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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study addresses the prevalence of ATM mutations and the association with breast cancer in Austrian families selected for a history of breast or ovarian cancer or both [hereditary breast and ovarian cancer (HBOC)]. In 270 HBOC families previously screened for BRCA1 and BRCA2 mutations, 137 different sequence alterations of ATM were identified. Seven of these were mutations presumed to cause ataxia telangiectasia based on their effect on the ATM protein, including five that caused a protein truncation and two missense mutations in the catalytic kinase domain of the highly conserved COOH terminus of the protein. The seven mutations were found in 10 families (3.7%). In addition, one missense variant, L1420F, was observed in 13 HBOC families (4.8%) but was not observed in any of the 122 healthy volunteers with no history of breast cancer. In addition, the variant segregated with breast cancer in some of the families, suggesting that it may be pathogenic for breast cancer. Sixty-two additional variants of potential significance were observed in 65 HBOC families, but not in healthy controls. These variants included 24 sequence alterations with possible effects on splicing or protein-protein interactions. This study indicates that there is a significant prevalence of ATM mutations in breast and ovarian cancer families and adds to a growing body of evidence that ATM mutations confer increased susceptibility to breast cancer.
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PMID:Contributions of ATM mutations to familial breast and ovarian cancer. 1281 Jun 66

Fanconi anemia (FA) is a recessive genomic instability syndrome characterized by developmental defects, progressive bone marrow failure, and cancer. FA is genetically heterogeneous, however; the proteins encoded by different FA loci interact functionally with each other and with the BRCA1, BRCA2, and ATM gene products. Although patients with FA are highly predisposed to the development of myeloid leukemia and solid tumors, the alterations in biochemical pathways responsible for the progression of tumorigenesis in these patients remain unknown. FA cells are hypersensitive to a range of genotoxic and cellular stresses that activate signaling pathways mediating apoptosis. Here we show that ionizing radiation (IR) induces modestly elevated levels of p53 in cells from FA type C (Fancc) mutant mice and that inactivation of Trp53 rescues tumor necrosis factor alpha-induced apoptosis in myeloid cells from Fancc-/- mice. Further, whereas Fancc-/- mice failed to form hematopoietic or solid malignancies, mice mutant at both Fancc and Trp53 developed tumors more rapidly than mice mutant at Trp53 alone. This shortened latency was associated with the appearance of tumor types that are found in patients with FA but not in mice mutant at Trp53 only. Collectively, these data demonstrate that p53 and Fancc interact functionally to regulate apoptosis and tumorigenesis in Fancc-deficient cells.
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PMID:Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis. 1285 57

Accumulating evidence indicates that germline missense mutations in the ATM gene predispose to breast cancer. To investigate the potential role of somatic ATM mutations in the tumorigenesis of breast cancer, the ATM gene was scanned in 58 mammary carcinomas using DOVAM-S (detection of virtually all mutations-SSCP [single-strand conformation polymorphism]), a robotically enhanced, highly redundant form of SSCP that detects virtually all mutations. A total of 1.65 megabases of tumor DNA sequence was scanned and 16 structural variants were identified, including one novel nonsense mutation, four novel missense mutations, and a common missense change in African-Americans. Sequencing from microdissected normal cells reveals that all variants were present in the germline. Thus, the ATM gene may be similar to the BRCA1/BRCA2 genes in that germline mutations are important in cancer predisposition, but somatic mutations are seldom present in tumors. Loss of heterozygosity (LOH) is common in these tumors, but ATM missense mutations occur with similar frequencies when LOH is present or absent (P=0.73). If germline ATM missense mutations predispose to breast cancer, the unmasking of a recessive missense allele by LOH does not seem to be a critical step in breast neoplasia.
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PMID:Absence of somatic ATM missense mutations in 58 mammary carcinomas. 1293 33

