Molecular Classification of High Grade Endometrial Cancers: Extending TCGAFindings to a Diverse Population

 描述（由申请人提供）：子宫内膜癌是最常见的妇科癌症，在美国发病率正在上升。它也是所有常见癌症中生存率差异最大的癌症之一，与白色女性相比，非裔美国女性在诊断后5年的生存率约低20%，这种差异在各个阶段和组织学亚型中都存在。在这里，我们试图检查一个特别积极的亚型子宫内膜癌，高级别肿瘤，包括子宫内膜样癌，浆液性癌，透明细胞癌和混合癌。这些癌症是子宫内膜癌死亡人数不成比例的原因，并且在非洲裔美国人中也更常见。具体而言，我们的目标是：1。评估500名诊断为高级别子宫内膜癌的女性（250名非洲裔美国人，250名白色人）的无进展生存率和子宫内膜癌相关生存率，如当前病理标准所定义的; 2.分子特征（通过全外显子组测序和基因表达分析）来自这些在密歇根州底特律的两家大型研究医院接受手术治疗的妇女的肿瘤。我们将进行综合分析，将肿瘤分为生物学和临床相关组，3.分析分子分类在无进展生存期和子宫内膜癌相关生存期方面的性能，调整相关人口统计学、临床、共病和治疗信息。癌症基因组图谱（TCGA）已经在这方面做了初步工作，但纳入的肿瘤主要来自白色女性，只有10例非裔美国女性的类胶质瘤和11例浆液性肿瘤用于分子重新分类分析。因此，我们的项目将解决当前知识的巨大差距。公共卫生意义：识别新的体细胞突变和了解分子变异谱，特别是在非洲裔美国人中，将有助于我们进一步走向个性化医疗，有可能减少子宫内膜癌生存的种族差异，并最终提高所有子宫内膜癌患者的生存率。

 DESCRIPTION (provided by applicant): Endometrial cancer is the most common gynecological cancer and incidence is increasing in the United States. It also has one of the largest survival disparities of all common cancers, with approximately 20% fewer African American women surviving 5 years after diagnosis compared to white women, and this disparity holds across stages and histologic subtypes. Here we seek to examine a particularly aggressive subtype of endometrial cancers, high grade tumors including endometrioid, serous, clear cell and mixed carcinomas. These cancers are responsible for a disproportionate number of deaths from endometrial cancer, and are also more frequently diagnosed in African Americans. Specifically, we aim to: 1. Assess progression free survival and endometrial cancer-related survival in 500 women (250 African American, 250 white) diagnosed with high grade endometrial cancers, as defined by current pathologic standards; 2. Molecularly characterize (through whole exome sequencing and gene expression analysis) tumors from these women who received surgical treatment at two large research hospitals in Detroit, Michigan. We will perform integrated analysis to classify the tumors into biologically and clinically relevant groups and 3. Analyze the performance of the molecular classifications with respect to progression free survival and endometrial cancer- related survival, adjusting for relevant demographic, clinical, co-morbidity and treatment information. Preliminary work in this area has been done by The Cancer Genome Atlas (TCGA), but the tumors included were primarily from white women, with only 10 endometrioid and 11 serous tumors from African American women used to inform the molecular reclassification analysis. Thus, our project will address a large gap in current knowledge. Public Health Significance: The identification of novel somatic mutations and understanding of the spectrum of molecular variation, particularly among African Americans, will help us move further toward personalized medicine, with the potential to reduce the racial disparities in endometrial cancer survival and ultimately improve survival for all women with endometrial cancer.