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。对铂类化合物的原发性和获得性耐药性都是严重的临床问题。乳腺癌/卵巢癌易感基因BRCA 1和BRCA 2（BRCA 1/2）在修复铂类化合物引起的DNA损伤中起着关键作用。因此，BRCA 1/2缺陷细胞对铂化合物过敏。最近，我们发现BRCA 1/2突变型癌症的铂类耐药可以通过BRCA 1/2中恢复野生型BRCA 1/2阅读框架的二次基因内突变介导。基于这一发现，我们推测BRCA 1/2的恢复与BRCA 1/2缺陷卵巢癌获得性铂类耐药有关。在本研究中，我们的重点是确定BRCA 1/2缺陷的遗传性和散发性卵巢癌中BRCA 1/2功能恢复的临床相关性。 首先，我们将确定恢复BRCA 1/2 DNA修复功能的继发性突变的发生是否与遗传性BRCA 1/2突变女性中发生的原发性和复发性遗传性卵巢癌的临床结局相关。其次，我们将评估BRCA 1表达的恢复是否与治疗前BRCA 1表达低的散发性卵巢癌患者获得性铂类耐药有关。我们还将确定在顺铂存在下，体外选择后BRCA 1表达降低的卵巢癌细胞是否获得恢复的BRCA 1功能，并评估导致恢复BRCA 1表达的调控机制。 通过这些研究，我们将评估BRCA 1/2功能恢复在BRCA 1/2缺陷卵巢癌治疗中的临床意义。

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.