Abstract C002: Dysregulation of fatty acid metabolism by TP53 mutations underlies more aggressive endometrial cancers in African American women

Abstract

Abstract In the United States, endometrial cancer is the fourth most common malignancy among women, with an estimated 61,380 new cases and 10,920 deaths in 2017 (1). The incidence is increasing more rapidly among African American (AfAm) women than other racial/ethnic groups (2), and the 5-year survival rate in AfAms is much lower than other racial/ethnic groups, including Caucasian Americans (CaAm) (62% vs. 84%) (3, 4). Endometrioid-type endometrial carcinoma (EEC) accounts for about 75% of all endometrial carcinomas. Many patients with early-stage and low-grade EEC can be cured by surgery alone, but for women who present with higher-grade advanced-stage EEC, more aggressive therapy is needed. Studies have shown a close gene/environment interaction in endometrial cancer development and progression (5-7); however, why AfAm women have a higher mortality rate and why their incidence of endometrial cancer is increasing more rapidly remain unknown. To address this issue, we analyzed gene mutation profiles in AfAm and CaAm women with EEC, using samples and genomic data from The Cancer Genome Atlas (TCGA) including 397 patients with EEC (284 CaAm, 67 AfAm, and 46 other races) (8). We found that tumor suppressor gene, TP53, was the top differentially mutated gene that occurred more frequently in AfAm patients with EEC. This is consistent with our recent publication that the TP53 tumor suppressor is more frequently mutated in AfAm patients compared to CaAm patients when several cancer types (e.g., lung, colorectal, bladder, prostate and breast cancer) were analyzed together (9). Moreover, survival analysis of TCGA patients with EEC showed that patients with TP53 mutations have generally poorer outcomes than those with wild-type TP53. Furthermore, our pathway analysis using the RNA sequencing (RNA-Seq) data from TCGA showed that fatty acid metabolism pathway is upregulated in AfAm patients with EEC compared to their CaAm counterparts. Further analysis showed that TP53 mutations are also associated with downregulation of AMP-activated protein kinase (AMPK) and activation of mTOR (mammalian target of rapamycin) pathways, which can lead to dysregulation of fatty acid metabolism and promotion of tumorigenesis (10). Furthermore, obesity is a significant risk factor for EC (11, 12), consistent with our TCGA data analysis showing that AfAm patients with EEC were more likely to be obese than CaAm patients (39.1 vs. 34.6, mean BMI indexes) and with our observation in a cohort of 247 patients, including 47 AfAm and 196 CaAm patients with EEC (35.5 vs. 33.6, mean BMI indexes) from the Precision Oncology Initiative (POI) at Wake Forest Baptist Cancer Center (WFBCC). Of note, inhibition of AMPK activity also leads to obesity and type 2 diabetes (13). Thus, differential TP53 mutations emerge as a major genetic factor that contributes to cancer health disparity. Citation Format: Farideh Mehraein-Ghomi, Liang Liu, Umit Topaloglu, Karen Winkfield, Michael Kelly, Boris Pasche, Wei Zhang. Dysregulation of fatty acid metabolism by TP53 mutations underlies more aggressive endometrial cancers in African American women [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C002.