Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

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

Previously we have shown that angiotensin II (Ang II) suppresses long-term potentiation (LTP) in the lateral nucleus of the amygdala (LA) of horizontal slices. This study examines the effect of Ang II on long-term depression (LTD) in the LA. Low frequency stimulation (1 Hz, 15 min; LFS) applied to fibers running within the LA induced a long-lasting reduction of the amplitudes of field potentials in the LA of mice. We have previously shown that this LTD is sensitive to the NMDA receptor blocker D-AP5 and is dependent on group II mGlu receptors. Ang II blocked dose-dependent LTD. Losartan, an AT1 receptor antagonist, blocked the Ang II-induced suppression of LTD, whereas PD 123 319, an AT2 receptor antagonist, had no effect. Co-administration of nifedipine, an L-type calcium channel antagonist, abolished Ang II-induced suppression of LTD. When applied alone nifedipine reduced the magnitude of LA-LTD. According to our previous results, stimulation of external capsule (EC) fibers in rats did not cause LTD in mice. Similarly, Ang II did not induce long-lasting changes of activity when EC stimulation site was used. The results support the view that angiotensins are involved in mechanisms of learning and memory including the plasticity changes in the LA.
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PMID:Angiotensin II suppresses long-term depression in the lateral amygdala of mice via L-type calcium channels. 1728 61

Several genes are associated with hereditary susceptibility to breast cancer. Most notably these include BRCA1 and BRCA2; however, other less common gene mutations which confer elevated breast cancer risk are associated with Cowden syndrome, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, ataxia-telangiectasia heterozygosity and hereditary diffuse gastric cancer. In this article we highlight the genetic epidemiology, gene function, genotype-phenotype correlations, cancer risks and clinicopathologic findings for the cancer susceptibility genes related to these syndromes. We also examine genes, such as CHEK2, which confer a lower penetrance for breast cancer in comparison to these highly penetrant genes.
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PMID:Susceptibility to breast cancer: hereditary syndromes and low penetrance genes. 1791 39

Head and neck squamous cell carcinoma (HNSCC) include squamous cell carcinomas of the oral cavity, pharynx, and larynx. Epidemiologic data suggest that the etiology and pathogenesis of HNSCC are influenced by environmental and lifestyle-related factors, such as tobacco use, ethanol consumption, papilloma virus infection, dietary factors and exposure to toxic substances. DNA repair systems and carcinogen-metabolizing enzymes can increase the risk for HNSCC but no definite causal mechanism has been demonstrated. There are several well-characterized entities that are associated with risk and prognosis of head and neck cancer, including Lynch-II syndrome, Bloom syndrome, Fanconi's anemia, xeroderma pigmentosum, ataxia telangiectasia, and Li-Fraumeni syndrome. This review aims to present the current status in our understanding of HNSCC and highlight controversies relating to the role of several factors in the genesis of the cancer.
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PMID:Genetic and environmental factors in head and neck cancer genesis. 1856 29

Herein we used single-cell observation methods to gain insight into the roles of p16(INK4A) and p21(WAF1) (hereafter p16 and p21) in replicative senescence and ionizing radiation-induced accelerated senescence in human [normal, ataxia telangiectasia (AT) and Li-Fraumeni syndrome (LFS)] fibroblast strains. Cultures of all strains entered a state of replicative senescence at late passages, as evident from inhibition of growth, acquisition of flattened and enlarged cell morphology, and positive staining for senescence-associated beta-galactosidase. In addition, proliferating early-passage cultures of these strains exhibited accelerated senescence in response to ionizing radiation. Immunofluorescence microscopy revealed the heterogeneous expression of p16 in normal and AT fibroblast strains, with the majority of the cells exhibiting undetectable levels of p16 irrespective of in vitro culture age. Importantly, replicative senescence as well as accelerated senescence triggered by ionizing radiation were accompanied by sustained nuclear accumulation of p21, but did not correlate with p16 expression in p53-proficient (normal and AT) fibroblasts. In p53-deficient (LFS) fibroblasts, on the other hand, replicative senescence and ionizing radiation-triggered accelerated senescence strongly correlated with expression of p16 but not of p21. Furthermore, senescence in LFS fibroblasts was associated with genomic instability encompassing polyploidy. Our findings are compatible with a model in which p16 serves as a backup regulator of senescence, triggering this response preferentially in the absence of wild-type p53 activity. The possibility that one of the tumor-suppressor functions of p16 may be associated with genomic instability, preventing the emergence of malignant progeny from polyploid giant cells, is also supported by these results.
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PMID:Single-cell analysis of p16(INK4a) and p21(WAF1) expression suggests distinct mechanisms of senescence in normal human and Li-Fraumeni Syndrome fibroblasts. 2003 73

The tumor suppressor gene TP53, encoding the p53 protein, has its gene locus on the short arm of chromosome 17 p13.1 (1,2). p53 has been denoted "guardian of the genome" (3) owing to its essential cellular functions in apoptosis control, cell-cycle control, chromosomal segregation, gene transcription, and genomic stability (4). The gene encodes a protein of 393 amino acids (5). The tertiary structure of the p53 protein is known to a relatively large extent; the DNA binding region has been localized to amino acids 102 to 292. Murine double minute-2 (MDM2) binds to the amino terminal of the p53 protein and is a negative regulator of p53 (6). p53 is normally activated by ultraviolet (UV)-light, radiation, cytostatics, and carcinogens. The activation by these may involve interaction with the ataxia telangiectasia gene (ATM). The p53 gene can be inactivated by somatic or germ-line mutations. Somatic mutations in the p53 gene is the most common genetic abnormality so far described in human cancer (7). Patients with germ-line p53 mutation's are part of the Li-Fraumeni syndrome. These patients have an increased risk of developing adrenocortical, breast, gastrointestinal tract, and lung carcinoma, as well as soft-tissue sarcoma and malignant melanoma (8,9). Studies on mice have revealed that induced deficiency of both alleles of the p53 gene is associated within an increased risk of lymphomas and sarcomas (10). p53 can also be inactivated by certain viral oncoproteins, such as human papilloma virus protein E6, SV40 large T-antigen, hepatitis B viral X protein, and adenovirus protein E1B (4).
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PMID:Analysis of the p53 Status of Tumors : An Overview of Methods. 2137 38

