Abstract 750: Whole exome sequencing of uterine serous carcinomas reveals racial differences in known and novel driver mutations

Abstract Background: Uterine serous carcinomas (USC) comprise 10-15% of all uterine cancers, but are responsible for approximately 40% of all deaths due to the disease. African American women have the highest incidence of and mortality from USC of any racial or ethnic group. Assessment of racial differences in driver mutation frequency may partially explain the survival disparity, and identification of novel alterations may provide avenues for targeted treatment. Methods: Two academic hospitals in Detroit, Michigan identified 125 women who had surgical treatment for USC and formalin fixed, paraffin-embedded tissue available for whole exome sequencing (WES). Detailed clinical and pathological data were also available, including long-term follow up. WES was performed using Illumina’s NovaSeq 6000 platform and data were processed via the Genome Analysis Toolkit (GATK), with additional filtering to account for excess artifacts resulting from formalin fixation. Functional mutations were determined by ANNOVAR and the ClinVar database, while putative driver mutations were identified via the IntOGen pipeline. Percentages were used to describe the proportion of tumors harboring a gene mutation, and the Fisher’s exact test was used to test for statistically significant differences in African American (AA) versus non-Hispanic white (NHW) mutation frequencies. Results: The majority of tumors were from AA women (n=87, 69.6%), with the remaining from NHW women (n=38, 30.4%). The overall mutational burden in tumors from AA women was similar to tumors from NHW women (median=122 and 166.5, respectively, p-value=0.12).TP53 was the most frequently mutated, with 77% of tumors from AA women and 65.8% of tumors from NHW women harboring a mutation (p-value=0.20), followed by PPP2R1A (AA=19.5%, NHW=28.9%, p-value=0.25) and PIK3CA (AA=13.8%, NHW=23.7%, p-value=0.20). Of the 66 driver genes in uterine cancer identified from IntOGen, only 3 differed significantly by race: ARID1A (AA=5.7%, NHW=28.9%; p-value=0.001), PTEN (AA=1.1%, NHW=15.8%; p-value=0.003) and FGFR2 (AA=0%, NHW=7.9%, p-value=0.02). Examination of genes with mutational frequencies ≥10% in AA or NHW tumors and with significant differences in mutation distribution by race (n=96) identified an additional 10 genes with mutations that are considered drivers in other cancer types that have not been described in uterine cancers. Conclusions: There are potential driver mutations undescribed in USC that are clinically important in other cancers. Additionally, we noted several differences in the mutation frequency by race which highlights the importance of including racially diverse samples in research, particularly AA women who have the largest burden of USC. Defining the somatic landscape of USC will lead to identification of actionable molecular targets, which will ultimately improve the prognosis of this aggressive subtype. Citation Format: Michele L. Cote, Greg Dyson, Douglas Craig, Julie J. Ruterbusch, Julie Boerner, Mohamed A. Elshaikh, Thomas P. Conrads, Nicholas W. Bateman, George L. Maxwell, Kathleen M. Darcy, Sasha Makohon-Moores, Timothy D. O'Connor, Hassan Abdallah, Logan Corey, Mira Kheil, Rouba Ali-Fehmi. Whole exome sequencing of uterine serous carcinomas reveals racial differences in known and novel driver mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 750.