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)

The average length of linkage disequilibrium (LD) blocks in European populations is about 22 kb. In this study, we have selected 20 genes with LD blocks larger than 60 kb (with a median length of 88 kb) from a total of 121 cancer-related genes. We observed limited haplotype diversity, with an average of three haplotypes per gene accounting for more than 90% of the diversity, two of these being a Yin-Yang pair in 95% of the LD blocks. The mean frequency of the most common haplotype in the Spanish population was just below 50%, similar to those for the HapMap CEU and African samples, but lower than the 60% observed in Asian samples. Genes involved in the regulation of nucleobases and nucleic acid metabolism were overrepresented among these 20 genes with long LD blocks (eight genes ATM, BRCA1, BRCA2, ERCC6, MLH1, MSH3, RAD54B and XRCC4) relative to the other 101 cancer-related genes studied (P=1.23 x 10(-6)). The ancestral haplotype was observed at a frequency greater than 3 in 67% of the genes either in the Spanish or one of the HapMap sampled populations. When observed, the ancestral haplotype had an average 15% frequency in the Spanish sample, less than half that observed in Asian and African samples. The Spanish Yin-Yang haplotype pair represented over 35% of haplotypes in African samples and over 65% in non-African samples. We detected differences in SNP frequencies between populations for five genes (ALDH2, APC, PIK3CB, RB1 and XRCC4, all with Fst>0.4); however, these genes did not show evidence of positive selection. Finally, we found no evidence that the haplotypes formed by SNPs in the 20 genes are associated with breast cancer.
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PMID:Haplotype patterns in cancer-related genes with long-range linkage disequilibrium: no evidence of association with breast cancer or positive selection. 1800 May 25

Fanconi anemia (FA) predisposes to hematopoietic failure, birth defects, leukemia, and squamous cell carcinoma of the head and neck (HNSCC) and cervix. The FA/BRCA pathway includes 8 members of a core complex and 5 downstream gene products closely linked with BRCA1 or BRCA2. Precancerous lesions are believed to trigger the DNA damage response (DDR), and we focused on the DDR in FA and its putative role as a checkpoint barrier to cancer. In primary fibroblasts with mutations in the core complex FANCA protein, we discovered that basal expression and phosphorylation of ATM (ataxia telangiectasia mutated) and p53 induced by irradiation (IR) or mitomycin C (MMC) were upregulated. This heightened response appeared to be due to increased basal levels of ATM in cultured FANCA-mutant cells, highlighting the new observation that ATM can be regulated at the transcriptional level in addition to its well-established activation by autophosphorylation. Functional analysis of this response using gamma-H2AX foci as markers of DNA double-stranded breaks (DSBs) demonstrated abnormal persistence of only MMC- and not IR-induced foci. Thus, we describe a processing defect that leads to general DDR upregulation but specific persistence of DNA crosslinker-induced damage response foci. Underscoring the significance of these findings, we found resistance to DNA crosslinker-induced cell cycle arrest and apoptosis in a TP53-mutant, patient-derived HNSCC cell line, whereas a lymphoblastoid cell line derived from this same individual was not mutated at TP53 and retained DNA crosslinker sensitivity. Our results suggest that cancer in FA may arise from selection for cells that escape from a chronically activated DDR checkpoint.
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PMID:Upregulated ATM gene expression and activated DNA crosslink-induced damage response checkpoint in Fanconi anemia: implications for carcinogenesis. 1822 51

Breast cancer is one of the most frequent cancers in the world. The majority of cases are sporadic but around 15% show some type of familial aggregation and about 5% exhibit a clear hereditary pattern. Common and rare low- moderate-penetrance genes, and high-penetrance genes are thought to explain the genetic susceptibility to the disease. Only around 20% of the inherited risk to breast cancer is explained by germline mutations in the known high-penetrance susceptibility genes BRCA1 and BRCA2. Mutations in genes such as TP53 and PTEN have also been linked with high risk for breast cancer within specific cancer syndromes and rare germline variants in genes such as CHEK2 and ATM have been found to confer modest risk to breast cancer. However, we can say that less than 30% of familial risk of breast cancer is due to known genes. Identification in 2002 of the Fanconi anaemia (FA) gene FANCD1 as BRCA2 and recent studies indicating that heterozygous mutations in FANCN/PALB2 and FANCJ/ BRIP1 predispose to breast cancer have emphasised an important connection between the FA and BRCA pathway. Here we review the emerging DNA-damage response network consisting of FA and BRCA proteins, summarise what is currently known about the direct involvement of these molecules in breast cancer susceptibility and discuss the prospect offered by this pathway in order to identify more breast cancer related genes. We finally present the current stage of therapeutic options specifically targeting the FA/BRCA pathway and summarise the challenges this field encounters.
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PMID:The Fanconi anaemia/BRCA pathway and cancer susceptibility. Searching for new therapeutic targets. 1825 6

Heterozygous carriers of ATM (ataxia telangiectasia mutated gene) mutations have increased risk of breast cancer (BC). We have estimated the prevalence of mutations in the ATM gene among Spanish patients with early-onset BC. Forty-three patients diagnosed with BC before the age of 46 years, and negative for BRCA1 and BRCA2 mutations, were analysed for the presence of ATM mutations. A total of 34 ATM sequence variants were detected: 1 deleterious mutation, 10 unclassified variants and 23 polymorphisms. One patient (2.3%) carried the ATM deleterious mutation (3802delG that causes ataxia telangiectasia in the homozygous state) and 13 patients carried the 10 ATM unclassified variants. The truncating mutation 3802delG and eight of the rare variants were not detected in a control group of 150 individuals. Different bioinformatic sequence analysis tools were used to evaluate the effects of the unclassified ATM changes on RNA splicing and function protein. This in silico analysis predicted that the missense variants 7653 T>C and 8156 G>A could alter the splicing by disrupting an exonic splicing enhancer motif and the 3763 T>G, 6314 G>C, and 8156 G>A variants would affect the ATM protein function. These are the initial results concerning the prevalence of germline mutations in the ATM gene among BC cases in a Spanish population, and they suggest that ATM mutations can confer increased susceptibility to early-onset BC.
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PMID:ATM germline mutations in Spanish early-onset breast cancer patients negative for BRCA1/BRCA2 mutations. 1838 26

In recent years, our understanding of genetic predisposition to breast cancer has advanced significantly. Three classes of predisposition factors, categorized by their associated risks of breast cancer, are currently known. BRCA1 and BRCA2 are high-penetrance breast cancer predisposition genes identified by genome-wide linkage analysis and positional cloning. Mutational screening of genes functionally related to BRCA1 and/or BRCA2 has revealed four genes, CHEK2, ATM, BRIP1, and PALB2; mutations in these genes are rare and confer an intermediate risk of breast cancer. Association studies have further identified eight common variants associated with low-penetrance breast cancer predisposition. Despite these discoveries, most of the familial risk of breast cancer remains unexplained. In this review, we describe the known genetic predisposition factors, expound on the methods by which they were identified, and consider how further technological and intellectual advances may assist in identifying the remaining genetic factors underlying breast cancer susceptibility.
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PMID:Genetic predisposition to breast cancer: past, present, and future. 1854 32

A woman typically presents for genetic counselling because she has a strong family history and is interested in knowing the probability she will develop disease in the future; that is, her absolute risk. Relative risk for a given factor refers to risk compared with either population average risk (sense a), or risk when not having the factor, with all other factors held constant (sense b). Not understanding that these are three distinct concepts can result in failure to correctly appreciate the consequences of studies on clinical genetic testing. Several studies found that the frequencies of mutations in ATM, BRIP1, PALB2 and CHEK2 were many times greater for cases with a strong family history than for controls. To account for the selected case sampling (ascertainment), a statistical model that assumes that the effect of any measured variant multiplies the effect of unmeasured variants was applied. This multiplicative polygenic model in effect estimated the relative risk in the sense b, not sense a, and found it was in the range of 1.7 to 2.4. The authors concluded that the variants are "low penetrance". They failed to note that their model fits predicted that, for some women, absolute risk may be as high as for BRCA2 mutation carriers. This is because the relative risk multiplies polygenic risk, and the latter is predicted by family history. Therefore, mutation testing of these genes for women with a strong family history, especially if it is of early onset, may be as clinically relevant as it is for BRCA1 and BRCA2.
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PMID:Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories? 1855 94

