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At least 307 records · Page 17Linked to original sources
PubMed1997

Loss of heterozygosity at 11q23.1 in breast carcinomas: indication for involvement of a gene distal and close to ATM.

Previous reports have suggested that heterozygotes for ataxia-telangiectasia (A-T) have an increased risk of cancer, in particular breast cancer. The ATM gene, responsible for A-T, was recently cloned. Loss of heterozygosity (LOH) in the chromosome band 11q23, where the ATM gene is located, has been reported in several types of tumours including breast carcinomas. Whether the ATM gene is the target, and the sole target, for the LOH seen in this region is not yet known. In this study, 169 primary breast carcinomas and 10 metastases were examined for allelic imbalance (AI) using 10 microsatellite markers mapping to 11q23.1. Nine of the markers reside within a 10 Mb region surrounding the ATM gene, whereas the tenth locus, APOC-3, is located more than 12 Mb telomeric from this region. The highest frequencies of alteration were found for APOC-3 (45%), and for two markers located approximately 200 and 900 kb telomeric from ATM, D11S1294 (44%) and D11S1818 (44%). The marker located within the ATM gene, D11S2179, was altered in 37% of the informative tumours. The present deletion map indicates that three distinct regions at 11q23.1 may be involved in breast cancer development; one between the markers D11S1294 and D11S1818, a second close to APOC-3, and a third that is possibly the ATM-gene itself.

Adult↗
PubMed2003

Checkpoint signaling: epigenetic events sound the DNA strand-breaks alarm to the ATM protein kinase.

The ATM protein kinase is centrally involved in the cellular response to ionizing radiation (IR) and other DNA double-strand-break-inducing insults. Although it has been well established that IR exposure activates the ATM kinase domain, the actual mechanism by which ATM responds to damaged DNA has remained enigmatic. Now, a landmark paper provides strong evidence that DNA-strand breaks trigger widespread activation of ATM through changes in chromatin structure (1). This review discusses a checkpoint activation model in which chromatin perturbations lead to the conversion of inactive ATM domains to phosphorylated, active ATM monomers. The new findings underscore the critical importance of epigenetic events in genome function and surveillance in mammalian cells.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2001

Expression of ATM in ataxia telangiectasia fibroblasts rescues defects in DNA double-strand break repair in nuclear extracts.

Ataxia telangiectasia (A-T) is a human genetic disorder characterized by progressive cerebellar degeneration, hypersensitivity to ionizing radiation (IR), immunodeficiency, and high cancer risk. At the cellular level, IR sensitivity and increased frequency of spontaneous and IR-induced chromosomal breakage and rearrangements are the hallmarks of A-T. The ATM gene, mutated in this syndrome, has been cloned and codes for a protein sharing homology with DNA-PKcs, a protein kinase involved in DNA double-strand break (DSB) repair and DNA damage responses. The characteristics of the A-T cellular phenotypes and ATM gene suggest that ATM may play a role similar to that of DNA-PKcs in DSB repair and that there is a primary DNA repair defect in A-T cells. In the current study, the function of ATM in DNA DSB repair was evaluated in an in vitro system using two plasmids, carrying either an EcoRI-induced DSB within the lacZalpha gene or various endonuclease-induced DSB in the SupF suppressor tRNA gene. We found that the DSB repair efficiency in A-T nuclear extracts was comparable to, if not higher than, that in normal nuclear extracts. However, the repair fidelity in A-T nuclear extracts was decreased when repairing DSB with short 5' and 3' overhangs (<4 base pairs (bp)) or blunt ends, but not 5' 4-bp overhangs. Sequencing of the mutant plasmids revealed that deletions involving 1-6 nucleotide microhomologies were the major class of mutations in both A-T and normal extracts. However, the size of the deletions in plasmids from A-T nuclear extracts was larger than that from normal nuclear extracts. Expression of the ATM protein in A-T cells corrected the defect in DSB repair in A-T nuclear extracts. These results suggest that ATM plays a role in maintaining genomic stability by preventing the repair of DSB from an error-prone pathway.

Ataxia Telangiectasia↗
PubMed2004

Germ-line ATM gene alterations are associated with susceptibility to sporadic T-cell acute lymphoblastic leukemia in children.

