Characterizing Molecular Subtypes of Ovarian Cancer in African-American Women

非裔美国女性卵巢癌分子亚型特征

• 批准号: 9386358
• 负责人: Jennifer A. Doherty
• 金额: $ 55.57万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386358
• 关键词: Accounting; African American; Age; American; Anatomy; Behavior; Cancer Etiology; Cessation of life; Clinical; Data; Databases; Development; Disease; Enrollment; Epidemiologic Studies; Epidemiology; Epithelial ovarian cancer; Epithelium; Etiology; European; Evolution; Formalin; Frequencies; Future; Gene Expression; Gene Expression Profile; Gene Mutation; Genetic; Health Services Accessibility; Histologic; Incidence; Individual; Investigation; Malignant Neoplasms; Malignant neoplasm of ovary; Medical Genetics; Molecular; Molecular Profiling; Mutation; Newly Diagnosed; Ovarian; Ovarian Tissue; Paraffin Embedding; Participant; Pathway interactions; Pattern; Play; Population; Race; Reporting; Research; Resources; Sampling; Serous; Site; Socioeconomic Factors; Staging; Surface; The Cancer Genome Atlas; United States; Woman; Work; base; cancer epidemiology; cancer gene expression; cancer risk; cancer subtypes; cancer survival; cancer type; comparative; epidemiology study; exome sequencing; infancy; mRNA Expression; malignant breast neoplasm; molecular subtypes; mortality; outcome forecast; ovarian neoplasm; peripheral blood; population based; protein expression; public health relevance; socioeconomics; survival prediction; targeted treatment; therapeutic development; therapeutic target; transcriptome; tumor

 DESCRIPTION (provided by applicant): Epithelial ovarian cancer (EOC) accounts for 5% of malignancies and while it is the eighth most common cancer in US women, it is the fifth leading cause of cancer deaths. It is now considered not as a single disease, but rather as a diverse group of tumors with distinct origins, histotypes, mutation profiles, protein and gene expression profiles, and prognosis. Over 75% of EOC is high-grade serous (HGSC), accounting for 90% of disease-specific mortality. Systematic molecular characterization of HGSC by the Cancer Genome Atlas (TCGA) and others has demonstrated robust gene expression subtypes of HGSC. HGSC subtypes have been studied almost exclusively in individuals of European ancestry, and it is thus unknown whether these or other subtypes exist in populations with different genetic backgrounds and exposures. Indeed five-year relative survival from EOC is only 36.4% for African American (AA) women, compared to 44.3% for European American (EA) women. For breast cancer, aggressive subtypes are more common among AA women than EA women, and this partially explains survival differences. It is possible that aggressive subtypes of HGSC are overrepresented in AA women, but analogous research in EOC is in its infancy because it is one ninth as common as breast cancer, and molecular subtypes have only recently been identified. The African American Cancer Epidemiology Study (AACES) is an ongoing multi-site population-based study which will ultimately include 850 AA women with newly diagnosed EOC and their age-matched controls. This study will examine socioeconomic, epidemiologic, genetic and clinical factors and ovarian cancer risk and survival. As the only epidemiologic study of EOC in AA women to date, it provides a rich resource to examine molecular features of this disease. For 300 AACES participants, we propose to generate whole transcriptome data from their formalin-fixed paraffin-embedded HGSC ovarian tumors and exome sequencing data from these tumors and corresponding peripheral blood to: determine gene expression-based, and mutation-based, subtypes of HGSC tumors in AA women, compare the relative frequencies of subtypes in AA and EA populations, and evaluate whether subtype-specific survival differs by population; and characterize similarities and differences in gene expression patterns and mutational spectra across each of the molecular subtypes in AA and EA women to define key subtype-specific and population-specific pathways. The results from this study will provide key information to understand survival differences in AA women, and will more precisely define molecular subtypes allowing for future functional characterization and therapeutic development.

 描述(申请人提供)：上皮性卵巢癌(EOC)占恶性肿瘤的5%，虽然它是美国女性第八种最常见的癌症，但它是癌症死亡的第五大原因。它现在被认为不是一个单一的疾病，而是一个不同的肿瘤组，具有不同的起源、组织类型、突变情况、蛋白质和基因表达情况以及预后。超过75%的卵巢癌为高度浆液性卵巢癌(HGSC)，占疾病特异性死亡的90%。肿瘤基因组图谱(TCGA)等对HGSC进行了系统的分子鉴定，证实了HGSC基因亚型的强健表达。HGSC亚型几乎只在欧洲血统的个体中进行研究，因此尚不清楚这些亚型或其他亚型是否存在于具有不同遗传背景和暴露环境的人群中。事实上，非洲裔美国人(AA)女性的五年相对存活率仅为36.4%，而欧洲裔美国人(EA)女性的五年相对存活率为44.3%。对于乳腺癌，AA女性的侵袭性亚型比EA女性更常见，这在一定程度上解释了存活率差异。攻击性亚型可能是 HGSC在AA女性中的比例过高，但类似的研究在EOC中还处于初级阶段，因为它的发病率是乳腺癌的九分之一，而且分子亚型直到最近才被确定。这个 非裔美国人癌症流行病学研究(AACES)是一项正在进行的基于人群的多地点研究，最终将包括850名新诊断为EOC的AA妇女及其年龄匹配的对照。这项研究将研究社会经济、流行病学、遗传和临床因素与卵巢癌风险和存活率。作为迄今为止唯一一项AA妇女EOC的流行病学研究，它为研究这种疾病的分子特征提供了丰富的资源。对于300名AACES参与者，我们建议从他们的福尔马林固定石蜡包埋HGSC卵巢肿瘤以及这些肿瘤和相应外周血的外显子组测序数据中生成完整的转录组数据，以：确定AA女性中基于基因表达和突变的HGSC肿瘤亚型，比较AA和EA人群中亚型的相对频率，并评估亚型特异性生存是否因人群而不同；并表征AA和EA女性中每个分子亚型之间的基因表达模式和突变谱的异同，以确定关键的亚型特异性和人群特异性通路。这项研究的结果将为了解再生障碍性贫血患者的生存差异提供关键信息，并将更准确地确定分子亚型，从而为未来的功能表征和治疗开发提供依据。