BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation.

Hdl Handle:
http://hdl.handle.net/10147/324083
Title:
BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation.
Authors:
Stordal, Britta; Timms, Kirsten; Farrelly, Angela; Gallagher, Danielle; Busschots, Steven; Renaud, Mickaël; Thery, Julien; Williams, Deborah; Potter, Jennifer; Tran, Thanh; Korpanty, Greg; Cremona, Mattia; Carey, Mark; Li, Jie; Li, Yang; Aslan, Ozlem; O'Leary, John J; Mills, Gordon B; Hennessy, Bryan T
Affiliation:
Department of Histopathology, St James' Hospital and Trinity College Dublin, Dublin 8, Ireland. stordalb@tcd.ie
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
Journal:
Molecular oncology
Issue Date:
Jun-2013
URI:
http://hdl.handle.net/10147/324083
DOI:
10.1016/j.molonc.2012.12.007
PubMed ID:
23415752
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.
Item Type:
Article
Language:
en
Keywords:
CANCER; GENETICS; BREAST CANCER; OVARIAN CANCER
Local subject classification:
ONCOLOGY
MeSH:
Antineoplastic Agents; BRCA1 Protein; BRCA2 Protein; Base Sequence; Cell Line, Tumor; DNA Methylation; DNA Mutational Analysis; Drug Resistance, Neoplasm; Female; Humans; Loss of Heterozygosity; Mutation; Ovarian Neoplasms; Ovary; Poly(ADP-ribose) Polymerases
ISSN:
1878-0261

Full metadata record

DC FieldValue Language
dc.contributor.authorStordal, Brittaen_GB
dc.contributor.authorTimms, Kirstenen_GB
dc.contributor.authorFarrelly, Angelaen_GB
dc.contributor.authorGallagher, Danielleen_GB
dc.contributor.authorBusschots, Stevenen_GB
dc.contributor.authorRenaud, Mickaëlen_GB
dc.contributor.authorThery, Julienen_GB
dc.contributor.authorWilliams, Deborahen_GB
dc.contributor.authorPotter, Jenniferen_GB
dc.contributor.authorTran, Thanhen_GB
dc.contributor.authorKorpanty, Gregen_GB
dc.contributor.authorCremona, Mattiaen_GB
dc.contributor.authorCarey, Marken_GB
dc.contributor.authorLi, Jieen_GB
dc.contributor.authorLi, Yangen_GB
dc.contributor.authorAslan, Ozlemen_GB
dc.contributor.authorO'Leary, John Jen_GB
dc.contributor.authorMills, Gordon Ben_GB
dc.contributor.authorHennessy, Bryan Ten_GB
dc.date.accessioned2014-08-01T08:50:15Z-
dc.date.available2014-08-01T08:50:15Z-
dc.date.issued2013-06-
dc.identifier.citationSotrdal B et al. BRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation. Mol Oncol 2013, 7 (3):567-79en_GB
dc.identifier.issn1878-0261-
dc.identifier.pmid23415752-
dc.identifier.doi10.1016/j.molonc.2012.12.007-
dc.identifier.urihttp://hdl.handle.net/10147/324083-
dc.description.abstractMutations 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.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to Molecular oncologyen_GB
dc.subjectCANCERen_GB
dc.subjectGENETICSen_GB
dc.subjectBREAST CANCERen_GB
dc.subjectOVARIAN CANCERen_GB
dc.subject.meshAntineoplastic Agents-
dc.subject.meshBRCA1 Protein-
dc.subject.meshBRCA2 Protein-
dc.subject.meshBase Sequence-
dc.subject.meshCell Line, Tumor-
dc.subject.meshDNA Methylation-
dc.subject.meshDNA Mutational Analysis-
dc.subject.meshDrug Resistance, Neoplasm-
dc.subject.meshFemale-
dc.subject.meshHumans-
dc.subject.meshLoss of Heterozygosity-
dc.subject.meshMutation-
dc.subject.meshOvarian Neoplasms-
dc.subject.meshOvary-
dc.subject.meshPoly(ADP-ribose) Polymerases-
dc.subject.otherONCOLOGYen_GB
dc.titleBRCA1/2 mutation analysis in 41 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation.en_GB
dc.typeArticleen
dc.contributor.departmentDepartment of Histopathology, St James' Hospital and Trinity College Dublin, Dublin 8, Ireland. stordalb@tcd.ieen_GB
dc.identifier.journalMolecular oncologyen_GB
dc.description.fundingOtheren
dc.description.provinceLeinsteren
dc.description.peer-reviewpeer-reviewen

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