Comparison of the clinical and genomic profiles of endometrial cancer in Appalachian and non-Appalachian patients.

person Taylor A Rives Division of Gynecologic Oncology, University of Kentucky, Lexington, KY info_outline Taylor A Rives, Abu Saleh Mosa Faisal, Jinpeng Liu, Hye Sook Chon, Casey Cosgrove, Bradley Corr, Robert Dood, Stephen B. Edge, Aliza L. Leiser, Christina Washington, Bodour Salhia, Chris Moskaluk, Neil T. Phippen, Lisa Michelle Landrum, Dava West Piecoro, Michelle Churchman, Charles S Dietrich, Frederick R Ueland, Chi Wang, Jill Kolesar

Authors person Taylor A Rives Division of Gynecologic Oncology, University of Kentucky, Lexington, KY info_outline Taylor A Rives, Abu Saleh Mosa Faisal, Jinpeng Liu, Hye Sook Chon, Casey Cosgrove, Bradley Corr, Robert Dood, Stephen B. Edge, Aliza L. Leiser, Christina Washington, Bodour Salhia, Chris Moskaluk, Neil T. Phippen, Lisa Michelle Landrum, Dava West Piecoro, Michelle Churchman, Charles S Dietrich, Frederick R Ueland, Chi Wang, Jill Kolesar Organizations Division of Gynecologic Oncology, University of Kentucky, Lexington, KY, Division of Biostatistics and Bioinformatics, Biostatistics and Bioinformatics Shared Resource Facility, University of Kentucky, Lexington, KY, Department of Biostatistics, University of Kentucky, Lexington, KY, Department of Gynecologic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, Division of Gynecologic Oncology, The Ohio State University James Cancer Center, Columbus, OH, Division of Gynecologic Oncology, University of Colorado Cancer Center, Aurora, CO, Division of Gynecologic Oncology, University of Utah Huntsman Cancer Institute, Salt Lake City, UT, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, Division of Gynecologic Oncology, Rutgers Cancer Institue of New Jersey, New Brunswick, NJ, Division of Gynecologic Oncology, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, Department of Translational Genomics, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, Department of Pathology, University of Virginia, Charlottesville, VA, John P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD, Division of Gynecologic Oncology, Indiana University, Indianapolis, IN, Department of Pathology, University of Kentucky, Lexington, KY, Aster Insights, Tampa, FL, Division of Gynecology Oncology, University of Kentucky, Lexington, KY, Department of Pharmacology, University of Kentucky, Lexington, KY Abstract Disclosures Research Funding NCI Cancer Center Support Grant Markey Cancer Center Biospecimen Procurement and Translational Pathology Shared Resource Facility, Cancer Research Informatics Shared Resource Facility, Biostatistics and Bioinformatics Shared Resource Background: Kentucky has the highest incidence and mortality from gynecologic cancer in the United States, and the incidence of endometrial cancer (EC) in the Kentucky Appalachian (AP) population is even higher than non-Appalachian (non-AP). The purpose of this study is to compare demographics, molecular profiles, and outcomes between AP and non-AP populations. Methods: Using the Total Cancer Care prospective cohort study, we evaluated 836 women with EC, 40 AP (4.8%), 700 non-AP (83.7%), and 96 with unknown residence (11.5%). We used descriptive statistics and univariate analyses to compare AP vs non-AP and MutSig to identify significantly mutated genes. RNASeq data was trimmed and processed with STAR. Differential expression and pathway enrichment analyses were processed with EdgeR and GSEA, respectively. We grouped patients by POLE mutation first, then microsatellite instability (MSI) high. We identified CN clusters with hierarchical clustering and grouped the remainder by CN status. We compared overall survival (OS) among molecular subgroups using Kaplan-Meier curves and log-rank tests. Results: Most participants were white (90.2%), had a median age of 62.7 years, median BMI of 34.0 mg/m 2 , had stage I disease (64.6%), and endometrioid histology (83.3%). AP women were diagnosed at a higher stage (stage IV 25.8% vs 7.7%, p=0.0008) and were more likely to have serous carcinoma (33.3% vs 9.0%, p<0.0001). There was no difference in age, race, or BMI between AP and non-AP. The AP group had significantly more EVI5 mutations than the non-AP group (17.5% vs 6.0%, p=0.012), as well as significant differences in RNA expression, specifically upregulation in oxidative phosphorylation pathways. Cluster (c) analysis identified 6 CN clusters; c 2 corresponded to the TCGA CN high group, and we divided the TCGA CN low group into two distinct molecular subgroups: CN moderate (c 1,3,4,6) and CN low (c 5) as there was significant differences in CN alteration between these clusters. CN high had worse OS, CN moderate had improved OS, and CN low had intermediate OS (p<0.0001); significance persisted when controlling for covariates. Most patients were in CN moderate (n=245, 29.52%), followed by MSI High (n=210, 25.3%), CN low (n=175, 21.1%), CN high (n=160, 19.3%), and POLE mutated (n=40, 4.8%). Conclusions: This is a larger independent replicate of TCGA molecular subtyping, which includes a previously unevaluated AP population. We identified additional CN clusters and a new CN group with significantly different survival. AP patients were more likely to have advanced stage disease, serous histology, and EVI5 mutations, which is an oncogene involved in cell cycle regulation not previously implicated in EC. AP patients also have significant differences in RNA expression. These molecular differences may reveal opportunities for treatment and reduce cancer disparities.