The BRCA1 gene was isolated in 1994; germline mutations of this gene are known to confer susceptibility to breast and ovarian cancer in high-risk families. Since its discovery, several mutations have been identified in this gene; these are scattered throughout the gene, and include insertion and deletion frameshifts, base substitutions, and inferred regulatory mutations. It role in the pathogenesis of breast cancer, which accounts for almost 95%, although unproven to date, cannot be ruled out. The functional inactivation of both copies of this gene in sporadic tumor cells does not follow the traditional mode: the loss of function in BRCA1 is not accompanied by underlying mutation of the gene in tumor cells with loss of heterozygosity for the BRCA1 gene. Several studies now suggest that an alternate mechanism of inactivation, involving promoter hypermethylation that results in reduced expression of the gene, may be common to a significant proportion of sporadic breast and ovarian cancers. BRCA1 as a tumor suppressor plays an important role in maintaining genomic stability. BRCA1 has the ability to interact with numerous proteins and to form complexes that are involved in recognizing and subsequently repairing DNA. BRCA1 contains several functional domains that directly or indirectly interact with a variety of proteins via protein-protein interaction; these include tumor suppressors (BRCA2, p53, Rb and ATM), oncogenes (c-Myc, casein kinase II and E2F), DNA damage repair proteins (RAD50 and RAD51), cell cycle regulators (cyclins and cyclin dependent kinases), transcriptional activators and repressors (RNA polymerase II, RHA, histone deacetylase complex and CtIP), DNA damage-sensing complex and mismatch repair proteins (BRCA1- Associated Surveillance Complex; BASC) and signal transducer and activator of transcription (STAT) among others Formation of foci containing BRCA1 by inherited mutations, or epigenetic mechanisms (promoter methylation) in sporadic cancers leads to a loss of DNA repair ability, disrupts the potential to form complexes with other proteins that are crucial for DNA repair pathways. Thus, BRCA1 plays a significant role in maintaining genomic stability and serves as a tumor suppressor in breast cancer tumorigenesis.
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PMID:BRCA1 in cancer, cell cycle and genomic stability. 1295 14

We provide an overview of the functional interrelationship between genes and proteins related to DNA repair by homologous recombination and cell cycle regulation in relation to the progression and therapy resistance of human tumours. To ensure the high-fidelity transmission of genetic information from one generation to the next, cells have evolved mechanisms to monitor genome integrity. Upon DNA damage, cells initiate complex response pathways including cell cycle arrest, activation of genes and gene products involved in DNA repair, and under some circumstances, the triggering of programmed cell death. Deregulation of this co-ordinated response leads to genetic instability and is fundamental to the aetiology of human cancer. Homologous recombination involved in DNA repair is induced by environmental damage as well as misreplication during the normal cell cycle. However, when not regulated properly, it can result in the loss of heterozygocity or genetic rearrangements, central to the process of carcinogenesis. The central step of homologous recombination is the DNA strand exchange reaction catalysed by the eukaryotic Rad51 protein. Here, we describe the recent progress in our understanding of how Rad51 is involved in the signalling and repair of DNA damage and how tumour suppressors, such as p53, ATM, BRCA1, BRCA2, BLM and FANCD2 are linked to Rad51-dependent pathways. An increased knowledge of the role of Rad51 in DNA repair by homologous recombination and its effects on cell cycle progression, tumour development and tumour resistance may provide opportunities for identifying improved diagnostic markers and developing more effective treatments for cancer.
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PMID:Homologous recombination and cell cycle checkpoints: Rad51 in tumour progression and therapy resistance. 1459 70

Epidemiological studies over the past several decades have consistently supported the concept that a proportion of breast cancers develop as the result of an inherited familial predisposition. However, until recently our understanding and knowledge of the underlying genetic processes involved have been limited. Current advances in molecular biology have shown that hereditary breast cancer may arise as the result of mutations of several specific gene loci including BRCA1, BRCA2, ATM gene, PTEN and p53. Several other less frequently occurring predisposition genes such as the androgen receptor gene (AR), the HNPCC genes and the oestrogen receptor gene may also be involved, but to a lesser extent. It is estimated that approximately 5-10% of all breast cancers involve one of these inherited predisposition genes, with BRCA1 and BRCA2 accounting for up to 90% of this group. Mutation analysis is complex in nature and is presently in a developmental and evolving phase, for which reason genetic testing should be offered on a selective basis and through genetic counselling clinics. This report reviews the current knowledge and roles of the various predisposition genes and discusses the management implications for both affected and nonaffected members of breast cancer families. Comprehensive and informative counselling is critical for women with an inherited predisposition to breast cancer and this has led to the evolution of familial cancer clinics involving a multi-disciplinary specialist team approach. Familial cancer clinics can provide individuals with information about their risk of developing breast cancer and offer advice regarding the various management options presently available.
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PMID:The management of familial breast cancer. 1473 74

