UMLS:C0004135 - FACTA Search

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Query: UMLS:C0004135 (ATM)
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Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia, and variable degrees of humoral and cellular immunodeficiency. Affected individuals are known to exhibit a high incidence of lymphoma and leukemia. Because of increased chemosensitivity, the treatment of A-T patients with malignancies requires extremely careful planning and caution with respect to the use of chemotherapy. The authors report on a 12-year-old boy with A-T who developed B-cell lymphoma. He received a half-dose of the drugs administered according to the acute lymphoblastic leukemia (ALL) protocol issued by our children's cancer study group (9104 Standard Risk Protocol, Tokai Pediatric Oncology Study Group). As a result, he continues to be in complete remission and free of treatment complications 32 months after the diagnosis of B-cell lymphoma.
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PMID:Ataxia telangiectasia associated with B-cell lymphoma: the effect of a half-dose of the drugs administered according to the acute lymphoblastic leukemia standard risk protocol. 978 9

A Task Group of the ICRP Committee 1 (Radiation Effects) has reviewed relevant data with the objective of advising the Main Commission of the ICRP on the possible implications for radiological protection of emerging views on genetic susceptibility to cancer (Chapter 1). Chapter 2 considers DNA damage and its processing/repair after ionising radiation and serves principally to demonstrate that a few rare cancer-prone, human recessive genetic disorders show DNA repair deficiency and profound increases in radiosensitivity. Less dramatic changes in radiosensitivity are also apparent in a wider range of such disorders. The cellular mechanisms that underly the association between DNA damage processing and tumorigenesis are discussed. Chapter 3 reviews the mechanisms and genetics of solid tumours illustrating the ways in which mutations in proto-oncogenes, tumour suppressor genes together with those in DNA repair and cell cycle control genes can contribute to tumour development. Specific examples are given of how germ line mutation of such genes can predispose to familial cancer. It is judged that up to 5% of all solid tumours have a recognisable genetic component. Heritable organ-specific effects are most usual and cancers of the breast and colon tend to show the most obvious genetic components. Clearly discernible genetic effects are seen when rare dominant germ line mutations express strongly as familial cancer (high penetrance mutations), but the existence of perhaps less rare low penetrance mutations and gene-gene interactions are recognised but not well understood. Chapter 4 considers the mechanisms and genetics of lympho-haemopoietic tumours. Specific chromosomal translocations and proto-oncogene activation events are much more frequent in human leukaemia/lymphoma than in solid tumours. Genetic predisposition to leukaemia/lymphoma is found in a number of non-familial recessive genetic disorders of DNA processing and/or chromosomal instability. Familial manifestation of susceptibility to these tumours is, however, extremely rare. The genetic component, although poorly defined, is judged to be less than that of solid tumours and expressed largely in childhood. Chapter 5 reviews and discusses limited data that comment upon tumorigenic radiosensitivity in cancer-prone genetic conditions. From knowledge of the fundamental processes involved it is judged that in most, but not all, cases genetic susceptibility to spontaneous tumours will be accompanied by a greater-than-normal risk after radiation. A review of epidemiological, clinical and experimental data relevant to this issue suggests that although a wide range of different sensitivities may be involved, a factor of 10 increase in sensitivity broadly accords with the limited human data available. This interim judgement of a factor of 10 increase in radiation risk in such human genetic disorders is made for the purposes of illustrative modelling and calculation. In addition, specific attention is given to breast cancer risk in heterozygotes for the radiosensitive human disorder, ataxia-telangiectasia; this association, while in no way discounted, is judged to be less strong than that claimed by some. Chapter 6 discusses and develops computational modelling procedures that aim to describe the impact of genetic factors on radiation-tumorigenesis in human populations. Estimates of the prevalence of known cancer-prone genetic disorders are made but breast cancer susceptibility is used to illustrate the application of the model developed. The most important message to emerge from this work is that, even at an assumed high level of radiation sensitivity, the prevalence of familial (high penetrance) genetic disorders in the population is too low (<1%) for there to be a significant impact on risk in typical human populations. In principle, however, there is the potential for such impact in atypical inbred sub-populations where these mutations can be more common. (ABSTRACT TRUNCATED)
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PMID:Genetic susceptibility to cancer. ICRP publication 79. Approved by the Commission in May 1997. International Commission on Radiological Protection. 1040 27

