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

EC, Bourton; HA, Foster

doi:10.4172/2157-7412.1000146

J Genet Syndr Gene Ther

2013

DOI: 10.4172/2157-7412.1000146

|View full text |Cite

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

Bourton EC¹,

Foster HA²

Abstract: 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… Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...

Citation Types

Supporting

Mentioning

Contrasting

Year Published

2013

2020

Publication Types

Select...

Article2

Relationship

Self Cite0

Independent2

Authors

Journals

Cited by 2 publications

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Genome-Wide Gene Expression Analyses of BRCA1- and BRCA2-Associated Breast and Ovarian Tumours

Wiggins

Walker

Pearson

2020

Cancers

View full text Add to dashboard Cite

Germline pathogenic variants in BRCA1 and BRCA2 increase cumulative lifetime risk up to 75% for breast cancer and 76% for ovarian cancer. Genetic testing for BRCA1 and BRCA2 pathogenic variants has become an important part of clinical practice for cancer risk assessment and for reducing individual risk of developing cancer. Genetic testing can produce three outcomes: positive (a pathogenic variant), uninformative (no pathogenic variant) and uncertain significance (a variant of unknown clinical significance). More than one third of BRCA1 and BRCA2 variants identified have been classified as variants of uncertain significance, presenting a challenge for clinicians. To address this important clinical challenge, a number of studies have been undertaken to establish a gene expression phenotype for pathogenic BRCA1 and BRCA2 variant carriers in several diseased and normal tissues. However, the consistency of gene expression phenotypes described in studies has been poor. To determine if gene expression analysis has been a successful approach for variant classification, we describe the design and comparability of 23 published gene expression studies that have profiled cells from BRCA1 and BRCA2 pathogenic variant carriers. We show the impact of advancements in expression-based technologies, the importance of developing larger study cohorts and the necessity to better understand variables affecting gene expression profiles across different tissue types.

show abstract

Genome-Wide Gene Expression Analyses of BRCA1- and BRCA2-Associated Breast and Ovarian Tumours

Wiggins

Walker

Pearson

2020

Cancers

View full text Add to dashboard Cite

show abstract

The PARP-1 Inhibitor Olaparib Causes Retention of γ-H2AX Foci in <i>BRCA</i>1 Heterozygote Cells Following Exposure to Gamma Radiation

Bourton¹,

Plowman²,

Harvey³

et al. 2013

JCT

View full text Add to dashboard Cite

A novel treatment for cancer patients with homozygous deletions of BRCA1 and BRCA2 is to use drugs that inhibit the enzyme poly(ADP-ribose) polymerase (PARP). Specific inhibition of PARP-1 can induce synthetic lethality in irradiated cancer cells while theoretically leaving normal tissue unaffected. We recently demonstrated in a cell survival assay that lymphoblastoid cells with mono-allelic mutations of BRCA1 were hypersensitive to gamma radiation in the presence of the PARP-1 inhibitor Olaparib compared to normal cells and mono-allelic BRCA2 cells. To determine if the enhanced radiation sensitivity was due to a persistence of DNA strand breaks, we performed γ-H2AX foci analysis in cells derived from two normal individuals, three heterozygous BRCA1 and three heterozygous BRCA2 cell lines. Cells were exposed to 2 Gy gamma radiation in the presence or absence of 5 µM Olaparib. Using immunofluorescence and imaging flow cytometry, foci were measured in untreated cells and at 0.5, 3, 5 and 24 hours post-irradiation. In all lymphoblastoid cells treated with 2 Gy gamma radiation, there was a predictable induction of DNA strand breaks, with a modest but significant retention of foci over 24 hours in irradiated cells treated with Olaparib (ANOVA P < 0.05). However, in mono-allelic BRCA1 cells, there was a failure to fully repair DNA double-strand breaks (DSB) in the presence of Olaparib, evidenced by a significant retention of foci at 24 hours' post irradiation (t-Test P < 0.05). These data show that the cellular hypersensitivity of mono-allelic BRCA1 lymphoblastoid cells to gamma radiation in the presence of the Olaparib is due to the retention of DNA DSB. These data may indicate that patients with inherited mutations in the BRCA1 gene treated with radiotherapy and PARP-1 inhibitors may experience elevated radiation-associated normal tissue toxicity.

show abstract

scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.

Contact Info

hi@scite.ai

10624 S. Eastern Ave., Ste. A-614

Henderson, NV 89052, USA

Blog Terms and Conditions API Terms Privacy Policy Contact Cookie Preferences Do Not Sell or Share My Personal Information

Made with 💙 for researchers

Part of the Research Solutions Family.

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

Cited by 2 publications

References 21 publications

Genome-Wide Gene Expression Analyses of BRCA1- and BRCA2-Associated Breast and Ovarian Tumours

Genome-Wide Gene Expression Analyses of BRCA1- and BRCA2-Associated Breast and Ovarian Tumours

The PARP-1 Inhibitor Olaparib Causes Retention of γ-H2AX Foci in <i>BRCA</i>1 Heterozygote Cells Following Exposure to Gamma Radiation

Contact Info

Product

Resources

About

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

Cited by 2 publications

References 21 publications

Genome-Wide Gene Expression Analyses of BRCA1- and BRCA2-Associated Breast and Ovarian Tumours

Genome-Wide Gene Expression Analyses of BRCA1- and BRCA2-Associated Breast and Ovarian Tumours

The PARP-1 Inhibitor Olaparib Causes Retention of γ-H2AX Foci in &lt;i&gt;BRCA&lt;/i&gt;1 Heterozygote Cells Following Exposure to Gamma Radiation

Contact Info

Product

Resources

About

The PARP-1 Inhibitor Olaparib Causes Retention of γ-H2AX Foci in <i>BRCA</i>1 Heterozygote Cells Following Exposure to Gamma Radiation