PROJECT 4
Clinical implication of the acquisition of BRCA1/2 function in BRCA1/2 deficient ovarian carcinoma (Abbrev: Restoration of BRCA 1/2)
Toshiyasu Taniguchi, MD, PhD - Fred Hutchinson Cancer Research Center
Elizabeth Swisher, MD - University of Washington
Platinum compounds, such as cisplatin and carboplatin, are key drugs for the treatment of ovarian carcinoma. Both primary and acquired resistance to platinum compounds are serious clinical problems. The breast/ovarian cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2) play a critical role in repairing the DNA damage caused by platinum compounds. Consequently, BRCA1/2-deficient cells are hypersensitive to platinum compounds. Recently, we found that platinum resistance of BRCA1/2-mutated cancer can be mediated by secondary intragenic mutations in BRCA1/2 that restore the wild-type BRCA1/2 reading frame. Based on this finding, we hypothesize that restoration of BRCA1/2 is involved in acquired platinum resistance of BRCA1/2-deficient ovarian carcinomas. In this proposal, we focus on determining clinical relevance of restoration of BRCA1/2 function in BRCA1/2-deficient hereditary and sporadic ovarian carcinomas.
First, we will determine whether the occurrence of secondary mutations that restore DNA repair function of BRCA1/2 correlates with clinical outcomes of primary and recurrent hereditary ovarian carcinomas occurring in women with inherited BRCA1/2 mutations. Second, we will evaluate whether restoration of BRCA1 expression is involved in acquired resistance to platinum in sporadic ovarian carcinomas that initially have low BRCA1 expression before treatment. We will also determine whether ovarian cancer cells with reduced BRCA1 expression acquire restored BRCA1 function after in vitro selection in the presence of cisplatin and evaluate regulatory mechanisms that lead to restored BRCA1 expression.
With these studies, we will determine the clinical significance of the restoration of BRCA1/2 function in the treatment of BRCA1/2-deficient cancer as shown in the figure. Our study will provide critical information about the mechanisms of platinum-resistance of BRCA1/2-deficient tumors, which will enable us to predict platinum resistance of recurrent carcinomas, and may eventually lead to new therapeutic strategies to overcome platinum resistance.
Other Research
Project 1
Project 2
Project 3
Project 4
Project 5
Clinical Core
Informatics Core
Specimen Core
Leadership Core
Project 4 Publications
1. Sakai W, Swisher EM, Jacquemont C, Chandramohan KV, Couch FJ, Langdon SP, Wurz K, Higgins J, Villegas E, Taniguchi T. Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma. Cancer Res. 2009 Aug 15;69(16):6381-6. PMCID: PMC2754824
2. Chisholm KM, Goff BA, Garcia R, King MC, Swisher EM. Genomic structure of chromosome 17 deletions in BRCA1-associated ovarian cancers. Cancer Genet Cytogenet. 2008 May;183(1):41-8. PMCID: PMC2413294
3. Swisher EM, Sakai W, Karlan BY, Wurz K, Urban N, Taniguchi T. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res. 2008 Apr 15;68(8):2581-6. PMCID: PMC2674369
4. Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, Villegas E, Jacquemont C, Farrugia DJ, Couch FJ, Urban N, Taniguchi T. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature. 2008 Feb 28;451(7182):1116-20. PMCID: PMC2577037
5. Chiang JW, Karlan BY, Cass L, Baldwin RL. BRCA1 promoter methylation predicts adverse ovarian cancer prognosis. Gynecol Oncol 2006;101(3):403-10.
6. Chirnomas D, Taniguchi T, de la Vega M, Vaidya AP, Vasserman M, Hartman AR, Kennedy R, Foster R, Mahoney J, Seiden MV, D'Andrea AD. Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway. Mol Cancer Ther. 2006; 5:952-61.
7. Cass I, Baldwin RL, Varkey T, Moslehi R, Narod SA, Karlan BY. Improved survival in women with BRCA-associated ovarian carcinoma. Cancer 2003;97(9):2187-95.
8. Taniguchi T, Tischkowitz M, Ameziane N, Hodgson SV, Mathew CG, Joenje H, et al. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat Med 2003;9(5):568-574.
9. Baldwin RL, Nemeth E, Tran H, Shvartsman H, Cass I, Narod S, et al. BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study. Cancer Res 2000;60(19):5329-33.