Cells contain numerous pathways designed to protect them from the genomic instability or toxicity that can result when their DNA is damaged. The p53 tumor suppressor is particularly important for regulating passage through G1 phase of the cell cycle, while other checkpoint regulators are important for arrest in S and G2 phase. Tumor cells often exhibit defects in these checkpoint proteins, which can lead to hypersensitivity; proteins in this class include ataxia-telangiectasia mutatated (ATM), Meiotic recanbination 11 (Mre11), Nijmegen breakage syndrome 1 (Nbs 1), breast cancer susceptibility genes 1 and 2 (BRCA1), and (BRCA2). Consequently, tumors should be assessed for these specific defects, and specific therapy prescribed that has high probability of inducing response. Tumors defective in p53 are frequently considered resistant to apoptosis, yet this defect also provides an opportunity for targeted therapy. When their DNA is damaged, p53-defective tumor cells preferentially arrest in S or G2 phase where they are susceptible to checkpoint inhibitors such as caffeine and UCN-01. These inhibitors preferentially abrogate cell cycle arrest in p53-defective cells, driving them through a lethal mitosis. Wild type p53 can prevent abrogation of arrest by elevating levels of p21(waf1) and decreasing levels of cyclins A and B. During tumorigenesis, tumor cells frequently loose checkpoint controls and this facilitates the development of the tumor. However, these defects also represent an Achilles heel that can be targeted to improve current therapeutic strategies.
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PMID:Cell cycle checkpoints and their impact on anticancer therapeutic strategies. 1474 82

Clinicians should recognize the genetic syndromes that predispose to the development of breast cancer so that patients may be afforded the opportunity to have genetic testing to assist them and their family members in making medical management decisions. Approximately 80%-90% of hereditary breast cancer cases are caused by mutations in the BRCA1 and BRCA2 genes. Other important clinical genetic predispositions include Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, and ataxia-telangiectasia. The key to identifying women who are at risk for a hereditary breast cancer lies in obtaining an adequate, three-generation family history, including ethnic background. For unaffected women, breast cancer risks can be estimated using the quantitative models of Gail and Claus, but there are limitations to these models. Other quantitative models predict the likelihood that a patient is carrying a mutated gene. Genetic testing is available at selected laboratories for each of the hereditary syndromes described, and there are three possible outcomes to testing. These outcomes and their management implications are described in detail. Clinical management options for women at high risk for breast cancer include surveillance, chemoprevention, and prophylactic surgery. Application of these principles can reduce morbidity in women with genetic predispositions to breast cancer.
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PMID:Recognition and management of hereditary breast cancer syndromes. 1475 11

Two mutations of the ATM gene were recently suggested to confer breast cancer risks similar to mutations of BRCA1 or BRCA2. Here, we set out to confirm these findings in 961 families with non-BRCA1/BRCA2 breast cancer from diverse geographical regions. We did not detect the ATM 7271T-->G mutation in any family. The ATM IVS10-6T-->G mutation was detected in eight families, which was similar to its frequency among population-matched control individuals (pooled Mantel-Haenszel odds ratio = 1.60; 95% confidence interval = 0.48 to 5.35; P = 0.44). Bayesian analysis of linkage in the ATM IVS10-6T-->G-positive families showed an overall posterior probability of causality for this mutation of 0.008. We conclude that the ATM IVS10-6T-->G mutation does not confer a significantly elevated breast cancer risk and that ATM 7271T-->G is a rare event in familial breast cancer.
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PMID:Are ATM mutations 7271T-->G and IVS10-6T-->G really high-risk breast cancer-susceptibility alleles? 1487 10

As many as 5% of human cancers appear to be of hereditable etiology. Of the more than 50 characterized familial cancer syndromes, most involve disease affecting multiple organs and many can be traced to one or more abnormalities in specific genes. Studying these syndromes in humans is a difficult task, especially when it comes to genes that may manifest themselves early in gestation. It has been made somewhat easier with the development of genetically engineered mice (GEM) that phenotypically mimic many of these inheritable human cancers. The past 15 years has seen the establishment of mouse lines heterozygous or homozygous null for genes known or suspected of being involved in human cancer syndromes, including APC, ATM, BLM, BRCA1, BRCA2, LKB1, MEN1, MLH, MSH, NF1, TP53, PTEN, RB1, TSC1, TSC2, VHL, and XPA. These lines not only provide models for clinical disease and pathology, but also provide avenues to investigate molecular pathology, gene-gene and protein-tissue interaction, and, ultimately, therapeutic intervention. Possibly of even greater importance, they provide a means of looking at placental and fetal tissues, where genetic abnormalities are often first detected and where they may be most easily corrected. We will review these mouse models, examine their usefulness in medical research, and furnish sources of animals and references.
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PMID:Mouse models of human familial cancer syndromes. 1520 8


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