Lung cancer is the leading cause of cancer-related death worldwide, with a 5-year survival rate of ~18% (1-3). Non-small cell lung cancer (NSCLC) comprises 85% of all lung cancer cases. Great strides have been made with the development of more advanced diagnosis, prognosis, and treatment strategies. Despite improvements, African American patients (AAs) continue to present with more advanced stages and later-stage metastatic tumors of lung cancer at diagnosis. The severe types of lung cancer can reduce the 5-year survival rate to only 4% (4). The disparities may partially be due to the socioeconomic disadvantages of AAs in receiving cancer services (5). Etiologically, cigarette smoking and exposure to secondhand smoking are leading preventable causes of lung cancer and premature death in the United States (US) (5). Notably, menthol cigarettes, which have been particularly marketed to communities with high AA population (7), can cause deeper inhalation, increased absorption of tobacco toxicants, a higher nicotine dependence and reduced cessation success (6-8). Some genetic alterations have been suggested to contribute to the disparities of breast cancer (9), but genetic factors have not been well studied in lung cancer disparities. Utilizing the genomic data from the Precision Oncology Initiative (POI) cohort at the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC), our initial analysis has shown that TP53 has a significantly higher mutation rate in AA patients, which was validated with the TCGA cohort (10). Furthermore, codons including Cysteine 176 (C176) and C242 mutated more frequently in AA than CA patients. Considering the four amino acids in the zinc-binding region (C176, Histidine 179 [H179], C238, and C242), AA patients have a higher mutation rate than CA patients within both our POI (15% v.s. 5%, P=5E-4) and the TCGA (14% vs. 6%, P<5E-4) cohorts. NSCLC patients with TP53 mutations experienced a poorer survival outcome, and, importantly, mutant AA had shorter overall survival than their CA counterparts. Utilizing RNA-Seq data of NSCLC patients from the TCGA cohort and Gene Set Enrichment Analysis (GSEA), we also identified increased transcriptional activation of fatty acid metabolism and reactive oxygen species (ROS) among TP53 mutation carriers; both pathways/processes are related to an immunosuppressive tumor microenvironment (TME). More importantly, significantly increased expression of these two gene sets was observed in AA cases with TP53 mutations than in their CA counterparts. The immunosuppressive TME in TP53-mutant (vs. wild-type) and mutant AA (vs. CA) patients were further validated by analyzing the immune cell components in each patient using computation algorithm CIBERSORT (11). These analyses implicate that mutated TP53 differentially contributes to cancer disparities in the AA population through metabolism and immune suppression, and mutations in the zinc-binding domain of p53 protein are specifically crucial.
Citation Format: Liang Liu, Farideh Mehraein-Ghomi, Elizabeth Forbes, Umit Topaloglu, W. Jeffrey Petty, Stefan Grant, Jimmy Ruiz, Kristie L. Foley, Karen Winkfield, Boris Pasche, Wei Zhang. TP53 mutations reprogram fatty acid metabolism and tumor microenvironment in African American patients with non-small cell lung cancer [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 C001.