) nor mitomycin-C-induced increments in SCEs showed any significant differences among family members or between AT heterozygotes or homozygotes. Chromosome breakage in first-division metaphases was found to be moderately elevated in three of the five AT homozygotes (range 1-12%); breakage in the six AT obligate heterozygotes was within normal limits (0-4%). Analysis of Giemsa-banded metaphases indicated the presence of a clone bearing a paracentric inversion of chromosome #14 in addition to other chromosome #14 abnormalities in one AT homozygote. The same inversion was also found in this individual's affected sister and his obligate heterozygous father. A discussion regarding the relationship of the specificity of breakage and reunion of bands q12 and q23 on chromosome #14 and the high incidence of malignancy in AT is included.
UI - 6981453
AU - Wake N; Minowada J; Park B; Sandberg AA
TI - Chromosomes and causation of human cancer and leukemia. XLVIII. T-cell acute leukemia in ataxia telangiectasia.
SO - Cancer Genet Cytogenet 1982 Aug;6(4):345-7
Cytogenetic and immunologic studies were performed on the cells of an 18-year-old female with ataxia telangiectasia (AT) associated with acute lymphocytic leukemia (ALL). At the onset of the leukemia 15.4% of peripheral blood cells stimulated with phytohemagglutinin (PHA) contained a tandem translocation of the long arm of chromosome #14, i.e., t(14;14). To ascertain if these karyotypically abnormal cells and the leukemic cells had a common lineage, chromosome analyses were performed on bone marrow cells. Examination of the marrow cells on the seven occasions when leukemic cells were present in the marrow, including times when they were predominant, showed only a normal karyotype without the presence of t(14;14). However, an abnormal clone, which had the karyotype 45,XX,-9,t(9;6)(q12;q13), was identified in the marrow cells on the last examination during the terminal phase of the leukemia. Immunologically, the ALL was classified as an atypical type which had characteristics in common with certain T-cell subsets. We suggest that the malignant cells did not originate from the preexisting cells with a tandem duplication of the 14q.
UI - 6749441
AU - Schroeder TM
TI - Genetically determined chromosome instability syndromes.
SO - Cytogenet Cell Genet 1982;33(1-2):119-32
Spontaneously increased chromosomal instability is well documented in the three autosomal recessive diseases, Fanconi's anemia (FA), Bloom's syndrome (BS), and ataxia telangiectasia (AT). Other conditions have been reported to be associated with chromosomal breakage. Some are still single observations: in Werner's syndrome only fibroblasts are affected, and systemic sclerosis may not be an inherited disease. Various aspects of FA, BS, and AT are discussed which have emerged since recent reviews have been published. The differential diagnosis in FA has become more important than it was in the past. Proven heterogeneity in FA demands definition of what to name FA and FA variants. The analysis of cancer frequencies and types in FA and AT lacks important clues. This should stimulate all of us to mutual exchange of data and creation of registries not only of patients and follow-ups, but also of characterized cell strains. A synopsis of results from cell and cytogenetic studies demonstrates similarities and differences in detail of the general phenomenon of chromosomal instability which FA, BS, and AT share. Results from biochemical studies at the DNA level together with cytogenetic findings indicate different but still undefined failures in DNA metabolism or DNA repair mechanisms due to the different genes. A new approach to analyzing the impairment of DNA repair in FA is briefly described. DNA related enzymes are produced in the cytoplasm and have to be transported to the nucleus. The subcellular distribution of topoisomerase activity was found to be unusual in three placentas of FA patients. Other DNA enzymes were distributed normally. Thus, a specific mechanism for movement of the enzyme through the nuclear membrane seems to be defective.
UI - 3934345
AU - Davis MM; Gatti RA; Sparkes RS
TI - Neoplasia and chromosomal breakage in ataxia-telangiectasia: a 2:14 translocation.