A major feature of ataxia-telangiectasia (A-T) is an increased risk of cancer, particularly of lymphoid malignancies. We studied ATM gene involvement in leukemic cells derived from 39 pediatric T-cell acute lymphoblastic leukemias (ALLs). Two types of sequence changes--truncating and missense--were identified in 8 T-cell ALL samples: 3 truncating changes, all previously identified in A-T (R35X, -30del215, 2284delCT), and 3 missense variants (V410A, F582L, F1463C) were found, none associated with loss of heterozygosity (LOH). In all patients studied, the mutation was present in the germ-line. A-T carriers, defined by the finding of truncating mutations, were found to be 12.9 times more frequent than in the normal population (P = 0.004). A normally ethnically matched population was screened for the 3 missense variants, and their frequency was significantly more prevalent (4.9-fold excess) than in the normal population (P = 0.03). Our data suggest there is some evidence of an association between missense alterations in the ATM gene and T-cell ALL. A significant difference in the mean age at diagnosis of T-cell ALL was noted between patients harboring an ATM sequence change and those with no change, 5.4 years and 9.7 years, respectively (P = 0.001). No ATM alterations were identified in relapse samples, indicating that ATM does not play a role in disease progression. The high prevalence of germ-line truncating and missense ATM gene alterations among children with sporadic T-cell ALL suggests an association with susceptibility to T-cell acute leukemia and supports the model of predisposition to cancer in A-T heterozygotes.

Ataxia Telangiectasia↗
PubMed2006

Regulation of the Atm promoter in vivo.

While ATM, the protein defective in the human genetic disorder ataxia-telangiectasia (A-T), is primarily activated as a preexisting protein by radiation, there is also evidence that expression of the protein can be regulated at the transcriptional level. Activation of the ATM promoter by ionizing radiation has been reported only in quiescent cells in culture. To investigate how the Atm promoter is regulated in vivo, we generated transgenic mice that express the luciferase reporter gene under the control of the murine Atm promoter. Using a biophotonic imaging system luciferase activity was monitored in vivo. Strong promoter activity was detected throughout the transgenic animals with particularly high signals from the thymus, abdominal region, and reproductive organs. This activity further increased in response to both ionizing radiation and heat stress in a time dependent manner. Luciferase activity, measured in vitro in extracts from different tissues, showed highest activities in testes, ovaries, and cerebellum. Subjecting these mice to a single dose of 4 Gy total body radiation led to a time-dependent activation of the promoter with the strongest response observed in the peritoneal membrane, skin, and spleen. For most tissues tested, maximal promoter activity was reached 8 hr after radiation. The observed changes in promoter activity largely correlated with levels and activity of Atm protein in tissue extracts. These results demonstrate that, in addition to activation by autophosphorylation, Atm can also be regulated in vivo at the transcriptional level possibly ensuring a more sustained response to radiation and other stimuli.

Animals↗
PubMed2005

Two ATM variants and breast cancer risk.

The ATM gene is mutated in ataxia-telangiectasia (AT). Heterozygote female relatives of AT cases have a 2-7fold increased risk of breast cancer. We previously reported high risks of breast cancer associated with certain ATM variants. To estimate the risks more precisely, we have examined two ATM variants, c.1066-6T>G (IVS10-6T>G) and c.4258C>T (p.Leu1420Phe), in additional cases and controls from the same Australian cohorts previously used to estimate the risk of breast cancer associated with c.1066-6T>G. A total of 775 and 84 population-based controls were genotyped for the c.1066-6T>G and c.4258C>T ATM variants respectively, as were index cases from 378 and 373 non-BRCA1/2 breast cancer families. Penetrance was estimated by Bayes factor analysis. The allele frequencies of ATM c.1066-6T>G and c.4258C>T estimated from controls were 0.005 (95% CI=0.002 to 0.009) and 0.012 (95% CI=0.001 to 0.042), respectively. We identified three new breast cancer families with c.1066-6T>G, and seven families with c.4258C>T. Combining with the two c.1066-6T>G families previously reported, the estimated penetrance to age 70 of c.1066-6T>G was 17.2% (95% CI=4.7% to 37.5%). For c.4258C>T, the estimated average penetrance was 4.8% (95% CI 1.7% to 10.1%). In conclusion, we found no evidence that the ATM c.4258C>T variant increases breast cancer risk, and little evidence that c.1066-6T>G confers an elevated risk. Analysis of additional families will be necessary to define more precisely the risk, if any, associated with c.1066-6T>G.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2005

Association of common ATM polymorphism with bilateral breast cancer.

