MOLECULAR CLASSIFICATION OF OVARIAN CANCERS

卵巢癌的分子分类

• 批准号: 6350458
• 负责人: JEFFREY ALLEN BOYD
• 金额: $ 21.78万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6350458
• 关键词: complementary DNA; cooperative study; female; fluorescent in situ hybridization; human tissue; immunocytochemistry; microarray technology; neoplasm /cancer classification /staging; neoplasm /cancer genetics; neoplasm /cancer relapse /recurrence; northern blottings; nucleic acid sequence; ovary neoplasms; polymerase chain reaction; tissue resource /registry; western blottings; women's health

Epithelial ovarian carcinoma is the leading cause of mortality among all gynecologic cancers. Poor survival rates associated with this malignancy are attributable to a frequently advanced stage at diagnosis and the inability to successively treat most cases of advanced stage disease using current standards of surgery and chemotherapy. While there are a number of clinical, surgical outcome, and histopathological variables that correlate with prognosis for ovarian cancer, there exists wide variation in the length of recurrence-free interval and survival among typical cases, i.e., post-menopausal women with moderately to poorly differentiated serous tumors of advanced surgical stage. This heterogeneity in clinical outcome presumably reflects differences in the underlying molecular genetic characteristics of individual cancers, but the molecular basis of ovarian cancer remains largely obscure. Thus, the long-term goal of this project is to address the hypothesis that a comprehensive molecular genetic classification of ovarian cancer will improve our ability to predict clinical outcome, specifically with regard to duration of recurrence-free interval following chemotherapy, and survival. Furthermore, elucidation of the molecular determinants of these clinical outcome parameters should provide substantial insights into the biological basis of ovarian tumorigenesis, as well as suggest potential new targets or strategies for ovarian cancer therapy. We propose that this goal may be accomplished through the systematic application of new, comprehensive molecular screening methodologies, specifically, use of cDNA microarrays for gene expression analysis and comparative genomic hybridization for genetic analysis, together with a large ovarian cancer tissue resource linked to extensive surgical, histopathological, and clinical data. The specific aims of this project are to: 1) obtain RNA expression profiles of a large number of ovarian cancers using cDNA microarrays to identify subgroups assembled by expression characteristics; 2) obtain comprehensive information concerning chromosomal imbalances in ovarian cancers by performing comparative genomic hybridizations on the same samples; 3) define distinct molecular and genetic subsets of ovarian cancer that will predict time to recurrence following chemotherapy, and survival, by correlating these molecular and genetic observations with clinical and pathological outcomes; and 4) confirm and refine observations from specific aims one and two using targeted assays and the development of tissue-based approaches. These aims will be accomplished by a National Cooperative Tumor Signature Group with expertise in molecular biology, genetics, cDNA and tissue array technology, bioinformatics, gynecologic oncology and pathology.

上皮性卵巢癌是所有妇科癌症中死亡率最高的原因。 与这种恶性肿瘤相关的低生存率可归因于诊断时经常处于晚期，并且使用当前标准的手术和化疗无法成功治疗大多数晚期疾病病例。 虽然有许多临床、手术结果和组织病理学变量与卵巢癌的预后相关，但在典型病例中，无复发间期和生存期的长度存在很大差异，即，绝经后妇女中分化至低分化浆液性肿瘤的晚期手术阶段。 这种临床结果的异质性可能反映了个体癌症潜在的分子遗传学特征的差异，但卵巢癌的分子基础在很大程度上仍不清楚。 因此，该项目的长期目标是解决这样一个假设，即卵巢癌的综合分子遗传学分类将提高我们预测临床结果的能力，特别是关于化疗后无复发间隔的持续时间和生存率。此外，这些临床结果参数的分子决定因素的阐明应该提供实质性的见解卵巢肿瘤发生的生物学基础，以及建议卵巢癌治疗的潜在新靶点或策略。 我们建议，这一目标可以通过系统地应用新的，全面的分子筛选方法，具体地说，使用cDNA微阵列的基因表达分析和比较基因组杂交的遗传分析，连同一个大的卵巢癌组织资源与广泛的手术，组织病理学和临床数据。 该项目的具体目标是：1）利用cDNA微阵列获得大量卵巢癌的RNA表达谱，以确定由表达特征组装的亚组; 2）通过对相同样品进行比较基因组杂交，获得关于卵巢癌染色体不平衡的全面信息; 3）通过将这些分子和遗传观察与临床和病理结果相关联，定义卵巢癌的不同分子和遗传子集，其将预测化疗后的复发时间和生存期;以及4）使用有针对性的分析和开发基于组织的方法来确认和完善具体目标一和二的观察结果。 这些目标将由一个在分子生物学、遗传学、cDNA和组织阵列技术、生物信息学、妇科肿瘤学和病理学方面具有专长的国家合作肿瘤签名小组来实现。