SO - Kroc Found Ser 1985;19():197-203
Four common sites of chromosome breakage have been observed in patients with ataxia-telangiectasia (AT): 7p14, 7q35, 14q11.2, and 14q32. These sites appear to coincide with the location of genes for the T-cell receptor subunits (alpha, beta, and gamma) and IGH. Each of these genes involves rearrangements of DNA for its expression, suggesting that an abnormal DNA processing enzyme or family of enzymes underlies this propensity for chromosomal breakage in AT patients. Such a defect could also explain the radiation hypersensitivity of AT fibroblasts. In view of these findings, it is perhaps surprising that AT patients do not manifest more severe immunological defects although they would explain the lack of uniformity of these defects from one patient to the next. Two other genes utilize DNA rearrangement, IGK (on chromosome 2p12) and IGL (on chromosome 22q11), and have not been noted previously to be involved in translocations in these patients. We report here a 2:14 translocation (p14:q32) in a phytohemagglutinin-stimulated lymphocyte from a patient with AT.
UI - 3906046
AU - Vekemans MJ; Trasler T
TI - A preliminary compilation of cytogenetic studies and of cultured cells derived from individuals homozygous or heterozygous for ataxia-telangiectasia.
SO - Kroc Found Ser 1985;19():205-14
UI - 3496017
AU - Hecht F; Hecht BK
TI - Chromosome changes connect immunodeficiency and cancer in ataxia-telangiectasia.
SO - Am J Pediatr Hematol Oncol 1987 Summer;9(2):185-8
Ataxia-telangiectasia (AT) is a primary genetic immunodeficiency disease predisposing to cancer. Approximately 40% of patients with AT develop malignancy, usually of the lymphoid system. Increased chromosome breakage in AT leads to rearrangements such as translocations and inversions. The preferred chromosome breakpoints in AT involve genes in the immune system: the immunoglobulin (Ig) gene loci in chromosome bands 2p12, 14q32, and 22q11 and the T cell receptor (TCR) gene loci in chromosome bands 7p13, 7q35, and 14q11. Identical chromosome breakpoints are observed in chromosome rearrangements in normal T cells, Burkitt's lymphoma, and adult T cell leukemia. Molecular analysis of these chromosome rearrangements reveals recombination between an oncogene and Ig or between Ig and TCR. In AT, chromosome rearrangements connect the immune system to lymphoid cancer.
UI - 6627224
AU - Cohen MM; Fruchtman CE; Simpson SJ; Boughman JA
TI - Chemical clastogenicity in lymphoid cell lines of chromosomal instability syndromes.
SO - Cancer Genet Cytogenet 1983 Nov;10(3):267-76
Long-term lymphoid cell lines (LCL) derived from normal individuals, patients with ataxia telangiectasia (A-T), xeroderma pigmentosum (XP), and Fanconi anemia (FA) were exposed to various concentrations of 11 chemical clastogens. The agents were chosen to represent a variety of suggested modes of action. In contrast to all other genotypes, the FA lines demonstrated significant rates of spontaneous chromosomal breakage and showed hypersensitivity to all of the clastogens employed. Variability among lines within a genotype suggested individual responses to specific agents. Computation of "corrected values" to address the problem of baseline disparity removed some of the significant differences between the FA and other lines. Nonetheless, following correction, the FA genotype was still delineated by clastogens which are not DNA cross-linkers. The A-T lines were specifically identified by the induction of chromosome damage by bleomycin and neocarzinostatin.
UI - 3430541
AU - Taylor AM; Flude E; Laher B; Stacey M; McKay E; Watt J; Green SH;
TI - Harding AE Variant forms of ataxia telangiectasia.
SO - J Med Genet 1987 Nov;24(11):669-77
AD - Department of Cancer Studies, Medical School, Birmingham.
