Polymorphisms in double strand break repair related genes influence radiosensitivity phenotype in lymphocytes from healthy individuals

Mumbrekar, Kamalesh Dattaram; Venkatesh, Goutham Hassan; Vadhiraja, BM; Sadashiva, Satish Rao Bola

doi:10.1016/j.dnarep.2016.02.006

Cited by 36 publications

(27 citation statements)

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“…Additionally, there is evidence that the DSBs assayed several hours after the initial radiation challenge that still remain unrepaired known as residual DNA damage, may be predictive of individual susceptibility to complex DNA lesions that can be lethal [18]. Current evidence suggests that there is a large inter-individual variation in DSB DNA repair capacity in lymphocytes from healthy individuals [19][20][21]. Further, clinical radiosensitivity is often linked to defects in DNA repair [5,22,23].…”

Section: Introductionmentioning

confidence: 99%

Development of a high-throughput γ-H2AX assay based on imaging flow cytometry

et al. 2019

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Background: Measurement of γ-H2AX foci levels in cells provides a sensitive and reliable method for quantitation of the radiation-induced DNA damage response. The objective of the present study was to develop a rapid, highthroughput γ-H2AX assay based on imaging flow cytometry (IFC) using the ImageStream® X Mk II (ISX) platform to evaluate DNA double strand break (DSB) repair kinetics in human peripheral blood cells after exposure to ionizing irradiation. Methods: The γ-H2AX protocol was developed and optimized for small volumes (100 μL) of human blood in Matrix™ 96-tube format. Blood cell lymphocytes were identified and captured by ISX INSPIRE™ software and analyzed by Data Exploration and Analysis Software. Results: Dose-and time-dependent γ-H2AX levels corresponding to radiation exposure were measured at various time points over 24 h using the IFC system. γ-H2AX fluorescence intensity at 1 h after exposure, increased linearly with increasing radiation dose (R 2 = 0.98) for the four human donors tested, whereas the dose response for the mean number of γ-H2AX foci/cell was not as robust (R 2 = 0.81). Radiation-induced γ-H2AX levels rapidly increased within 30 min and reached a maximum by~1 h, after which time there was fast decline by 6 h, followed by a much slower rate of disappearance up to 24 h. A mathematical approach for quantifying DNA repair kinetics using the rate of γ-H2AX decay (decay constant, K dec), and yield of residual unrepaired breaks (F res) demonstrated differences in individual repair capacity between the healthy donors. Conclusions: The results indicate that the IFC-based γ-H2AX protocol may provide a practical and high-throughput platform for measurements of individual global DNA DSB repair capacity which can facilitate precision medicine by predicting individual radiosensitivity and risk of developing adverse effects related to radiotherapy treatment.

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Section: Introductionmentioning

confidence: 99%

Development of a high-throughput γ-H2AX assay based on imaging flow cytometry

et al. 2019

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“…BRCA2 is a well-known cancer susceptibility gene involved in the repair of double-stranded DNA breaks which functions by regulating the intracellular shuttling and activity of RAD51, another critical protein in homologous recombination [8–10]. Studies have shown that cancer carcinogenesis is related to abnormalities in DNA repair mechanisms partially caused by a change in gene function which can result from genetic polymorphisms [11, 12]. …”

Section: Introductionmentioning

confidence: 99%

Association between theBRCA2rs144848 polymorphism and cancer susceptibility: a meta-analysis

Guan

Qiao

et al. 2017

Oncotarget

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The BRCA2 gene plays an important role in cancer carcinogenesis, and polymorphisms in this gene have been associated with cancer risk. The BRCA2 rs144848 polymorphism has been associated with several cancers, but results have been inconsistent. In the present study, a meta-analysis was performed to assess the association between the rs144848 polymorphism and cancer risk. Literature was searched from the databases of PubMed, Embase and Google Scholar before April 2016. The fixed or random effects model was used to calculate pooled odd ratios on the basis of heterogeneity. Meta-regression, sensitivity analysis, subgroup analysis and publication bias assessment were also performed using STATA 11.0 software according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009. A total of 40 relevant studies from 30 publications including 34,911 cases and 48,329 controls were included in the final meta-analysis. Among them, 22 studies focused on breast cancer, seven on ovarian cancer, five on non-Hodgkin lymphoma, and the remaining six studies examined various other cancers. The meta-analysis results showed that there were significant associations between the rs144848 polymorphism and cancer risk in all genetic models. Stratified by cancer type, the rs144848 polymorphism was associated with non-Hodgkin lymphoma. Stratified by study design, the allele model was associated with breast cancer risk in population-based studies. The meta-analysis suggests that the BRCA2 rs144848 polymorphism may play a role in cancer risk. Further well-designed studies are warranted to confirm these results.

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“…DDR pathway defects may contribute to increased DNA damage in IR-exposed subjects and risk of cancer 7. In addition, disturbances in DDR may be associated with polymorphisms of OGG1 and XRCC1, thus influencing the radiosensitivity phenotype 26. Germline variants in DNA repair genes are associated with risk of thyroid cancer in patients exposed to diagnostic radiation 27.…”

Section: Discussionmentioning

confidence: 99%