BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation.
dc.contributor.author | Stordal, Britta | |
dc.contributor.author | Timms, Kirsten | |
dc.contributor.author | Farrelly, Angela | |
dc.contributor.author | Gallagher, Danielle | |
dc.contributor.author | Busschots, Steven | |
dc.contributor.author | Renaud, Mickaël | |
dc.contributor.author | Thery, Julien | |
dc.contributor.author | Williams, Deborah | |
dc.contributor.author | Potter, Jennifer | |
dc.contributor.author | Tran, Thanh | |
dc.contributor.author | Korpanty, Greg | |
dc.contributor.author | Cremona, Mattia | |
dc.contributor.author | Carey, Mark | |
dc.contributor.author | Li, Jie | |
dc.contributor.author | Li, Yang | |
dc.contributor.author | Aslan, Ozlem | |
dc.contributor.author | O'Leary, John J | |
dc.contributor.author | Mills, Gordon B | |
dc.contributor.author | Hennessy, Bryan T | |
dc.date.accessioned | 2014-08-01T08:50:15Z | |
dc.date.available | 2014-08-01T08:50:15Z | |
dc.date.issued | 2013-06 | |
dc.identifier.citation | Sotrdal B et al. BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation. Mol Oncol 2013, 7 (3):567-79 | en_GB |
dc.identifier.issn | 1878-0261 | |
dc.identifier.pmid | 23415752 | |
dc.identifier.doi | 10.1016/j.molonc.2012.12.007 | |
dc.identifier.uri | http://hdl.handle.net/10147/324083 | |
dc.description.abstract | Mutations in BRCA1/2 increase the risk of developing breast and ovarian cancer. Germline BRCA1/2 mutations occur in 8.6-13.7% of unselected epithelial ovarian cancers, somatic mutations are also frequent. BRCA1/2 mutated or dysfunctional cells may be sensitive to PARP inhibition by synthetic lethality. The aim of this study is to comprehensively characterise the BRCA1/2 status of a large panel of ovarian cancer cell lines available to the research community to assist in biomarker studies of novel drugs and in particular of PARP inhibitors. The BRCA1/2 genes were sequenced in 41 ovarian cell lines, mRNA expression of BRCA1/2 and gene methylation status of BRCA1 was also examined. The cytotoxicity of PARP inhibitors olaparib and veliparib was examined in 20 cell lines. The cell line SNU-251 has a deleterious BRCA1 mutation at 5564G > A, and is the only deleterious BRCA1/2 mutant in the panel. Two cell lines (UPN-251 and PEO1) had deleterious mutations as well as additional reversion mutations that restored the protein functionality. Heterozygous mutations in BRCA1/2 were relatively common, found in 14.6% of cell lines. BRCA1 was methylated in two cell lines (OVCAR8, A1847) and there was a corresponding decrease in gene expression. The BRCA1 methylated cell lines were more sensitive to PARP inhibition than wild-type cells. The SNU-251 deleterious mutant was more sensitive to PARP inhibition, but only in a long-term exposure to correct for its slow growth rate. Cell lines derived from metastatic disease are significantly more resistant to veliparib (2.0 fold p = 0.03) compared to those derived from primary tumours. Resistance to olaparib and veliparib was correlated Pearsons-R 0.5393, p = 0.0311. The incidence of BRCA1/2 deleterious mutations 1/41 cell lines derived from 33 different patients (3.0%) is much lower than the population incidence. The reversion mutations and high frequency of heterozygous mutations suggest that there is a selective pressure against BRCA1/2 in cell culture similar to the selective pressure seen in the clinic after treatment with chemotherapy. PARP inhibitors may be useful in patients with BRCA1 deleterious mutations or gene methylation. | |
dc.language.iso | en | en |
dc.rights | Archived with thanks to Molecular oncology | en_GB |
dc.subject | CANCER | en_GB |
dc.subject | GENETICS | en_GB |
dc.subject | BREAST CANCER | en_GB |
dc.subject | OVARIAN CANCER | en_GB |
dc.subject.mesh | Antineoplastic Agents | |
dc.subject.mesh | BRCA1 Protein | |
dc.subject.mesh | BRCA2 Protein | |
dc.subject.mesh | Base Sequence | |
dc.subject.mesh | Cell Line, Tumor | |
dc.subject.mesh | DNA Methylation | |
dc.subject.mesh | DNA Mutational Analysis | |
dc.subject.mesh | Drug Resistance, Neoplasm | |
dc.subject.mesh | Female | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Loss of Heterozygosity | |
dc.subject.mesh | Mutation | |
dc.subject.mesh | Ovarian Neoplasms | |
dc.subject.mesh | Ovary | |
dc.subject.mesh | Poly(ADP-ribose) Polymerases | |
dc.subject.other | ONCOLOGY | en_GB |
dc.title | BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation. | en_GB |
dc.type | Article | en |
dc.contributor.department | Department of Histopathology, St James' Hospital and Trinity College Dublin, Dublin 8, Ireland. stordalb@tcd.ie | en_GB |
dc.identifier.journal | Molecular oncology | en_GB |
dc.description.funding | Other | en |
dc.description.province | Leinster | en |
dc.description.peer-review | peer-review | en |
refterms.dateFOA | 2018-08-24T14:37:05Z | |
html.description.abstract | Mutations in BRCA1/2 increase the risk of developing breast and ovarian cancer. Germline BRCA1/2 mutations occur in 8.6-13.7% of unselected epithelial ovarian cancers, somatic mutations are also frequent. BRCA1/2 mutated or dysfunctional cells may be sensitive to PARP inhibition by synthetic lethality. The aim of this study is to comprehensively characterise the BRCA1/2 status of a large panel of ovarian cancer cell lines available to the research community to assist in biomarker studies of novel drugs and in particular of PARP inhibitors. The BRCA1/2 genes were sequenced in 41 ovarian cell lines, mRNA expression of BRCA1/2 and gene methylation status of BRCA1 was also examined. The cytotoxicity of PARP inhibitors olaparib and veliparib was examined in 20 cell lines. The cell line SNU-251 has a deleterious BRCA1 mutation at 5564G > A, and is the only deleterious BRCA1/2 mutant in the panel. Two cell lines (UPN-251 and PEO1) had deleterious mutations as well as additional reversion mutations that restored the protein functionality. Heterozygous mutations in BRCA1/2 were relatively common, found in 14.6% of cell lines. BRCA1 was methylated in two cell lines (OVCAR8, A1847) and there was a corresponding decrease in gene expression. The BRCA1 methylated cell lines were more sensitive to PARP inhibition than wild-type cells. The SNU-251 deleterious mutant was more sensitive to PARP inhibition, but only in a long-term exposure to correct for its slow growth rate. Cell lines derived from metastatic disease are significantly more resistant to veliparib (2.0 fold p = 0.03) compared to those derived from primary tumours. Resistance to olaparib and veliparib was correlated Pearsons-R 0.5393, p = 0.0311. The incidence of BRCA1/2 deleterious mutations 1/41 cell lines derived from 33 different patients (3.0%) is much lower than the population incidence. The reversion mutations and high frequency of heterozygous mutations suggest that there is a selective pressure against BRCA1/2 in cell culture similar to the selective pressure seen in the clinic after treatment with chemotherapy. PARP inhibitors may be useful in patients with BRCA1 deleterious mutations or gene methylation. |