Indolent lymphomas are a markedly heterogeneous group of lymphoproliferative disorders including B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mantle cell lymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma. The molecular pathophysiology of indolent lymphoma is characterized by distinct genetic pathways which selectively associate with different clinico-pathologic categories of the disease. At diagnosis, B-cell chronic lymphocytic leukemia frequently display deletions of 13q14, trisomy 12 and alterations of the ATM gene, whereas evolution to Richter's syndrome is associated with disruption of p53. Lymphoplasmacytoid lymphoma carries t(9;14) (p13;q32) in approximately 50% of cases, leading to the deregulated expression of the PAX-5 gene. Follicular lymphoma consistently harbors rearrangement of BCL-2. With time, a fraction of follicular lymphoma accumulates mutations of p53 and of p16 and evolves into a high grade lymphoma. MALT-lymphoma frequently associates with alterations of API2/MLT and, in some cases, of p53, BCL-6 and BCL-10. Studies of genotypic and phenotypic markers of histogenesis have shown that mantle cell lymphoma and a fraction of B-CLL/SLL derive from naive B-cells, whereas follicular lymphoma, lymphoplasmacytoid lymphoma and MALT-lymphoma originate from germinal center (GC) or post-GC B-cells. The identification of distinct genetic categories of indolent lymphoma may help in the therapeutic stratification of these disorders. In addition, genetic lesions of indolent lymphoma provide useful molecular markers for disease monitoring by high sensitivity techniques.
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PMID:Molecular pathophysiology of indolent lymphoma. 1068 15

Motor incoordination, immune deficiencies, and an increased risk of cancer are the characteristic features of the hereditary disease ataxia-telangiectasia (A-T), which is caused by mutations in the ATM gene. Through gene targeting, we have generated a line of Atm mutant mice, Atm(y/y) mice. In contrast to other Atm mutant mice, Atm(y/y) mice show a lower incidence of thymic lymphoma and survive beyond a few months of age. Atm(y/y) mice exhibit deficits in motor learning indicative of cerebellar dysfunction. Even though we found no gross cerebellar degeneration in older Atm(y/y) animals, ectopic and abnormally differentiated Purkinje cells were apparent in mutant mice of all ages. These findings establish that some neuropathological abnormalities seen in A-T patients also are present in Atm mutant mice. In addition, we report a previously unrecognized effect of Atm deficiency on development or maintenance of CD4(+)8(+) thymocytes. We discuss these findings in the context of the hypothesis that abnormal development of Purkinje cells and lymphocytes contributes to the pathogenesis of A-T.
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PMID:Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. 1071 18

Deficiencies in the ability of cells to sense and repair damage in individuals with rare genetic instability syndromes increase the risk of developing cancer. Ataxia-telangiectasia (A-T), such a condition, is associated with a high incidence of leukemia and lymphoma that develop in childhood. Although A-T is an autosomal recessive disorder, some penetrance appears in individuals with one mutated ATM gene (A-T carriers), namely, an increased risk of developing breast cancer. The gene mutated in A-T, designated ATM, is homologous to several DNA damage recognition and cell cycle checkpoint control genes from other organisms. Recent studies suggest that ATM is activated primarily in response to double-strand breaks, the major cytotoxic lesion caused by ionizing radiation, and can directly bind to and phosphorylate c-Abl, p53, and replication protein A (RPA). Analysis of ATM mutations in patients with A-T or with sporadic non-A-T cancers has suggested the existence of two classes of ATM mutation: null mutations leading to A-T and dominant negative missense mutations predisposing to cancer in the heterozygous state. Studies with A-T mouse models have helped determine the basis of lymphoid tumorigenesis in A-T and have shown that ATM plays a critical role in maintaining genetic stability by ensuring high-fidelity execution of chromosomal events. Thus, ATM appears to act as a caretaker of the genome.
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PMID:Cancer risk and the ATM gene: a continuing debate. 1081 74

