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

详细信息    查看全文

• 作者：Britta Stordal^a ; ^{stordalb@tcd.ie} ; Kirsten Timms^b ; ^{ktimms@myriad.com} ; Angela Farrelly^c ; ^{angelafarrelly@rcsi.ie} ; Danielle Gallagher^c ; ^{daniellegallagher@rcsi.ie} ; Steven Busschots^a ; ^{busschos@tcd.ie} ; Mickaë ; l Renaud^c ; ^{renaud.mickael@yahoo.fr} ; Julien Thery^a ; ^{julien-thery@orange.fr} ; Deborah Williams^b ; ^{dtrem@myriad.com} ; Jennifer Potter^b ; ^{jpotter@myriad.com} ; Thanh Tran^b ; ^{thanh@myriad.com} ; Greg Korpanty^d ; ^{greg.korpanty@gmail.com} ; Mattia Cremona^c ; ^{mattiacremona@rcsi.ie} ; Mark Carey^e ; ^{Mark.carey@vch.ca} ; Jie Li^e ; ^{jane.li@mdanderson.org} ; Yang Li^e ; ^{yli2@mdanderson.org} ; Ozlem Aslan^c ; ^{ozlemaslan@rcsi.ie} ; John J. O'Leary^a ; ^{olearyjj@tcd.ie} ; Gordon B. Mills^e ; ¹ ; ^{gmills@mdanderson.org} ; Bryan T. Hennessy^c ; ^d ; ^e ; ¹ ; ^{bryanhennessy74@gmail.com}
• 关键词：BRCA1/2 ; Ovarian ; Mutation ; Methylation ; Parp inhibitor ; Olaparib ; Veliparib
• 刊名：Molecular Oncology
• 出版年：2013
• 出版时间：June, 2013
• 年：2013
• 卷：7
• 期：3
• 页码：567-579
• 全文大小：671 K

文摘

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.