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Secondary BRCA1 Mutations in BRCA1-Mutated Ovarian carcinomas with platinum resistance.

Swisher, Elizabeth M. and Sakai, Wataru and Karlan, Beth Y. and Wurz, Kaitlyn and Urban, Nicole and Taniguchi, Toshiyasu (2008) Secondary BRCA1 Mutations in BRCA1-Mutated Ovarian carcinomas with platinum resistance. Cancer Research, 68 (8). pp. 2581-2586. ISSN 1538-7445

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Although ovarian carcinomas with mutated BRCA1 or BRCA2 are sensitive to platinum compounds, such carcinomas eventually develop platinum resistance. Previously, we showed that acquired resistance to cisplatin in BRCA2-mutated tumors can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. Here, we show that secondary mutations of BRCA1 also occur in BRCA1-mutated ovarian cancer with platinum resistance. We evaluated nine recurrent BRCA1-mutated ovarian cancers previously treated with platinum compounds, including five with acquired platinum resistance, one with primary platinum resistance, and three with platinum sensitivity. Four of the six recurrent platinum-resistant tumors had developed secondary genetic changes in BRCA1 that restored the reading frame of the BRCA1 protein, whereas none of the three platinum-sensitive recurrent tumors developed BRCA1 sequence alterations. We immunohistochemically confirmed restored expression of BRCA1 protein in two cases with secondary mutations. Intriguingly, the case with primary platinum resistance showed back mutation of BRCA1 in the primary tumor and showed another secondary mutation in the recurrent tumor. Our results suggest that secondary mutations in BRCA1 can mediate resistance to platinum in BRCA1-mutated ovarian tumors.

Item Type: Article or Abstract
Additional Information: This article is available to subscribers only via the URL above for the first 12 months post-publication.
DOI: 10.1158/0008-5472.CAN-08-0088
PubMed ID: 18413725
PMCID: PMC2674369
Grant Numbers: R01 CA125636-02, K08 CA096610-01
Keywords or MeSH Headings: Antineoplastic Agents/therapeutic use* BRCA1 Protein/genetics* BRCA1 Protein/metabolism Cisplatin/therapeutic use DNA, Neoplasm/genetics DNA, Neoplasm/isolation & purification Drug Resistance, Neoplasm* Female Humans Immunohistochemistry Models, Genetic Mutation* Ovarian Neoplasms/genetics* Platinum Compounds/therapeutic use* Polymerase Chain Reaction
Subjects: Cellular and Organismal Processes > Genetic processes > Mutation
Diseases > Solid tumors > Ovarian cancer
Therapeutics > Drug Therapy
Depositing User: authors@FHCRC Administrator-Import
Date Deposited: 03 Oct 2008 22:57
Last Modified: 14 Feb 2012 14:42

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