Testing for mutations of the ataxia telangiectasia gene in radiosensitive breast cancer patients

Ramsay, Jonathan; Birrell, Geoffrey W.; Lavin, Martin F.

doi:10.1016/s0167-8140(98)00014-0

Cited by 63 publications

(27 citation statements)

References 9 publications

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“…Screening for heterozygous mutations in the gene homozygously mutated in the cancer-prone, radiosensitivity disorder, ataxia-telangiectasia (ATM: AT mutated) in radiosensitive patients has been vigorously pursued during the past few years. However, data from several studies suggest that ATM gene defects are not a major cause of radiation hypersensitivity (Appleby et al, 1997;Clarke et al, 1998;Hall et al, 1998;Ramsay et al, 1998;Shayeghi et al, 1998;Oppitz et al, 1999). We have previously reported the results of mutation analysis of BRCA1 and BRCA2 cancer predisposition genes in a cohort of radiationhypersensitive cancer patients (Leong et al, 2000).…”

Section: Discussionmentioning

confidence: 95%

Radiation-hypersensitive cancer patients do not manifest protein expression abnormalities in components of the nonhomologous end-joining (NHEJ) pathway

et al. 2003

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Radiation therapy (RT) is utilised for the treatment of around half of all oncology patients during the course of their illness. Despite great clinical progress in the rational deployment of RT, the underlying molecular basis for its efficacy and toxicity are currently imperfectly understood. In this study, we took a biochemical approach to evaluate the potential role of key ionising radiation repair proteins in the treatment outcomes of patients with severe acute or late RT side effects. Lymphoblastoid cell lines were established from blood samples from 36 radiosensitive cases and a number of controls (the latter had had RT but did not develop significant toxicity). The expression level and migration of key proteins from the nonhomologous end-joining (NHEJ) pathway was evaluated by Western blot analysis on cases and controls. We did not observe any abnormalities in expression level or migration pattern of the following NHEJ proteins in radiosensitive cancer cases: Ku70, Ku80, XRCC4, DNA Ligase IV. These important negative results provide evidence that mutations that affect protein expression of these NHEJ components are unlikely to underlie clinical radiation sensitivity.

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Section: Discussionmentioning

confidence: 95%

Radiation-hypersensitive cancer patients do not manifest protein expression abnormalities in components of the nonhomologous end-joining (NHEJ) pathway

et al. 2003

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“…Heterozygosity for mutations in ATM, the gene mutated in AT, may occur in 1% of individuals and has been reported to confer moderate sensitivity to IR in tissue culture (9). However, relatively few adverse radiation reactions are associated with ATM mutations (10)(11)(12).…”

mentioning

confidence: 99%

Toxicity from radiation therapy associated with abnormal transcriptional responses to DNA damage

Rieger

Hong

Tusher

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

112

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Toxicity from radiation therapy is a grave problem for cancer patients. We hypothesized that some cases of toxicity are associated with abnormal transcriptional responses to radiation. We used microarrays to measure responses to ionizing and UV radiation in lymphoblastoid cells derived from 14 patients with acute radiation toxicity. The analysis used heterogeneity-associated transformation of the data to account for a clinical outcome arising from more than one underlying cause. To compute the risk of toxicity for each patient, we applied nearest shrunken centroids, a method that identifies and cross-validates predictive genes. Transcriptional responses in 24 genes predicted radiation toxicity in 9 of 14 patients with no false positives among 43 controls (P ‫؍‬ 2.2 ؋ 10 ؊7 ). The responses of these nine patients displayed significant heterogeneity. Of the five patients with toxicity and normal responses, two were treated with protocols that proved to be highly toxic. These results may enable physicians to predict toxicity and tailor treatment for individual patients.

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“…Nevertheless, many studies have failed to confirm the role of AT-causing mutations in breast cancer development and concluded that their contribution to familial breast cancer is minimal [51,52]. The studies that were focused on early onset or increased radiosensitivity breast cancer failed to provide evidence of increased frequency of ATM mutations compared to control subjects [53,54]. Other studies found a higher rate of amino acid substitutions in ATM in patients with breast cancer [52,55].…”

Section: Atm and Familial Breast Cancermentioning

confidence: 99%

The role of ATM in breast cancer development

Prokopcova

Kleibl

Banwell

et al. 2006

Breast Cancer Res Treat

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Complete or partial inability to sense and repair DNA damage increases the risk of developing cancer. The ataxia telangiectasia mutated (ATM) protein kinase has a crucial role in response to DNA double-strand breaks. Hereditary mutations in the ATM gene are the cause of a rare genomic instability syndrome ataxia telangiectasia (AT) characterized, among others, by elevated cancer risk. Although clear in homozygotes, numerous studies have failed to find a link between heterozygotes and cancer. However, there is increasing evidence that ATM heterozygotes have an increased risk of developing breast cancer. First, epidemiological studies conferred an increased risk of breast cancer among AT relatives. Second, in vitro studies of heterozygous cells provide strong evidence of hyperradiosensitivity. Third, some clinical studies found an increased frequency of ATM mutations among high-risk breast cancer families.

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Testing for mutations of the ataxia telangiectasia gene in radiosensitive breast cancer patients

Cited by 63 publications

References 9 publications

Radiation-hypersensitive cancer patients do not manifest protein expression abnormalities in components of the nonhomologous end-joining (NHEJ) pathway

Radiation-hypersensitive cancer patients do not manifest protein expression abnormalities in components of the nonhomologous end-joining (NHEJ) pathway

Toxicity from radiation therapy associated with abnormal transcriptional responses to DNA damage

The role of ATM in breast cancer development

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