Expression of theATM gene is significantly reduced in sporadic breast carcinomas

Waha, Andreas; Sturne, Chris; Kessler, Astrid; Koch, Anne; Kreyer, E.; Fimmers, Rolf; Wiestler, Otmar D.; Deimling, Andreas von; Krebs, D.; Schmutzler, Rita K.

doi:10.1002/(sici)1097-0215(19981029)78:3<306::aid-ijc8>3.0.co;2-z

Cited by 38 publications

(29 citation statements)

References 15 publications

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“…Studies of ATM and Ku80 expression in tumor tissues have yielded inconsistent findings across different cancer types, with some reporting higher expression, some reporting lower expression, and others reporting no changes. 12,19,20,[25][26][27] The inconsistency in ATM and Ku80 regulation in different tumor types suggests a remarkable difference on the molecular alterations related to the progression of cancer at different sites. In addition, the methodology of measuring mRNA expression and the selection of control genes also may contribute to the inconsistency of results.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of ataxia‐telangiectasia mutated, DNA‐dependent protein kinase catalytic subunit, and Ku heterodimeric regulatory complex 86‐kD subunit expression in patients with nonsmall cell lung cancer

Xing

Vaporciyan

et al. 2008

Cancer

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BACKGROUND.The double‐strand break (DSB) repair capacity has been implicated in the survival of patients in several cancer types. However, little is known about the prognostic importance of the key DSB repair genes—ataxia‐telangiectasia mutated (ATM), DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs), and the Ku heterodimeric regulatory complex 86‐kD subunit (Ku80)—in nonsmall cell lung cancer (NSCLC). To address this issue, the authors determined the messenger RNA (mRNA) expression of these genes in patients NSCLC and assessed their prognostic relevance.METHODS.mRNA expression levels of ATM, DNA‐PKcs, and Ku80 were measured in tumor and adjacent normal tissues from 140 patients with NSCLC by using quantitative real‐time polymerase chain reaction analysis. Then, a Cox proportional hazards regression model and Kaplan‐Meier plots were used to evaluate the association between the tumor:normal (T/N) expression ratios of the 3 genes and the overall survival rate and duration in patients with NSCLC.RESULTS.mRNA expression of ATM and DNA‐PKcs, but not of Ku80, was significantly higher in tumor tissues than in adjacent normal tissues (P = .003 and P < .001, respectively). The high T/N expression ratios of ATM and DNA‐PKcs were associated significantly with a 1.82‐fold increased risk of death (95% confidence interval, 1.05–2.70) and a 2.13‐fold increased risk of death (95% confidence interval, 1.21–3.76), respectively. However, no significant association with risk was observed for Ku80. Kaplan‐Meier analyses revealed that patients with high T/N expression ratios of ATM or DNA‐PKcs had notably shorter median survival than patients with low ratios.CONCLUSIONS.The current findings suggested that the T/N expression ratios of ATM and DNA‐PKcs may be useful for identifying NSCLC patients with a poor prognosis who may benefit from more aggressive therapy. Cancer 2008. ©2008 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Prognostic significance of ataxia‐telangiectasia mutated, DNA‐dependent protein kinase catalytic subunit, and Ku heterodimeric regulatory complex 86‐kD subunit expression in patients with nonsmall cell lung cancer

Xing

Vaporciyan

et al. 2008

Cancer

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“…This rationale supports our approach of simultaneously examining the role of three important genes (ATM, BRCA1 and TP53) involved in the DSB checkpoint/repair pathway. Although abnormalities of individual DSB checkpoint/repair genes or proteins have been reported (Waha et al, 1998;Wilson et al, 1999;Angèle et al, 2000), almost all of these have been studied in isolation without considering the common pathway involved. In contrast, in the present study, using a largely homogeneous group of 74 early-onset IDCs and a multigenetic model, we have evaluated the tumorigenic contribution of LOH and/or abnormal expression of these genes.…”

Section: Discussionmentioning

confidence: 99%

Abnormality of the DNA double-strand-break checkpoint/repair genes, ATM, BRCA1 and TP53, in breast cancer is related to tumour grade

Ding

Sheu

et al. 2004

Br J Cancer

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The role of the DNA double-strand-break (DSB) checkpoint/repair genes, ATM, BRCA1 and TP53, in sporadic breast cancer requires clarification, since ATM and BRCA1 mutations are rare in sporadic tumours. In an attempt to explain this phenomenon, we postulated that (i) in addition to genetic deletion, abnormal expression of DSB checkpoint/repair proteins might abolish the function of these genes and (ii) there might be a combined effect of individual defective genes during breast cancer pathogenesis. Using a largely homogenous group of 74 specimens of early-onset (p35 years of age) infiltrating ductal carcinomas, we examined associations between pathological grade and genetic deletion and/or abnormal protein expression of ATM, BRCA1 and TP53. The results showed that high-grade tumours displayed a high frequency of loss of heterozygosity (LOH) at, and/or abnormal expression of, ATM, BRCA1 and TP53. Multigenetic analysis showed abnormalities in BRCA1 to be independently associated with high-grade tumours. ATM and TP53 appeared to play an assistant role, abnormalities in these genes significantly increasing the possibility of poor differentiation in tumours with abnormalities in BRCA1. Furthermore, a higher number of abnormalities (LOH or abnormal expression) in these three genes correlated with poor tumour differentiation. Thus, this study suggests that combined changes in several DSB checkpoint/repair genes belonging to a common functional pathway are associated with breast cancer pathogenesis.