Ataxia telangiectasia is a multisystem disease with an autosomal recessive inheritance. It is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, humoral and cellular immunodeficiencies and high incidence of neoplasia and radiosensitivity. A 5 year retrospective survey included 24 patients belonging to 17 families. Cerebellar ataxia was the first clinical symptom and was usually noticed when the child began to walk. Mean age of onset was 2.9+/-1.8 years. Oculocutaneous telangiectasia was present in 17 cases and appeared between 2 and 8 years and then spread in a characteristic symmetrical pattern. When ocular telangiectasia was absent (6 cases), the diagnostic of ataxia telangiectasia was retained on oculomotor apraxia (2 cases), recurrent sinopulmonary infections (3 cases) and/or a sib with typical ataxia telangiectasia (1 case). Recurrent sinopulmonary infections, absence or low serum level of IgA (78 p.100) and lymphopenia revealed immunodeficiency. Among 12 patients, chromosomal instability was observed in 5. Balanced rearrangements involving chromosomes 2, 7, 14, 22, 1, 3 and 11. The responsible gene, ATM, encodes a large protein kinase with a phosphatidylinositol 3-kinase-like domain. Ataxia telangiectasia patients have a 100 fold higher risk of cancer than the general population. We reported, in the same family two patients who developed neoplasia, (lymphoma and leukemia). During follow-up, a progressive worsening was observed in all cases. Three patients have died.
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PMID:[Clinical, biological and genetic study of 24 patients with ataxia telangiectasia from southern Tunisia]. 1089 97

The goal of our current research was to investigate the antioxidative effects of methanolic extracts from different parts of adlay seed and their antiproliferative activity in malignant human cells. The methanolic extracts from different parts of adlay seeds were from the hull (AHM), testa (ATM), bran (ABM), and polished adlay (PAM). AHM exhibited greater capacity to scavenge superoxide anion radicals in the PMS-NADH system than ATM, ABM, or PAM. The scavenging capacities of AHM and ATM on hydrogen peroxides were about 20% at a dose of 250 microg/mL. Using the method of deoxyribose degradation to assess damage caused by hydroxyl radicals, AHM was found to inhibit damage in deoxyribose at a higher concentration. However, ATM, ABM, and PAM exhibited prooxidative activity at the same concentration. The inhibitory effect on enzymatic oxidation of xanthine to uric acid was found to follow the order AHM > ATM =. ABM. However, PAM was inactive. All test samples were positive for inhibition of TPA-induced free radical formation on neutrophil-like leukocytes and were found to follow the order AHM > ATM > ABM > PAM. When human histolytic lymphoma U937 monocytic cells were exposed to tert-butyl hydroperoxide, AHM protected the cells against the cytotoxicity caused by tert-butyl hydroperoxide. In addition, AHM exhibited antiproliferative activity against human histolytic lymphoma U937 monocytic cells in a dose-dependent manner. The antiproliferative properties of AHM appear to be attributable to its induction of apoptotic cell death as determined by flow cytometry. These results show that AHM displays multiple antioxidant effects and induces apoptosis of malignant human cells.
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PMID:Antagonism of free-radical-induced damage of adlay seed and its antiproliferative effect in human histolytic lymphoma U937 monocytic cells. 1131 97

Ataxia telangiectasia (A-T) is a rare autosomal recessive multisystem disease. The diagnosis of A-T is based on the typical clinical picture: ataxia and telangiectasia. However, an increase in (alpha-fetoprotein (AFP) level and the identification of the A-T mutated gene (ATM) assist in an early diagnosis. Here we report two cases of A-T diagnosed in our hospital (case 1: a 7-year-old boy; case 2: an 8-year-old girl). Both of these patients had typical clinical pictures of ataxia and telangiectasia, AFP was also increased (case 1:471.2 ng/dL; case 2: 196 ng/dL). T-cell dysfunction was noted in both patients. Case 1 had IgG2 deficiency and case 2 had IgA, IgG2 and IgG3 deficiency. Case 2 developed malignant lymphoma at 9 years of age and died of pneumonia with respiratory failure at 10 years of age. Because of rhe rarity of A-T in Taiwan, we report two cases to help pediatricians make an early diagnosis of A-T if they have a patient with progressive ataxia and oculocutaneous telangiectasia.
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PMID:Ataxia telangiectasia: report of two cases. 1132 Nov 31