The ATM kinase has an essential role in maintaining genomic integrity. Loss of both ATM alleles results in ataxia-telangiectasia (A-T), a rare autosomal recessive neuroimmunologic disorder associated with cancer susceptibility. Individuals heterozygous for germline ATM mutations have been reported to have an increased risk for malignancy, in particular, female breast cancer. In the current study, a full mutation analysis of the ATM gene was carried out in patients from 121 breast or breast-ovarian cancer families. We discovered that the combination of 5557G-->A in cis position with IVS38-8 T-->C was associated with bilateral breast cancer (OR = 10.2; 95% CI = 3.1-33.8; p = 0.001). As the 5557G-->A change has been reported to affect an exonic splicing enhancer, we hypothesized that the observed composite allele could have some effect on the correct splicing of exon 39. However, no aberrant transcripts were detected, but ATM expression levels of lymphoblast cell lines from heterozygous carriers of this combination allele were lower than from noncarriers (p = 0.09). Lowered gene expression levels may have direct influence on the activities in DNA damage recognition and response pathways, as well as other genome integrity maintenance functions. Based on the results, we propose a cancer risk-modifying effect for the ATM 5557G-->A, IVS38-8T-->C composite allele.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2005

Complex H2AX phosphorylation patterns by multiple kinases including ATM and DNA-PK in human cells exposed to ionizing radiation and treated with kinase inhibitors.

In eukaryotic cells, DNA double strand breaks (DSBs) cause the prompt phosphorylation of serine 139 at the carboxy terminus of histone H2AX to generate gamma-H2AX, detectable by Western blotting or immunofluorescence. The consensus sequence at the phosphorylation site implicates the phosphatidylinositol 3-like family of protein kinases in H2AX phosphorylation. It remains open whether ATM (ataxia telangiectasia mutated) is the major H2AX kinase, or whether other members of the family, such as DNA-PK (DNA dependent protein kinase) or ATR (ATM and Rad3 related), contribute in a functionally complementary manner. To address this question, we measured global H2AX phosphorylation in cell lysates and foci formation in individual cells of either wild type or mutant (ATM or DNA-PK) genetic background. Normal global phosphorylation kinetics is observed after irradiation in cells defective either in ATM or DNA-PK alone, suggesting a complementary contribution to H2AX phosphorylation. This is further supported by the observation that initial H2AX phosphorylation is delayed when both kinases are inhibited by wortmannin, as well as when ATM is inhibited by caffeine in DNA-PK deficient cells. However, robust residual global phosphorylation is detectable under all conditions of genetic or chemical inhibition suggesting the function of additional kinases, such as ATR. Treatment with wortmannin, caffeine, or UCN-01 produces a strong DNA-PK dependent late global hyperphosphorylation of H2AX, uncoupled from DNA DSB rejoining and compatible with an inhibition of late steps in DNA DSB processing. Evaluation of gamma-H2AX foci formation confirms the major conclusions made on the basis of global H2AX phosphorylation, but also points to differences particularly several hours after exposure to IR. The results in aggregate implicate DNA-PK, ATM and possibly other kinases in H2AX phosphorylation. The functional significance and the mechanisms of coordination in space and time of these multiple inputs require further investigation.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2005

ATM haplotypes and associated mutations in Iranian patients with ataxia-telangiectasia: recurring homozygosity without a founder haplotype.