Two ataxia telangiectasia patients with unusual clinical and cellular features are described. Cultured fibroblasts and PHA stimulated lymphocytes from these two patients showed a smaller increase of radiosensitivity than cells from other A-T patients, as measured by colony forming ability or induced chromosome damage respectively, after exposure to ionising radiation. The response of DNA synthesis to irradiation of these cells was, however, the same as for other A-T patients. Cells from a third patient with some clinical features of A-T but with a very protracted course also showed low levels of radiation induced chromosome damage, but colony forming ability and the response of DNA synthesis after irradiation were no different from cells of normal subjects. There was, however, an increased level of translocations and unstable chromosomal rearrangements in this patient's lymphocytes.
UI - 3122210
AU - Baer R; Heppell A; Taylor AM; Rabbitts PH; Boullier B; Rabbitts TH
TI - The breakpoint of an inversion of chromosome 14 in a T-cell leukemia: sequences downstream of the immunoglobulin heavy chain locus are implicated in tumorigenesis.
SO - Proc Natl Acad Sci U S A 1987 Dec;84(24):9069-73
AD - Medical Research Council Laboratory of Molecular Biology, Cambridge, England.
T-cell tumors are characterized by inversions or translocations of chromosome 14. The breakpoints of these karyotypic abnormalities occur in chromosome bands 14q11 and 14q32--the same bands in which the T-cell receptor (TCR) alpha-chain and immunoglobulin heavy chain genes have been mapped, respectively. Patients with ataxia-telangiectasia are particularly prone to development of T-cell chronic lymphocytic leukemia with such chromosomal abnormalities. We now describe DNA rearrangements of the TCR alpha-chain gene in an ataxia-telangiectasia-associated leukemia containing both a normal and an inverted chromosome 14. The normal chromosome 14 has undergone a productive join of TCR alpha-chain variable (V alpha) and joining (J alpha) gene segments. The other allele of the TCR alpha-chain gene features a DNA rearrangement, about 50 kilobases from the TCR alpha-chain constant (C alpha) gene, that represents the breakpoint of the chromosome 14 inversion; this breakpoint is comprised of a TCR J alpha segment (from 14q11) fused to sequences derived from 14q32 but on the centromeric side of C mu. These results imply that 14q32 sequences located at an undetermined distance downstream of the immunoglobulin C mu locus can contribute to the development of T-cell tumors.
UI - 6333737
AU - Weemaes CM; Taalman RD; Van Munster PJ; Hustinx TW; Bakkeren JA; Scheres
TI - JM [Immunologic and cytogenetic aspects of ataxia telangiectasia]
SO - Tijdschr Kindergeneeskd 1984 Aug;52(4):164-9
Immunological and cytogenetic studies were performed in 6 patients with ataxia telangiectasia (AT). Immunological disturbances were found in these patients: immunoglobulin deficiencies (IgA, IgE, IgG2 and IgG4), decreased cellular immunity and a defect in the synthesis of specific antibodies. Cytogenetic studies revealed chromosome 7 and/or 14 abnormalities in all patients. X-irradiation of AT cells induced an excessive increase in chromosome and chromatid breaks. The DNA synthesis inhibition after X rays was less in AT patients compared to controls. The possibilities of early diagnosis and the eventual relationship between immunological and cytogenetic findings are discussed.
UI - 6320395
AU - Germain D; Bernheim A
TI - [Chromosome instability syndromes]
SO - Sem Hop 1983 Dec 1;59(44):3065-79
Chromosome instability syndromes are defined by either an increase of chromosomal breakage or by an increase of sister chromatid exchange number, or by an increase of the two. Bloom's syndrome, Ataxia telangiectasia, Fanconi's Anemia are the main components of this group. The incidence of cancers or malignant blood diseases is high. The finding of DNA repair abnormalities in some of them and their high sensitivity to particular mutagenic agents make these syndromes an interesting model for oncogenesis.
UI - 7039714
AU - Carter DM
TI - Human diseases characterized by heritable DNA instability.
