Mutation analysis of BRCA1 and BRCA2 cancer predisposition genes in radiation hypersensitive cancer patients

Leong, Trevor; Whitty, Jonathan; Keilar, Michelle; Mifsud, Sharon; Ramsay, Jonathan; Birrell, Geoffrey W.; Venter, Deon J.; Southey, Melissa C.; McKay, Michael J.

doi:10.1016/s0360-3016(00)00728-8

Cited by 61 publications

(41 citation statements)

References 39 publications

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“…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: 94%

“…These transformed lymphocytes were propagated as described (Leong et al, 2000) to provide an accessible source of protein extracts.…”

Section: Lymphoblastoid Cell Linesmentioning

confidence: 99%

“…Various approaches might be considered in attempts to unravel the molecular basis of clinical radiosensitivity. These include screening candidate radiosensitivity genes for mutations (Leong et al, 2000;Severin et al, 2001), adopting functional genomics approaches (e.g. using DNA microarrays) or, as adopted here, screening for abnormalities in key candidate proteins.…”

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confidence: 99%

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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: 94%

“…These transformed lymphocytes were propagated as described (Leong et al, 2000) to provide an accessible source of protein extracts.…”

Section: Lymphoblastoid Cell Linesmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…We and others have taken different approaches in an attempt to discern which genes may be responsible. One is a candidate molecule approach, where dysfunction of genes and their products or regulators linked to radiosensitivity in other contexts/organisms, are tested for dysfunction in RS cancer patients (6)(7)(8)(9)(10). Another are genome-wide association studies (11), which to date have yielded some radiosensitivity susceptibility loci/genes, e.g., TANC1 (12).…”

Section: Introductionmentioning

confidence: 99%

Non-homologous end-joining protein expression screen from radiosensitive cancer patients yields a novel DNA double strand break repair phenotype

et al. 2017

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Background: Clinical radiosensitivity is a significant impediment to tumour control and cure, in that it restricts the total doses which can safely be delivered to the whole radiotherapy population, within the tissue tolerance of potentially radiosensitive (RS) individuals. Understanding its causes could lead to personalization of radiotherapy. Methods:We screened tissues from a unique bank of RS cancer patients for expression defects in major DNA double-strand break repair proteins, using Western blot analysis and subsequently reverse-transcriptase polymerase chain reaction and pulsed-field gel electrophoresis.Results: We hypothesized that abnormalities in expression of these proteins may explain the radiosensitivity of some of our cancer patients. The cells from one patient showed a reproducibly consistent expression reduction in two complex-forming DNA double-strand break repair protein components (DNA Ligase IV and XRCC4). We also showed a corresponding reduction in both gene products at the mRNA level. Additionally, the mRNA inducibility by ionizing radiation was increased for one of the proteins in the patient's cells. We confirmed the likely functional significance of the non-homologous end-joining (NHEJ) expression abnormalities with a DNA double strand break (DNA DSB) repair assay. Conclusions:We have identified a novel biological phenotype linked to clinical radiosensitivity. This is important in that very few molecular defects are known in human radiotherapy subjects. Such knowledge may contribute to the understanding of radiation response mechanisms in cancer patients and to personalization of radiotherapy.

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“…Indeed cellular clonogenic assays in cells derived from BRCA1 and BRCA2 heterozygotes reveal elevated radiosensitivity and chromosome aberrations when compared to cells derived from normal individuals, which is suggestive of a haplo-insufficient phenotype [13]. However, clinical evidence suggests that heterozygotes for both BRCA1 and BRCA2 do not experience abnormally severe NTT [14].…”

Section: Introductionmentioning

confidence: 96%

Hypersensitivity of BRCA1 Heterozygote Lymphoblastoid Cells to Gamma Radiation and PARP Inhibitors

EC¹,

HA²

2013

J Genet Syndr Gene Ther

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PARP inhibitors can be used to induce synthetic lethality in cells with bi-allelic BRCA1 and BRCA2 mutations. However the effect of PARP inhibitors in combination with radiation on cells with mono-allelic mutations of BRCA1 and BRCA2 is unknown. We have examined the cell survival response of lymphoblastoid cells derived from normal individuals and those derived from carriers of BRCA1 and BRCA2 mutations, following exposure to ionising radiation and the PARP inhibitor Olaparib.Two lymphoblastoid cell lines from normal individuals and three with mono-allelic mutations in BRCA1 and BRCA2 were exposed to increasing doses of gamma radiation either alone or in combination with 5 µM Olaparib. Cell survival was measured using the MTT assay.Exposure to increasing doses of gamma radiation caused a reduction in cell survival of all cell types. The combined exposure to gamma radiation and 5 µM Olaparib did not enhance cell kill in normal or BRCA2 heterozygote lymphoblastoid cells but significantly enhanced cell kill in cells derived from BRCA1 carriers (P = 0.02). The treatment of cancer patients carrying mutations in the BRCA1 gene with radiotherapy and the PARP inhibitor Olaparib may significantly enhance radiation induced normal tissue toxicity in these patients.Citation: Bourton EC, Foster HA, Plowman PN, Harvey AJ, Parris CN (2013) Hypersensitivity of BRCA1 Heterozygote Lymphoblastoid Cells to Gamma Radiation and PARP Inhibitors.

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Mutation analysis of BRCA1 and BRCA2 cancer predisposition genes in radiation hypersensitive cancer patients

Cited by 61 publications

References 39 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

Non-homologous end-joining protein expression screen from radiosensitive cancer patients yields a novel DNA double strand break repair phenotype

Hypersensitivity of BRCA1 Heterozygote Lymphoblastoid Cells to Gamma Radiation and PARP Inhibitors

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