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

 描述(申请人提供)：子宫内膜癌是最常见的妇科癌症，在美国的发病率正在上升。它也是所有常见癌症中生存差距最大的癌症之一，与白人女性相比，非洲裔美国女性在确诊后5年的存活率约低20%，而且这种差异存在于不同的分期和组织学亚型中。在这里，我们试图研究一种特别侵袭性的子宫内膜癌亚型，即包括子宫内膜样癌、浆液性癌、透明细胞癌和混合癌在内的高级别肿瘤。这些癌症导致了子宫内膜癌不成比例的死亡，而且在非裔美国人中被诊断出来的频率也更高。具体地说，我们的目标是：1.评估500名妇女(250名非洲裔美国人，250名白人)根据当前病理标准被诊断为高级别子宫内膜癌的无进展存活率和子宫内膜癌相关存活率；2.对在密歇根州底特律两家大型研究医院接受手术治疗的这些妇女的肿瘤进行分子特征(通过整个外显子测序和基因表达分析)。我们将进行综合分析，将肿瘤分为生物学和临床相关的组和3.分析分子分类在无进展生存和子宫内膜癌相关生存方面的表现，调整相关的人口学、临床、合并发病率和治疗信息。癌症基因组图谱(TCGA)已经在这一领域进行了初步工作，但包括的肿瘤主要来自白人女性，只有10个子宫内膜样癌和11个浆液性肿瘤来自非裔美国女性，用于分子重新分类分析。因此，我们的项目将解决当前知识中的一个巨大差距。公共卫生意义：识别新的体细胞突变和了解分子变异的频谱，特别是在非裔美国人中，将有助于我们进一步走向个性化药物，有可能减少子宫内膜癌存活率的种族差异，并最终提高所有患有子宫内膜癌的女性的存活率。

 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.