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“…If ATM does indeed have a suppressor role in breast cancer, lost or decreased wild-type ATM expression might reflect or substitute for mutational inactivation. So far, one expression analysis on breast cancer has been reported (39 cases), and this study found a reduction in the mean ATM transcript level in carcinomas vs normal breast tissues (26). However, the basis for the reduced expression was unclear since LOH analysis did not include the ATM gene itself and direct analysis of the PI3 kinase region of ATM failed to detect mutations (26).…”

Section: ^826 Kovalev Et At: Atm Gene Expression Loss Of Heterozygositymentioning

confidence: 71%

“…So far, one expression analysis on breast cancer has been reported (39 cases), and this study found a reduction in the mean ATM transcript level in carcinomas vs normal breast tissues (26). However, the basis for the reduced expression was unclear since LOH analysis did not include the ATM gene itself and direct analysis of the PI3 kinase region of ATM failed to detect mutations (26). With this background, we undertook a comprehensive ATM expression analysis using competitive RT-PCR on 89 randomly selected sporadic breast cancer samples and 29 normal breast tissues.…”

Section: ^826 Kovalev Et At: Atm Gene Expression Loss Of Heterozygositymentioning

confidence: 94%

Risk for Sporadic Breast Cancer in Ataxia Telangiectasia Heterozygotes

Moll¹

2000

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gatnermg ana maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and to the Office of Manaaement and Budget, Scope: The scope of this IDEA grant is to assess whether heterozygosity for the ATM gene, due to a loss of function mutation in one of the 2 alleles and found in about 1% of the general population, confers a significant increase in breast cancer risk for women with sporadic breast cancer (without a family history of breast cancer). This is called the AT -carrier risk hypothesis for sporadic breast cancer. Introduction:The characterization of BRCA1 and BRCA2 gene mutations as high risk factors in familial breast cancer served as paradigm for the assessment of other more common but less penetrant genes as potential genetic risk factors for sporadic breast cancer. The ATM gene is such a candidate, since AT homozygous patients have (among other symptoms) a cancer phenotype and their cells exhibit excessive radiosensitivity. Moreover, AT heterozygote carriers, which occur at a significant prevalence in the general population, show an intermediate in vitro radiosensitivity, although clinically they are free of AT symptoms. Three epidemiological studies, before the ATM gene was cloned had estimated a relative risk of breast cancer in AT heterozygotes of 3.9 (1-4). However, once the ATM gene was cloned, direct mutational analysis on cumulatively over 500 patients failed to support the hypothesis that a mutant ATM allele plays a role in carcinogenesis and that ATM is a suppressor gene (5-7). Also, in the few cancers which harbored a mutant allele (somatically or constitutionally), no selection pressure exists against the retained wild type allele. Moreover, ATM mutations also failed to correlate with complications in those breast cancer patients with complications after radiotherapy (8,9). Clearly, these studies show that diagnostic or occupational exposure to ionizing radiation is not enough to increase the relative risk significantly. LOH analysis in the 1 lq23 region does find a roughly 40% frequency of LOH in the region that includes but does not focus on the ATM locus, thereby leaving it unclear whether the true deletional target is ATM or another unknown suppressor gene(s) thought to reside at this locus.The overall picture that emerges from cytogenetic and mutational studies on over 1,200 breast cancers over the past 1 1/2 years is comprehensive and can be summarized as follows. ATM heterozygosity is not a significant genetic determinant in unselected sporadic breast cancer (10-18). All stu...

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Expression of theATM gene is significantly reduced in sporadic breast carcinomas

Cited by 38 publications

References 15 publications

Prognostic significance of ataxia‐telangiectasia mutated, DNA‐dependent protein kinase catalytic subunit, and Ku heterodimeric regulatory complex 86‐kD subunit expression in patients with nonsmall cell lung cancer

Prognostic significance of ataxia‐telangiectasia mutated, DNA‐dependent protein kinase catalytic subunit, and Ku heterodimeric regulatory complex 86‐kD subunit expression in patients with nonsmall cell lung cancer

Abnormality of the DNA double-strand-break checkpoint/repair genes, ATM, BRCA1 and TP53, in breast cancer is related to tumour grade

Risk for Sporadic Breast Cancer in Ataxia Telangiectasia Heterozygotes

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