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

铂类化合物，如顺铂和卡铂，是治疗卵巢癌的关键药物。铂类化合物的原发性和获得性耐药都是严重的临床问题。乳腺癌/卵巢癌易感基因BRCA1和BRCA2 （BRCA1/2）在修复铂类化合物引起的DNA损伤中起关键作用。因此，BRCA 1/2缺陷细胞对铂类化合物极度敏感。最近，我们发现BRCA1/2突变癌症的铂耐药性可以通过BRCA1/2的继发性基因内突变介导，从而恢复野生型BRCA1/2阅读框。基于这一发现，我们假设BRCA1/2的恢复参与了BRCA1/2缺陷卵巢癌获得性铂耐药。在本研究中，我们着重于确定BRCA1/2缺陷遗传性和散发性卵巢癌中BRCA1/2功能恢复的临床相关性。

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, BRCA 1/2-deficient cells are hypersensitive to platinum compounds. Recently, we found that platinum resistance of BRCA 1/2-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 BRCA 1/2-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 assess the clinical significance of restoration of BRCA1/2 function during the treatment of BRCA 1/2-deficient ovarian carcinoma.