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Abramson Cancer CenterNCI CANCERLIT® Search: Ataxia Telangiectasia - January 2002
National Cancer Institute®
Last Modified: January 1, 2002
Table of Contents
1
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.
2
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.
3
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.
4
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.
thilo.doerk.oststadt@klinikum-hannover.de
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.
5
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.
6
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
7
UI - 11710885
AU - Su Y; Swift M
TI -
Outcomes of adjuvant radiation therapy for breast cancer in women with
ataxia-telangiectasia mutations.
SO - JAMA 2001 Nov 14;286(18):2233-4
8
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. michael.kastan@stjude.org
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.
9
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. rgatti@mednet.ucla.edu
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.
10
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.
11
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.
12
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.
13
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.
14
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.
15
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.
16
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.
17
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.
18
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.
19
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).
20
UI - 6243421
AU - Kolata GB
TI -
Testing for cancer risk.
SO - Science 1980 Feb 29;207(4434):967-9
21
UI - 7411307
AU - Scheres JM; Hustinx TW; Weemaes CM
TI -
Chromosome 7 in ataxia-telangiectasia.
SO - J Pediatr 1980 Sep;97(3):440-1
22
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.
23
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.
24
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.
25
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.
26
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.
27
UI - 7163230
AU - Kaiser-McCaw B
TI -
Sorting out the heterogeneity in the chromosome-instability syndromes.
SO - Prog Clin Biol Res 1982;103 Pt B():349-58
28
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.
29
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
30
UI - 3731231
AU - German J
TI -
[What do the chromosome-breakage syndromes teach us about the care of
persons at increased risk for malignant diseases?]
SO - Cas Lek Cesk 1986 Jul 25;125(30):921-6
31
UI - 6336693
AU - Passarge E
TI -
[Correlations between chromosome aberrations and tumor genesis]
SO - Dtsch Med Wochenschr 1983 Jan 7;108(1):28-34
32
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.
33
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.
34
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.
35
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.
36
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.
37
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.
38
UI - 7039714
AU - Carter DM
TI -
Human diseases characterized by heritable DNA instability.
SO - Birth Defects Orig Artic Ser 1981;17(2):117-28
39
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.
40
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.
41
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.
42
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.
43
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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