Structural aberrations involving 11q are among the most common aberrations in a number of hematological malignancies. Most of the aberrations, such as translocations and deletions, often harbor a breakpoint at 11q23, which suggests that this region might contain a tumor suppressor gene important for the genesis of lymphoproliferative disorders. Interestingly, deletions are concentrated only in some subtypes of hematological malignancies, where they are detected at a relatively high frequency. In B-cell chronic lymphocytic leukemia (B-CLL), deletions have been detected in 20-30% of the cases, whereas almost half of the mantle cell lymphomas (MCL) show deletion at 11q23 in fluorescence in situ hybridization analysis. In T-cell prolymphocytic leukemia (T-PLL), deletions involving the region 11q23.3-23.1 have also been detected to be frequent. In B-cell chronic lymphocytic leukemia, 11q deletion is associated with more rapid disease progression and poor survival in a younger subgroup of patients. The putative tumor suppressor genes have remained unrevealed until recently, when the ATM gene was found to carry mutations in cases with deletion in B-CLL, MCL and T-PLL. These data suggest that 11q deletions and dysfunction of the ATM gene might have significance in the tumorigenesis of certain subsets of hematological malignancies. Importance of 11q deletion as a diagnostic marker needs to be further studied in a larger series of patients. Another issue that remains to be investigated is the involvement of other target genes in the deletion.
Leuk Lymphoma 2001 Jan
PMID:11q deletions in hematological malignancies. 1142 47

Ataxia telangiectasia (AT) is a rare multisystem, autosomal, recessive disease characterised by neuronal degeneration, genome instability, and an increased risk of cancer. Approximately 10% of AT homozygotes develop cancer, mostly of the lymphoid system. Lymphoid malignancies in patients with AT are of both B cell and T cell origin, and include Hodgkin's lymphoma, non-Hodgkin's lymphoma, and several forms of leukaemia. The AT locus was mapped to the chromosomal region 11q22-23 using genetic linkage analysis in the late 1980s and the causative gene was identified by positional cloning several years later. The ATM gene encodes a large protein that belongs to a family of kinases possessing a highly conserved C-terminal kinase domain related to the phosphatidylinositol 3-kinase domain. Members of this kinase family have been shown to function in DNA repair and cell cycle checkpoint control following DNA damage. Recent studies indicate that ATM is activated primarily in response to double strand breaks and may be considered a caretaker of the genome. Most mutations in ATM result in truncation and destabilisation of the protein, but certain missense and splicing errors have been shown to produce a less severe phenotype. AT heterozygotes have a slightly increased risk of breast cancer. Atm deficient mice exhibit many of the symptoms found in patients with AT and have a high frequency of thymic lymphoma. The association between mutation of the ATM gene and a high incidence of lymphoid malignancy in patients with AT, together with the development of lymphoma in Atm deficient mice, supports the proposal that inactivation of the ATM gene may be of importance in the pathogenesis of sporadic lymphoid malignancy. Loss of heterozygosity at 11q22-23 (the location of the ATM gene) is a common event in lymphoid malignancy. Frequent inactivating mutations of the ATM gene have been reported in patients with rare sporadic T cell prolymphocytic leukaemia (T-PLL), B cell chronic lymphocytic leukaemia (B-CLL), and most recently, mantle cell lymphoma (MCL). In contrast to the ATM mutation pattern in AT, the most frequent nucleotide changes in these sporadic lymphoid malignancies were missense mutations. The presence of inactivating mutations, together with the deletion of the normal copy of the ATM gene in some patients with T-PLL, B-CLL, and MCL, establishes somatic inactivation of the ATM gene in the pathogenesis of lymphoid malignancies, and strongly suggests that ATM functions as a tumour suppressor. The presence of missense mutations in the germline of patients with B-CLL has been reported, suggesting that some patients with B-CLL may be constitutional AT heterozygotes. The putative hereditary predisposition of B-CLL, although intriguing, warrants further investigation.
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PMID:Ataxia telangiectasia gene mutations in leukaemia and lymphoma. 1142 21

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