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder caused by mutations in the ATM gene. The ATM gene spans more than 150 kb at chromosomal region 11q23.1 and encodes a product of 3,056 amino acids. The ATM protein is a serine/threonine protein kinase and is involved in oxidative stress, cell cycle control, and DNA repair. We analyzed the 11q22-23 haplotypes and associated mutations of 16 Iranian families. We utilized standardized short tandem repeat (STR) haplotypes to enhance mutation identification. In addition to the STR markers, single-nucleotide polymorphism haplotypes were determined, using three critical polymorphisms. The entire gene was screened sequentially by protein truncation testing, single-strand conformation polymorphism, and denaturing high-performance liquid chromatography to identify the disease-causing mutations. Of the expected 32 mutations, 25 (78%) were identified. All but two mutations led to a truncated or null form of the ATM protein (nonsense, splice site, or frameshift). Twelve mutations were identified for 15 haplotypes. Five mutations were novel. Mutations were located throughout the entire gene, with no clustering. Despite the absence of an Iranian founder mutation, three-fourths of the families were homozygous, suggesting that many undetected ATM mutations still exist in Iran. This study establishes a database for Iranian A-T families, and extends the global spectrum of ATM mutations.

Ataxia Telangiectasia↗
PubMed2004

Stable siRNA-mediated silencing of ATM alters the transcriptional profile of HeLa cells.

The ATM protein, which is mutated in the inherited disease ataxia telangiectasia (AT), is a key regulator of the cells' DNA damage response. AT cells also exhibit constitutive activation of transcriptional regulators such as p53, E2F, AP1, and NFkappaB. Inactivation of ATM may therefore alter the cells' transcriptional profile. ATM expression in HeLa cells was silenced with siRNA expressed from a plasmid based vector, generating a stable cell line, HeLaATM601. HeLaATM601 cells displayed minimal levels of ATM protein and had a 10-fold increase in sensitivity to ionizing radiation. DNA microarray analysis demonstrated that 35 genes were upregulated and five genes were downregulated in HeLaATM601 cells. Genes upregulated in the absence of ATM included interferon-response proteins, cell cycle regulators, integral membrane proteins, and adhesion and extracellular matrix proteins. Using real-time PCR, these genes were also upregulated in cells derived from AT patients. Inactivation of the ATM protein therefore has a significant impact on the transcriptional profile of the cell.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2004

IGF-1 phosphorylates AMPK-alpha subunit in ATM-dependent and LKB1-independent manner.

Serine/threonine protein kinase AMP-activated protein kinase (AMPK) is a key metabolic stress-responsive factor that promotes the adaptation of cells to their microenvironment. Elevated concentrations of intracellular AMP, caused by metabolic stress, are known to activate AMPK by phosphorylation of the catalytic subunit. Recently, the tumor suppressor serine/threonine protein kinase LKB1 was identified as an upstream kinases, AMPKKs. In the current study, we found that stimulation with growth factors also caused AMPK-alpha subunit phosphorylation. Interestingly, even an LKB1-nonexpressing cancer cell line, HeLa, exhibited growth factor-stimulated AMPK-alpha subunit phosphorylation, suggesting the presence of an LKB1-independent pathway for AMPK-alpha subunit phosphorylation. In the human pancreatic cancer cell line PANC-1, AMPK-alpha subunit phosphorylation promoted by IGF-1 was suppressed by antisense ataxia telangiectasia mutated (ATM) expression. We found that IGF-1 also induced AMPK-alpha subunit phosphorylation in the human normal fibroblast TIG103 cell line, but failed to do so in a human fibroblast AT2-KY cell line lacking ATM. Immunoprecipitates of ATM collected from IGF-1-stimulated cells also caused the phosphorylation of the AMPK-alpha subunit in vitro. IGF-1-stimulated ATM phosphorylation at both threonine and tyrosine residues, and our results demonstrated that the phosphorylation of tyrosine in the ATM molecule is important for AMPK-alpha subunit phosphorylation during IGF-1 signaling. These results suggest that IGF-1 induces AMPK-alpha subunit phosphorylation via an ATM-dependent and LKB1-independent pathway.

AMP-Activated Protein Kinase Kinases↗
PubMed2005

Inhibition of Atm and/or Atr disrupts gene silencing on the inactive X chromosome.

