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

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 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.