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Nature 451, 1116-1120 (28 February 2008) | doi:10.1038/nature06633; Received 12 July 2007; Accepted 3 January 2008; Published online 10 February 2008

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Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers

Wataru Sakai1,2, Elizabeth M. Swisher3,4, Beth Y. Karlan5, Mukesh K. Agarwal6, Jake Higgins4,7, Cynthia Friedman1, Emily Villegas1,2, Céline Jacquemont1,2, Daniel J. Farrugia6, Fergus J. Couch6, Nicole Urban2 & Toshiyasu Taniguchi1,2

  1. Division of Human Biology,
  2. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA
  3. Department of Obstetrics and Gynecology,
  4. Department of Medicine, University of Washington, Seattle, Washington 98195-7720, USA
  5. Cedars-Sinai Medical Center, Women's Cancer Research Institute, Los Angeles, California 90048-1865, USA
  6. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA
  7. Department of Genome Sciences, University of Washington, Seattle, Washington 98195-7720, USA

Correspondence to: Toshiyasu Taniguchi1,2 Correspondence and requests for materials should be addressed to T.T. (Email: ttaniguc@fhcrc.org).

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Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds1. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown2. Here we show that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast-cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, Capan-1 (refs 3, 4), led to five different secondary mutations that restored the wild-type BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP) inhibitor (AG14361). Finally, we evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumour that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Our results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy.