BRCA1/2 mutation analysis in 43 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation

Stordal, Britta K. ORCID: https://orcid.org/0000-0002-7892-951X, Timms, Kirsten M., Renuad, Mickael, Thery, Julien, Farrelly, Angela, Williams, Deborah, Potter, Jennifer, Tran, Thanh, Korpanty, Greg, Cremona, Mattia, Carey, Mark S., Li, Jane, Li, Yang, Aslan, Ozlem, O'Leary, John J., Mills, Gordon B. and Hennessy, Bryan T. (2012) BRCA1/2 mutation analysis in 43 ovarian cell lines reveals only one functionally deleterious BRCA1 mutation. Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl). In: 103rd Annual Meeting of the American Association for Cancer Research (AACR), 31 Mar - 04 Apr 2012, Chicago. . [Conference or Workshop Item] (doi:10.1158/1538-7445.AM2012-78)

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Abstract

Introduction: Germline mutations in DNA repair genes 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 inhibition of two major DNA repair pathways. Therefore, there is a need to characterize ovarian cell lines for their BRCA1/2 status for in vitro studies of novel drugs. Methods: The BRCA1/2 genes were sequenced in 43 ovarian cell lines, mRNA expression of BRCA1/2 and gene methylation of BRCA1 were also examined. The cytotoxicity of PARP inhibitors olaparib and veliparib was examined in 10 cell lines. Results: Sequencing of BRCA1/2 revealed 18 and 33 different alterations respectively, mostly non-pathogenic polymorphisms. 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 which restore the function of the protein. BRCA1 was methylated in three cell lines (A1847, OVCAR8, EF021) and there was a corresponding decrease in gene expression in these cell lines. The deleterious mutant SNU-251 was relatively resistant to PARP inhibition, compared to wild-type cells. However, the methylated cell lines A1847 and OVCAR8 were more sensitive to PARP inhibition than wild-type cells. Conclusions: The incidence of BRCA1/2 deleterious mutations 1/43 cell lines (2.3%) is much lower than the population incidence. The reversion mutations suggest that there is a selective pressure against BRCA1/2 mutations in cell culture. PARP inhibitors may be useful in patients with BRCA1 methylation and reduced gene expression in their ovarian tumour.

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