Genomic Instability from Loss of XPG, a BRCA1/2 Partner: Role in Ovarian Cancer?

XPG（BRCA1/2 伙伴）缺失导致基因组不稳定：在卵巢癌中的作用？

• 批准号: 8885778
• 负责人: Priscilla K. Cooper
• 金额: $ 21.47万
• 依托单位: UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-03 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885778
• 关键词: Adenocarcinoma Cell; Anchorage-Independent Growth; Apoptosis; BRCA1 Mutation; BRCA1 Protein; BRCA1 gene; BRCA2 gene; CA-125 Antigen; Camptothecin; Cancer Etiology; Cancer cell line; Carboplatin; Cell Line; Cells; Cessation of life; Chromosomal Instability; Chromosome abnormality; Cisplatin; Coupled; DNA Double Strand Break; DNA repair protein; Data Set; Defect; Development; Down-Regulation; ERCC5 gene; Epithelial; Epithelial Cells; Etiology; Event; Frequencies; Gene Expression; Genes; Genetic Predisposition to Disease; Genome Stability; Genomic Instability; Genomics; Health; Impairment; Inherited; Investigation; Ionizing radiation; Lead; Left; Link; Maintenance; Malignant neoplasm of ovary; Mammalian Oviducts; Measures; Mutation; Neoplastic Cell Transformation; Nucleotide Excision Repair; Ovarian; Ovarian Serous Adenocarcinoma; Pathway interactions; Patients; Play; Predisposition; Proteins; Regulation; Resistance; Risk; Role; Serous; Simian virus 40; Staging; Stress; Surface; Syndrome; Testing; The Cancer Genome Atlas; Therapeutic; Tumor Suppressor Proteins; Up-Regulation; Woman; XPGC protein; adduct; cancer cell; cancer risk; carcinogenesis; cell growth; cell type; chemotherapeutic agent; homologous recombination; improved; inhibitor/antagonist; knock-down; member; metaplastic cell transformation; micronucleus; novel; novel marker; novel therapeutic intervention; novel therapeutics; ovarian neoplasm; p53-binding protein 1; precursor cell; protein protein interaction; recombinase; recombinational repair; scaffold; tumor

DESCRIPTION (provided by applicant): Ovarian cancer is the fifth leading cause of cancer death among U.S. women, primarily from advanced high-grade serous ovarian adenocarcinoma (HGS-OvCa). Inherited mutation of BRCA1 and BRCA2, which function in homologous recombination repair (HRR), leads to a substantial increase in ovarian cancer risk. The Cancer Genome Atlas (TCGA) project recently identified unusually high genomic instability as a prominent feature of HGS-OvCa tumors and estimated that ~50% have HRR defects. Since this frequency significantly exceeds that of BRCA mutations, it is likely that changes in HRR genes not known to be associated with inherited predisposition syndromes are important in the etiology of sporadic ovarian cancer. This project will explore a novel role for the highly multifunctional DNA repair protein XPG as a driver in ovarian carcinogenesis. Surprising recent findings have established that XPG functions in HRR through direct interaction with several members of the HRR pathway, notably including both BRCA proteins as well as the RAD51 recombinase, and that loss of XPG has significant consequences for impairment of BRCA1 and BRCA2 functions. Knockdown of XPG leads to reduced HRR, inability to restart stalled replication forks, and a dramatic increase in genomic instability. Conversely, the enzymatic function of XPG is required in nucleotide excision repair (NER) to remove adducts formed by many chemotherapeutic agents, and acquired resistance to first-line therapies such as cisplatin and carboplatin has been linked to over-expression of NER proteins including XPG. Importantly for development of new therapeutic approaches, tumors with diminished HRR due to low expression of XPG may be particularly sensitive to PARP inhibitors. The hypothesis to be tested by the proposed exploratory studies is that XPG is a novel tumor suppressor for ovarian carcinogenesis that its loss or down- regulation is a previously unidentified factor in the etiology of ovarian cancer, and that understanding XPG protein regulation and activity in ovarian cancer cells has direct therapeutic implications. This hypothesis will be tested through two specific aims. (1) The effect of XPG loss on genomic instability and cellular transformation in immortalized, non-tumorigenic ovarian surface epithelial (OSE) cells and fallopian tube secretory epithelial cells (FTSEC), which have each been proposed to be the precursor cell types for ovarian carcinogenesis, will be determined. (2) XPG protein amounts, function, and regulation will be examined in a panel of ovarian cancer cell lines that have been shown to most closely resemble primary HGS-OvCa tumors, including several that are known to have XPG mutations. If the hypothesis is correct that XPG, newly identified as an important HRR protein, plays a role in the initiating events in HGS-OvCa, these results have the potential to provide a new marker for ovarian cancer susceptibility, new therapeutic strategies, and improved understanding of mechanisms involved in ovarian carcinogenesis.

描述（由申请人提供）：卵巢癌是美国妇女癌症死亡的第五个主要原因，主要来自高级高级浆液卵巢腺癌（HGS-OVCA）。在同源重组修复（HRR）中起作用的BRCA1和BRCA2的遗传突变导致卵巢癌风险大幅增加。癌症基因组图集（TCGA）项目最近将异常高的基因组不稳定性视为HGS-ovca肿瘤的重要特征，并估计约有50％的人患有HRR缺陷。由于该频率显着超过了BRCA突变的频率，因此不知道与遗传性倾向综合征相关的HRR基因的变化在零星卵巢癌的病因中很重要。该项目将探讨高度多功能DNA修复蛋白XPG作为卵巢癌发生的驱动因素的新作用。令人惊讶的是，最近的发现表明，XPG通过与HRR途径的几个成员进行直接相互作用在HRR中的功能，特别是包括BRCA蛋白以及RAD51重组酶，并且XPG的丢失对BRCA1和BRCA2功能的损害产生了重大影响。 XPG的敲低导致HRR减少，无法重新开始停滞的复制叉以及基因组不稳定性的急剧增加。相反，在核苷酸切除修复（NER）中需要XPG的酶促功能去除许多化学治疗剂形成的加合物，并获得了对顺铂和卡泊蛋白等一线疗法的耐药性已与包括XPG在内的NER蛋白过表达的过表达相关。重要的是，对于开发新的治疗方法，由于XPG表达低而导致HRR降低的肿瘤可能对PARP抑制剂特别敏感。拟议的探索性研究要检验的假设是，XPG是卵巢癌变的一种新型肿瘤抑制因子，即其损失或下调是卵巢癌病因和卵巢癌病因的一个未识别因素， 了解XPG蛋白质调节和卵巢癌细胞的活性具有直接的治疗意义。该假设将通过两个具体目标进行检验。 （1）XPG丧失对永生的，非肿瘤的卵巢表面上皮（OSE）细胞和输卵管分泌上皮细胞（FTSEC）中基因组不稳定性和细胞转化的影响，这些细胞已被认为是卵巢致癌作用的前体细胞类型。 （2）将在一组卵巢癌细胞系中检查XPG蛋白质，功能和调节，这些小组已显示出与原发性HGS-ovca肿瘤的最紧密相似的，其中包括几种已知具有XPG突变的肿瘤。如果该假设是正确的，即新鉴定为重要的HRR蛋白的XPG在HGS-ovca的启动事件中发挥了作用，这些结果有可能为卵巢癌易感性，新的治疗策略，新的治疗策略提供新的标志，并提高对卵巢致癌物质的理解。