Clinical Implication of the Acquisition of BRCA1/2 Function in BRCA1/2-Deflcient

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Plafinum compounds, such as cisplafin and carboplafin, are key drugs for the treatment of ovarian carcinoma. Both primary and acquired resistance to plafinum compounds are serious clinical problems. The breast/ovarian cancer suscepfibility genes BRCA1 and BRCA2 (BRCA1/2) play a crifical role in repairing the DNA damage caused by plafinum compounds. Consequently, BRCA 7/2-deficient cells are hypersensitive to platinum compounds. Recenfiy, we found that platinum resistance of BRCA V2-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 Bf?CA 7/2-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 mutafions. Second, we will evaluate whether restoration of BRCA1 expression is involved in acquired resistance to plafinum in sporadic ovarian carcinomas that inifially 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 assess the clinical significance of restoration of BRCA1/2 function during the treatment of BRCA ¿//2-deficient ovarian carcinoma. RELEVANCE (See instructions): Our study will provide crifical informafion about the mechanisms of plafinum-resistance of BRCA1/2-deficient tumors, which will enable us to predict plafinum resistance of recurrent tumors, and may eventually lead to the establishment of a strategy to overcome platinum resistance.