Prognostic markers for ovarian cancer

描述（由申请人提供） 卵巢癌是美国女性第五常见的癌症，占癌症病例总数的4%，其中25%发生在女性生殖道。由于其治愈率低，它是负责所有癌症死亡的妇女的5%。据估计，2001年有13 000人死于卵巢癌。大多数卵巢癌病例在晚期（转移灶存在于卵巢以外）被发现，并且很少可以治愈。虽然80%的晚期卵巢癌对手术和化疗的初级治疗有反应，但这种疾病通常会复发，最终是致命的。虽然大多数患者在诊断后2年内死亡，但有一部分患者会发展成更慢性的卵巢癌，并可能在治疗后存活5年或更长时间。可能惰性癌症患者应与快速进展的卵巢癌患者进行不同的监测和治疗。在这一点上，临床医生没有工具来预测疾病的临床过程。拟议的研究旨在为此目的开发分子表征。我们建议应用新建立的cDNA阵列比较基因组杂交（CGH）技术来产生DNA拷贝数异常（CNA）配置文件从进入妇科肿瘤组（GOG）9404临床试验的患者收集的卵巢癌样本，其中有关于患者的结果后，主要的细胞减灭术和铂为基础的一线化疗的全面信息。使用cDNA阵列作为平台，我们已经确定在大多数卵巢肿瘤组织中细胞周期蛋白E扩增和过度表达。此外，使用GOG方案9404的标本，我们已经证明了细胞周期蛋白E是卵巢癌的预后标志物。基于这些有希望的初步数据，我们提出（1）通过cDNA阵列鉴定卵巢癌中的DNA拷贝数异常，（2）通过将cDNA阵列数据与临床终点如肿瘤部位、组织学亚型和分级、化学反应相关联，（3）通过荧光原位杂交（FISH）、定量PCR和免疫组化鉴定和验证具有预后价值的候选基因。对CNA谱和临床结局数据的相关性研究不仅可以深入了解预后相关性的生物学基础，而且还可以在未来的临床试验中确定用于分层患者的预后标志物，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.