Related Experiment Video
Updated: May 14, 2026
08:53
Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA1
Published on: February 17, 2011
BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation
Britta Stordal1, Kirsten Timms, Angela Farrelly
1Department of Histopathology, St James' Hospital and Trinity College Dublin, Dublin 8, Ireland. stordalb@tcd.ie
Molecular Oncology
|February 19, 2013
Summary
Ovarian cancer cell lines with BRCA1/2 mutations or methylation show sensitivity to PARP inhibitors. This study characterized BRCA1/2 status in cell lines to aid biomarker development for PARP inhibitor drugs.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Mutations in BRCA1/2 genes significantly elevate breast and ovarian cancer risks.
- Germline BRCA1/2 mutations are found in 8.6–13.7% of epithelial ovarian cancers; somatic mutations are also prevalent.
- BRCA1/2 mutated or dysfunctional cells present potential synthetic lethality vulnerabilities exploitable by PARP inhibition.
Purpose of the Study:
- To comprehensively characterize BRCA1/2 gene status in a large panel of ovarian cancer cell lines.
- To facilitate biomarker studies for novel therapeutics, particularly PARP inhibitors.
- To investigate the impact of BRCA1/2 status on sensitivity to PARP inhibitors olaparib and veliparib.
Main Methods:
- Sequencing of BRCA1/2 genes in 41 ovarian cancer cell lines.
- Analysis of BRCA1/2 mRNA expression and BRCA1 methylation status.
- Cytotoxicity assays evaluating olaparib and veliparib in 20 cell lines.
Main Results:
- Only one cell line (SNU-251) exhibited a deleterious BRCA1 mutation; two lines (UPN-251, PEO1) had reversion mutations restoring protein function.
- Heterozygous BRCA1/2 mutations were observed in 14.6% of cell lines.
- BRCA1-methylated cell lines demonstrated increased sensitivity to PARP inhibition compared to wild-type cells.
- Metastatic cell lines showed significantly higher resistance to veliparib than primary tumor-derived lines.
- Olaparib and veliparib resistance correlated significantly.
Conclusions:
- The incidence of deleterious BRCA1/2 mutations in cell lines (3.0%) is lower than in the general population, suggesting in vitro selective pressure.
- Reversion mutations and frequent heterozygous mutations indicate selective pressures against BRCA1/2 in cell culture.
- PARP inhibitors may offer therapeutic benefits for ovarian cancer patients with BRCA1 deleterious mutations or gene methylation.
More Related Videos
Related Concept Videos
01:20The Retinoblastoma Gene
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
02:21Cancers Originate from Somatic Mutations in a Single Cell
Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...
01:12Loss of Tumor Suppressor Gene Functions
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...