Prognostic markers for ovarian cancer

描述(由申请人提供) 卵巢癌是美国女性最常见的第五种癌症，占癌症病例总数的4%，其中25%发生在女性生殖道。由于其治愈率很低，女性所有癌症死亡中有5%是由它造成的。据估计，2001年有13000人死于卵巢癌。大多数卵巢癌病例是在晚期(卵巢以外存在转移)时被发现的，很少能治愈。虽然80%的晚期卵巢癌对手术和化疗的初步治疗有反应，但这种疾病通常会复发，最终是致命的。虽然大多数患者在确诊后两年内死亡，但也有一小部分患者发展为更慢性的卵巢癌，并可能通过治疗存活5年或更长时间。有可能对惰性癌症患者的监测和治疗应与快速进展的卵巢癌患者不同。在这一点上，临床医生没有工具来预测临床病程。拟议的研究试图为此目的开发一种分子表征。我们建议应用新建立的cDNA阵列比较基因组杂交(CGH)技术来生成卵巢癌样本的DNA拷贝数异常(CNA)谱，该样本来自参加妇科肿瘤组(GOG)9404临床试验的患者，该临床试验具有关于初次细胞减灭术和铂类一线化疗患者预后的详细信息。以该基因芯片为平台，我们鉴定了大多数卵巢肿瘤组织中Cyclin E的扩增和过表达。此外，使用GOG方案9404的样本，我们已经证明了细胞周期蛋白E是卵巢癌的预后标记物。基于这些有希望的初步数据，我们建议(1)通过基因芯片识别卵巢癌中的DNA拷贝数异常，(2)利用来自妇科肿瘤组(GOG)9404方案的患者的数据，通过将基因阵列数据与临床终点(如肿瘤部位、组织亚型和分级、化疗反应和长期生存)相关联来建立卵巢癌的遗传预后模型，以及(3)通过荧光原位杂交(FISH)、定量PCR和免疫组织化学来识别和验证具有预后价值的候选基因。对CNA谱和临床结果数据的相关性研究不仅将提供对预后关联的生物学基础的洞察，还将在未来的临床试验中为分层患者寻找预后标志物，以评估化疗在卵巢癌治疗中的作用。

DESCRIPTION (provided by applicant) Ovarian cancer is the fifth most common form of cancer in women in the United States, accounting for 4% of the total number of cancer cases and 25% of those cases occur in the female genital tract. Because of its low cure rate, it is responsible for 5% of all cancer deaths in women. It was estimated that 13,000 deaths was caused by ovarian cancer in the year 2001. A majority of ovarian cancer cases are detected at an advanced stage (where metastases are present beyond the ovaries) and are rarely curable. Although 80% of advanced ovarian cancers respond to primary treatment with surgery and chemotherapy, the disease usually recurs and is ultimately fatal. Though most patients die within 2 years of diagnosis, a subset of patients develop a more chronic form of ovarian cancer, and may survive 5 years or more with treatment. It is possible that patients with indolent cancer should be monitored and treated differently from patients with rapidly progressing ovarian cancer. At this point, clinicians do not have the tools to predict the clinical course of disease. The proposed studies seek to develop a molecular characterization for this purpose. We propose to apply the newly established cDNA array comparative genomic hybridization (CGH) technique to generate DNA copy number abnormality (CNA) profiles on ovarian cancer samples collected from patients entered into the Gynecologic Oncology Group (GOG) 9404 clinical trial, which has thorough information regarding patient outcome following primary cytoreductive surgery and platinum-based first-line chemotherapy. Using the cDNA array as a platform, we have identified cyclin E amplification and over-expression in a majority of ovarian tumor tissue. Furthermore, using the specimens from the GOG protocol 9404, we have demonstrated that cyclin E is a prognostic marker for ovarian cancer. Based on these promising preliminary data, we propose (1) to identify DNA copy number abnormalities in ovarian cancer by cDNA array, (2) to develop a genetic prognostic model for ovarian cancer utilizing the data from patients entered on Gynecologic Oncology Group (GOG) protocol 9404 by correlating cDNA array data with clinical end points such as tumor site, histological subtype and grade, chemoresponse, and long-term survival, and (3) to identify and validate candidate genes with prognostic values by fluorescence in situ hybridization (FISH), quantitative PCR, and immunohistochemistry. The correlation study on CNA profiles and clinical outcome data will not only provide insights into the biological basis of the prognostic associations, but also identify prognostic markers for stratifying patients in future clinical trials to assess the role of chemotherapy in the treatment of ovarian cancer.