ATM and ATR are well documented for their roles in maintaining the integrity of genomic DNA by responding to DNA damage and preparing the cell for repair. Since ATM and ATR have been reported to exist in complexes with histone deacetylases, we asked whether Atm and Atr might also uphold gene silencing by heterochromatin. We show that the Atm/Atr inhibitor 2-aminopurine causes the inactive X chromosome to accumulate abnormal chromatin and undergo unwanted gene reactivation. We provide evidence that this gene expression from the inactive X chromosome is not a byproduct of the accumulation of DNA breaks. Individually inhibiting Atm and Atr by either small interfering RNA or the expression of dominant-negative ATM and ATR constructs also compromised X-inactivation. Atm and Atr, therefore, not only function in responding to DNA damage but perhaps also are involved in gene silencing via the maintenance of heterochromatin.

2-Aminopurine↗
PubMed2006

Effect of the reduction of superoxide dismutase 1 and 2 or treatment with alpha-tocopherol on tumorigenesis in Atm-deficient mice.

Atm-deficient mice, a cancer-prone model of the human disease ataxia-telangiectasia, display increased levels of oxidative stress and damage. Chronic treatment of these mice with the nitroxide antioxidant and superoxide dismutase (SOD) mimetic Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) resulted in an increased latency to tumorigenesis. We initially hypothesized that the chemopreventative effect of Tempol was due to its SOD mimetic activity reducing cellular oxidative stress and damage. However, it is also possible that the chemopreventative effect of Tempol results from mechanisms other than directly reducing superoxide radical-induced oxidative stress and damage. To help distinguish between these possibilities, we attempted to genetically increase oxidative stress in Atm-deficient mice by either removing cytosolic Sod1 or reducing mitochondrial Sod2, or we attempted to decrease oxidative stress by treatment of Atm-deficient mice with alpha-tocopherol. Surprisingly, we found that reducing both Atm and Sod1 or Atm and Sod2 did not shorten latency to tumorigenesis or significantly affect life span. Furthermore, continuous administration of alpha-tocopherol did not affect latency to thymic lymphomas. Thus, genetically reducing Sod in Atm-deficient mice or treatment with alpha-tocopherol had no effect on survival or tumorigenesis, suggesting that the chemopreventative effect of Tempol may be at least partially independent of its effects on reducing oxidative damage and stress.

Animals↗
PubMed2005

ATM sequence variants and risk of radiation-induced subcutaneous fibrosis after postmastectomy radiotherapy.

PURPOSE: To examine the hypothesis that women who are carriers of genetic alterations in the ATM gene are more likely to develop subcutaneous fibrosis after radiotherapy for treatment of breast cancer compared with patients who do not possess DNA sequence variations in this gene. METHODS AND MATERIALS: DNA samples isolated from fibroblast cell lines established from 41 women treated with postmastectomy radiotherapy for breast cancer were screened for genetic variants in ATM using denaturing high-performance liquid chromatography (DHPLC). A minimum follow-up of 2 years enabled analysis of late effects to generate dose-response curves and to estimate the dose that resulted in a 50% incidence of Grade 3 fibrosis (ED50). RESULTS: A total of 26 genetic alterations in the expressed portions of the ATM gene, or within 10 bases of each exon in regions encompassing putative splice sites, were detected in 22 patients. The ED50 (95% confidence interval) of 60.2 (55.7-65.1) Gy calculated for patients without a sequence variation did not differ significantly from the ED50 of 58.4 (54.0-63.1) Gy for the group of patients with any ATM sequence abnormality. The ED50 of 53.7 (50.2-57.5) Gy for those patients who were either homozygous or heterozygous for the G-->A polymorphism at nucleotide 5557, which results in substitution of asparagine for aspartic acid at position 1853 of the ATM protein, was substantially lower than the ED50 of 60.8 (57.0-64.8) Gy for patients not carriers of this sequence alteration. This resulted in an enhancement ratio (ratio of the ED50 values) of 1.13 (1.05-1.22), which was significantly greater than unity. CONCLUSION: The results of this study suggest an association between the ATM codon 1853 Asn/Asp and Asn/Asn genotypes with the development of Grade 3 fibrosis in breast cancer patients treated with radiotherapy.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2005

Mutation analysis of the ATM gene in two Chinese patients with ataxia telangiectasia.