Ionizing radiation induces DNA Double-Strand Breaks (DSBs) which activate the ATM/CHEK2/p53 pathway leading to cell cycle arrest and apoptosis through transcription of genes including CDKN1A (p21) and BBC3 (PUMA). This pathway prevents genomic instability and tumorigenesis as demonstrated in heritable syndromes [e.g. Ataxia Telangiectasia (AT); Li-Fraumeni syndrome (LFS)]. Here, a simple assay based on gene expression in peripheral blood to measure accurately ATM/CHEK2/p53 pathway activity is described. The expression of p21, Puma and Sesn2 was determined in blood from mice with different gene copy numbers of Atm, Trp53 (p53), Chek2 or Arf and in human blood and mitogen stimulated T-lymphocyte (MSTL) cultures from AT, AT carriers, LFS patients, and controls, both before and after ex vivo ionizing irradiation. Mouse Atm/Chek2/p53 activity was highly dependent on the copy number of each gene except Arf. In human MSTL, an AT case, AT carriers and LFS patients showed responses distinct from healthy donors. The relationship between gene copy number and transcriptional induction upon radiation was linear for p21 and Puma and correlated well with cancer incidence in p53 variant mice. This reliable blood test provides an assay to determine ATM/CHEK2/p53 pathway activity and demonstrates the feasibility of assessing the activity of this essential cancer protection pathway in simple assays. These findings may have implications for the individualized prediction of cancer susceptibility.
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PMID:A minimally invasive assay for individual assessment of the ATM/CHEK2/p53 pathway activity. 2153 12

Breast cancer is the most common malignancy among females. 5%-10% of breast cancer cases are hereditary and are caused by pathogenic mutations in the considered reference BRCA1 and BRCA2 genes. As sequencing technologies evolve, more susceptible genes have been discovered and BRCA1 and BRCA2 predisposition seems to be only a part of the story. These new findings include rare germline mutations in other high penetrant genes, the most important of which include TP53 mutations in Li-Fraumeni syndrome, STK11 mutations in Peutz-Jeghers syndrome, and PTEN mutations in Cowden syndrome. Furthermore, more frequent, but less penetrant, mutations have been identified in families with breast cancer clustering, in moderate or low penetrant genes, such as CHEK2, ATM, PALB2, and BRIP1. This paper will summarize all current data on new findings in breast cancer susceptibility genes.
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PMID:Hereditary breast cancer: the era of new susceptibility genes. 2358 58

20% of children suffering from high hyperdiploid acute lymphoblastic leukemia develop recurrent disease. The molecular mechanisms are largely unknown. Here, we analyzed the genetic landscape of five patients at relapse, who developed recurrent disease without prior high-risk indication using whole-exome- and whole-genome-sequencing. Oncogenic mutations of RAS pathway genes (NRAS, KRAS, FLT3, n=4) and deactivating mutations of major epigenetic regulators (CREBBP, EP300, each n=2 and ARID4B, EZH2, MACROD2, MLL2, each n=1) were prominent in these cases and virtually absent in non-recurrent cases (n=6) or other pediatric acute lymphoblastic leukemia cases (n=18). In relapse nucleotide variations were detected in cell fate determining transcription factors (GLIS1, AKNA). Structural genomic alterations affected genes regulating B-cell development (IKZF1, PBX1, RUNX1). Eleven novel translocations involved the genes ART4, C12orf60, MACROD2, TBL1XR1, LRRN4, KIAA1467, and ELMO1/MIR1200. Typically, patients harbored only single structural variations, except for one patient who displayed massive rearrangements in the context of a germline tumor suppressor TP53 mutation and a Li-Fraumeni syndrome-like family history. Another patient harbored a germline mutation in the DNA repair factor ATM. In summary, the relapse patients of our cohort were characterized by somatic mutations affecting the RAS pathway, epigenetic and developmental programs and germline mutations in DNA repair pathways.
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PMID:Next-generation-sequencing of recurrent childhood high hyperdiploid acute lymphoblastic leukemia reveals mutations typically associated with high risk patients. 2618 8

Oral squamous cell carcinoma is the most common malignancy of the oral cavity, which is usually preceded by a myriad of oral potentially malignant disorders (OPMDs). In the classification of OPMDs, inherited cancer syndromes (ICSs) were proposed as one of the categories. Inherited cancer syndromes are genetic disorders in which inherited genetic mutation in one or more genes predispose the affected individuals to the development of cancer and may also cause its early onset. Many of these syndromes are caused by mutations in tumor suppressor genes, oncogenes, and genes involved in angiogenesis. General dental practitioners frequently come across OPMDs in their day-to-day practice. It becomes of paramount importance to have knowledge about these rare but prognostically important OPMDs. With this view in mind, in this article, efforts have been made to comprehensively discuss about various ICSs that have higher potential of transformation into oral cancer. The ICSs discussed in this article are xeroderma pigmentosum (XP), ataxia telangiectasia (AT), Bloom syndrome (BS), Fanconi's anemia (FA), and Li-Fraumeni syndrome (LFS), with special emphasis on signs, symptoms, and genetic considerations.
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PMID:Oral Cancer-related Inherited Cancer Syndromes: A Comprehensive Review. 2748 6


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