Six genes confer a high risk for developing breast cancer (BRCA1/2, TP53, PTEN, STK11, CDH1). Both BRCA1 and BRCA2 have DNA repair functions, and BRCA1/2 deficient tumors are now being targeted by poly(ADP-ribose) polymerase inhibitors. Other genes conferring an increased risk for breast cancer include ATM, CHEK2, PALB2, BRIP1 and genome-wide association studies have identified lower penetrance alleles including FGFR2, a minor allele of which is associated with breast cancer. We review recent findings related to the function of some of these genes, and discuss how they can be targeted by various drugs. Gaining deeper insights in breast cancer susceptibility will improve our ability to identify those families at increased risk and permit the development of new and more specific therapeutic approaches.
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PMID:Hereditary breast cancer: new genetic developments, new therapeutic avenues. 1857 92

BRCA1/BRCA2 germline mutations substantially increase breast and ovarian cancer risk, yet penetrance is incomplete. We hypothesized that germline epigenetic gene silencing may affect mutant BRCA1/2 penetrance. To test this notion, we determined the methylation status, using methylation-specific quantitative PCR of the promoter in putative modifier genes: BRCA1, BRCA2, ATM, ATR and P53 in Jewish BRCA1/BRCA2 mutation carriers with (n = 41) or without (n = 48) breast cancer, in sporadic breast cancer (n = 52), and healthy controls (n = 89). Promoter hypermethylation was detected only in the BRCA1 promotor in 5.6-7.3% in each of the four subsets of participants, regardless of health and BRCA1/2 status.Germline promoter hypermethylation in the BRCA1 gene can be detected in about 5% of the female Israeli Jewish population, regardless of the BRCA1/2 status. The significance of this observation is yet to be determined.
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PMID:Promoter methylation patterns of ATM, ATR, BRCA1, BRCA2 and p53 as putative cancer risk modifiers in Jewish BRCA1/BRCA2 mutation carriers. 1864 75

Hereditary breast cancer accounts for up to 5-10% of all breast carcinomas. Recent studies have demonstrated that mutations in two high-penetrance genes, namely BRCA1 and BRCA2, are responsible for about 16% of the familial risk of breast cancer. Even though subsequent studies have failed to find another high-penetrance breast cancer susceptibility gene, several genes that confer a moderate to low risk of breast cancer development have been identified; moreover, hereditary breast cancer can be part of multiple cancer syndromes. In this review we will focus on the hereditary breast carcinomas caused by mutations in BRCA1, BRCA2, Fanconi anaemia (FANC) genes, CHK2 and ATM tumour suppressor genes. We describe the hallmark histological features of these carcinomas compared with non-hereditary breast cancers and show how an accurate histopathological diagnosis may help improve the identification of patients to be screened for mutations. Finally, novel therapeutic approaches to treat patients with BRCA1 and BRCA2 germ line mutations, including cross-linking agents and PARP inhibitors, are discussed.
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PMID:Hereditary breast cancer: from molecular pathology to tailored therapies. 1868 20

Apoptosis is essential for complex multicellular organisms and its failure is associated with genome instability and cancer. Interactions between apoptosis and genome-maintenance mechanisms have been extensively documented and include transactivation-independent and -dependent functions, in which the tumor-suppressor protein p53 works as a 'molecular node' in the DNA-damage response. Although apoptosis and genome stability have been identified as ancient pathways in eukaryote phylogeny, the biological evolution underlying the emergence of an integrated system remains largely unknown. Here, using computational methods, we reconstruct the evolutionary scenario that linked apoptosis with genome stability pathways in a functional human gene/protein association network. We found that the entanglement of DNA repair, chromosome stability and apoptosis gene networks appears with the caspase gene family and the antiapoptotic gene BCL2. Also, several critical nodes that entangle apoptosis and genome stability are cancer genes (e.g. ATM, BRCA1, BRCA2, MLH1, MSH2, MSH6 and TP53), although their orthologs have arisen in different points of evolution. Our results demonstrate how genome stability and apoptosis were co-opted during evolution recruiting genes that merge both systems. We also provide several examples to exploit this evolutionary platform, where we have judiciously extended information on gene essentiality inferred from model organisms to human.
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PMID:Evolutionary origins of human apoptosis and genome-stability gene networks. 1883 73


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