Endometrial somatic profile differences by race: A first step to narrow the disparity gap (012)

Abstract

<b>Objectives:</b> To evaluate the frequency of genomic alternations in endometrial cancer across racial groups. <b>Methods:</b> The American Association for Cancer Research (AACR) Project GENIE (Genomics Evidence Neoplasia Information Exchange; public version 10.0) was accessed and downloaded from Synapse. org and filtered for endometrial cancer type (<i>n</i>=3,721). Next-generation sequencing (NGS) tumor profiles, including structural variants, somatic point mutations, and copy-number alterations (CNA), from endometrial cancer patients across 16 institutions were retrieved. Mutational frequencies were calculated and compared by self-reported race (White, Black, Asian). Institutions provided NGS tumor profiles generated from several sequencing panels with differing numbers of genes and genetic architecture types. We accounted for these genes by differences in the genes tested in these panels. Mutation frequency was calculated using a denominator of the number of patients sequenced for that particular gene rather than the total number of patients sequenced. The somatic mutational burden was defined as the combination of somatic point mutations, structural variants, and CNA. All data quality control and analysis were performed in the statistical package R (3.6.1). <b>Results:</b> Among 3,282 patients with endometrial cancer (2,736 White, 316 Black, and 230 Asian), the most common histologies represented were endometrioid (<i>n</i>=1587; 89% White, 4% Black, and 7% Asian), serous (<i>n</i>=627, 76% White, 18% Black, and 6% Asian) and carcinosarcoma (<i>n</i>=399; 76% White, 19% Black, and 5% Asian). While the total somatic mutation burden of well-recognized genes in endometrial cancer, such as <i>PTEN, ARID1A,</i> and <i>PIK3CA</i>, was consistent across racial groups, many others, including <i>IL2RB</i> (involved in T cellmediated immune response), were more frequent in Black women than White women (50% vs 2.9%, respectively). Somatic mutations in <i>TRAP1</i> (increases cell proliferation and reduces apoptosis), <i>KREBBP</i> (involved in transcription factor activation), and <i>IL2RB</i> (involved in T cell-mediated immune response) were seen with much higher frequency in Black women. Somatic mutations in CD74 (regulates antigen presentation for immune response) and <i>PIK3R1</i> (associated with metabolic actions of insulin) were the most frequent in White women, whereas <i>EP300</i> (involved in transcription regulation including VEGF) was most frequent in Asian women. <b>Conclusions:</b> Racial disparities in cancer are extensively studied, documented, and discussed. These disparities likely occur due to an interaction of molecular, socio-demographic, and environmental factors. Here, we provide a descriptive evaluation of somatic burden in endometrial cancer by self-reported race to better understand and elucidate mechanistic insight into somatic mutations that may drive susceptibility to risk factors and treatment response and guide targets for clinical trial recruitment. Larger studies correlated with these risk factors and longitudinal clinical data showing treatment response and survival are needed to understand the implications of these findings and address disparities in endometrial cancer.Fig. 1