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Secondary BRCA1 Mutations in BRCA1-Mutated Ovarian Carcinomas with Platinum Resistance

Departments of ¹ Obstetrics and Gynecology and ² Medicine, University of Washington; Divisions of ³ Human Biology and ⁴ Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; and ⁵ Cedars-Sinai Medical Center, Women's Cancer Research Institute, Los Angeles, California

Requests for reprints: Toshiyasu Taniguchi, Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, C1-015, Seattle, WA 98109-1024. Phone: 206-667-7283; Fax: 206-667-5815; E-mail: ttaniguc{at}fhcrc.org.

Key Words: DNA damage and repair mechanisms • BRCA1 • BRCA2 • cisplatin • drug resistance

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. [Cancer Res 2008;68(8):2581–6]