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

普莱芬类化合物，如顺铂和卡铂是治疗卵巢癌的关键药物。 癌症。对普拉芬类化合物的原发和获得性耐药都是严重的临床问题。这个 乳腺癌/卵巢癌易感基因BRCA1和BRCA2(BRCA1/2)在乳腺癌的修复中起关键作用 Plafinum化合物引起的DNA损伤。因此，BRCA 7/2缺陷细胞对 铂化合物。最近，我们发现BRCA V2突变癌症的铂耐药可以是 由恢复野生型BRCA1/2阅读框的BRCA1/2的次级基因内突变所介导。 基于这一发现，我们假设BRCA1/2的修复与获得的铂有关 BRCA1/2基因缺陷卵巢癌的耐药性研究在这项建议中，我们重点确定临床 Bf？CA7/2缺陷遗传性和散发性卵巢BRCA1/2功能恢复的相关性 癌症。 首先，我们将确定是否发生了恢复DNA修复功能的二次突变 BRCA1/2与原发性和复发性遗传性卵巢癌的临床预后相关 患有遗传性BRCA1/2突变的女性。第二，我们将评估BRCA1是否恢复 在散发性卵巢癌中，表达与获得性耐药有关 治疗前BRCA1低表达。我们还将确定卵巢癌细胞是否减少了 BRCA1表达经体外筛选后获得恢复的BRCA1功能 评估导致BRCA1表达恢复的调控机制。 通过这些研究，我们将评估BRCA1/2功能恢复的临床意义。 BRCA？//2基因缺陷卵巢癌的治疗 相关性(请参阅说明)： 我们的研究将为BRCA1/2基因缺陷的血小板抵抗机制提供重要信息 肿瘤，这将使我们能够预测复发性肿瘤的平台耐药，并可能最终导致 建立克服铂金阻力的战略。

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.