SO - Birth Defects Orig Artic Ser 1981;17(2):117-28
UI - 2491181
AU - Curry CJ; O'Lague P; Tsai J; Hutchison HT; Jaspers NG; Wara D; Gatti RA;
TI - Hutchinson HT ATFresno: a phenotype linking ataxia-telangiectasia with the Nijmegen breakage syndrome.
SO - Am J Hum Genet 1989 Aug;45(2):270-5
AD - Department of Medical Genetics, Valley Children's Hospital, Fresno/University of California, San Francisco.
This report describes twin girls with typical features of ataxia-telangiectasia, including increased alpha-fetoprotein, radio-resistant DNA synthesis, characteristic chromosome abnormality, and immunodeficiency. They have, in addition, microcephaly and mental retardation. Complementation studies were performed utilizing Sendai virus--mediated fusion of fibroblast cell lines. Complementation was observed with patients in ataxia-telangiectasia complementation groups A, C, and E but not with the cell line from a patient with the Nijmegen breakage syndrome, in which patients have microcephaly, radio-resistant DNA synthesis, chromosome aberrations, and immunodeficiency but lack ataxia and telangiectasia. These data suggest that the Nijmegen breakage syndrome and the patients described here are not genetically distinct entities but form a spectrum of one disorder.
UI - 2658496
AU - Cohen MM; Levy HP
TI - Chromosome instability syndromes.
SO - Adv Hum Genet 1989;18():43-149, 365-71
AD - Department of Obstetrics and Gynecology, School of Medicine, University of Maryland, Baltimore.
UI - 8073914
AU - Ceroni M; Karau J; Pergami P; Ferrandi D; Savoldi F
TI - High incidence of gastrointestinal cancer in a family with ataxia-telangiectasia.
SO - Acta Neurol (Napoli) 1994 Feb-Apr;16(1-2):33-7
AD - Neurological Institute, IRCCS C. Mondino Foundation, University of Pavia, Italy.
Literature suggests that not only homozygotes but also heterozygotes for ataxia-telangiectasia have a high incidence of cancer, probably due to an impairment in DNA repair. The most frequent associations are with breast, lung, bladder, prostate and stomach tumors, while no correlation with colorectal cancer has been demonstrated. The affected family reported in this paper seems to have a high incidence of gastrointestinal tract tumors, including the colorectal ones.
UI - 7512106
AU - Chung EO; Bodensteiner JB; Noorani PA; Schochet SS Jr
TI - Cerebral white-matter changes suggesting leukodystrophy in ataxia telangiectasia.
SO - J Child Neurol 1994 Jan;9(1):31-5
AD - Department of Neurology, West Virginia University Health Science Center, Morgantown 26506.
Ataxia telangiectasia is an autosomal recessive disorder characterized by progressive cerebellar ataxia, recurrent sinopulmonary infections, oculocutaneous telangiectasia, selective immunoglobulin deficiency, and defective cellular immunity. We report a 4-year-old girl with ataxia telangiectasia whose initial magnetic resonance imaging (MRI) scan at 17 months of age showed leukoencephalopathy compatible with a leukodystrophy, a neuroimaging feature of ataxia telangiectasia that has not been described. Ataxia telangiectasia was not suspected until the child developed more typical clinical features. Diffuse white-matter high signal intensity on T2-weighted MRI scans may occur in the early stages of ataxia telangiectasia. This disease should be considered in the differential diagnosis of any child with a history and MRI findings suggestive of one of the leukodystrophies. The nonneurologic manifestations of ataxia telangiectasia may be of help diagnostically in this clinical setting.
UI - 7836846
AU - Weemaes CM; Smeets DF; van der Burgt CJ
TI - Nijmegen Breakage syndrome: a progress report.
SO - Int J Radiat Biol 1994 Dec;66(6 Suppl):S185-8
AD - Department of Pediatrics, University Hospital Nijmegen, The Netherlands.
We report the findings in t
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