Ataxia telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectasia, immunodeficiency, elevated alpha-fetoprotein level, chromosomal instability, predisposition to cancer, and radiation sensitivity. Although a lot of mutations in the ATM gene have been described, there is still no report about ATM mutations in Chinese population. Using a molecular approach, we screened for ATM mutations in two patients from two unrelated Chinese families. 100 normal controls were analyzed to exclude possibility of polymorphism. Two novel mutations in the ATM gene were identified. The first one is a novel, homozygous, 1346G>C (Gly449Ala) missense mutation. The second one is a compound heterozygous mutation, which consists of a novel, 610G>T (Gly204Stop) nonsense mutation, combined with a previously reported, 6679C>T (Arg2227Cys) missense mutation. The transversions 1346G>C (Gly449Ala) and 610G>T (Gly204Stop) are not localized either in the conserved PI-3 kinase domain or in the other domains of the ATM protein. The phenotypic features were characterized by progressive cerebellar ataxia, ocular telangiectasia, elevated alpha-fetoprotein level, immunodeficiency (agammaglo-bulinemia and T-cell defect), and rearrangements of chromosomes 7 and 14; brain MRI showed cerebellar atrophy, brain SPECT showed cerebellar regional cerebral blood flow (rCBF) hypoperfusion. To our knowledge, this is the first report of ATM mutations in Mainland China, in which the transversions 1346G>C (Gly449Ala) and 610G>T (Gly204Stop) are two novel, disease-causing mutations.

Adolescent↗
PubMed2006

Wip1 phosphatase modulates ATM-dependent signaling pathways.

Deletion of Ppm1d, the gene encoding the Wip1 phosphatase, renders cells resistant to transformation and mice resistant to tumor development. Here, we report that deficiency of Wip1 resulted in activation of the ataxia-telangiectasia mutated (ATM) kinase. In turn, overexpression of Wip1 was sufficient to reduce activation of the ATM-dependent signaling cascade after DNA damage. Wip1 dephosphorylated ATM Ser1981, a site critical for ATM monomerization and activation, and was critical for resetting ATM phosphorylation as cells repaired damaged DNA. We propose that the Wip1 phosphatase is an integral component of an ATM-dependent signaling pathway.

Animals↗
PubMed2006

Variation of ATM protein expression in response to irradiation of lymphocytes in lung cancer patients and controls.

The aim of this research work was to study the cellular response to ionizing radiation (IR) and its relationship with the ATM protein expression levels in lung cancer patients. Heparinized blood samples were collected from 22 controls and 22 lung cancer patients. Each sample was divided into two parts: non-irradiated sample and irradiated sample, which was exposed to 3 Gy X-ray. The spontaneous and IR-induced genetic damage in both lung cancer patients and controls was measured with comet assay and micronucleus (MN) assay, and the ATM protein expression levels of non-irradiated samples in lung cancer patients and controls were detected by Western blotting. The results indicated that the baseline values of average mean tail moment (MTM) and micronucleus rate (MNR) in lung cancer patients were 0.86 and 11.41 per thousand, respectively, which was significantly higher than those (0.64 and 6.77 per thousand) of controls (P<0.05 for MTM, P<0.01 for MNR). The IR-induced average MTM and MNR in lung cancer patients were 1.23 and 77.64 per thousand, respectively, which was also significantly higher than those (0.71 and 66.05 per thousand) of controls (P<0.05 for MTM, P<0.01 for MNR). The results of Western blotting showed that the ATM protein expression levels in lung cancer patients and controls were 0.64 and 1.71, respectively, and there was significant (P<0.01) difference between lung cancer patients and controls. In present investigation, it was found that the genetic instability measured with comet assay and MN assay in lung cancer patients were significantly higher than those in controls, on the contrary, ATM protein expression level in lung cancer patients were significantly lower than that in controls. However, no good correlation was found either between ATM protein expression and IR-induced MTM or between ATM protein expression and IR-induced MNR in lung cancer patients.

Adult↗
PubMed2003

Absence of somatic ATM missense mutations in 58 mammary carcinomas.

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.

Ataxia Telangiectasia Mutated Proteins↗