Abstract 5566: African American esophageal squamous cell carcinoma expression profile reveals dysregulation of stress response and detox networks

Abstract

Abstract Background: Esophageal carcinoma is the third most common gastrointestinal malignancy worldwide and is largely unresponsive to therapy. African-Americans have an increased risk for esophageal squamous cell carcinoma (ESCC), this subtype that shows a marked variation in geographic incidence. So far, the molecular architecture of African-American ESCC is still poorly understood. It is unclear why African-American ESCC is more aggressive and the survival rate of these patients worse than those of other ethnic groups. Our aim is to investigate the central question of whether there is a genetic basis for the aggressive nature of ESCC among African-Americans through analysis of genetic overlaps and differences between African-American ESCC and reported Asian data. Methods: We conducted microarray expression profiling in pairs of esophageal squamous cell tumors and matched controls to define genetic alterations that occur in African American ESCC. We then utilized Ingenuity Pathway Analysis (IPA) to analyze the differentially expressed genes in African-American ESCC. We conducted a meta-analysis of differentially expressed genes of African American ESCC and those of Asian ESCC through IPA. Results: Transcriptome profiling of African- American ESCC tumors versus adjacent normal esophageal tissues revealed significant differential expression of 756 genes. Among the most strongly up-regulated genes were keratin 17, immunoglobulin genes and ornithine decarboxylase 1. Genes that showed a great loss of expression included cysteine-rich secretory protein 3 and sciellin. We performed pathway and network analysis on significantly dysregulated genes using IPA to determine the overall biological impact of the widespread transcriptional aberration in African-American ESCC. We found significant dysregulation of genes encoding drug-metabolizing enzymes and stress response components of the NRF2- mediated oxidative damage pathway, potentially representing key genes in carcinogenesis in ESCC in African Americans. Loss of activity of drug metabolizing enzymes would confer increased sensitivity of esophageal cells to xenobiotics, such as alcohol and tobacco smoke, and may account for the high incidence and aggressiveness of ESCC in this ethnic group. A meta-analysis of ESCC expression profiles in our African American sample and those of several Asian samples determined genes in the NRF2 pathway are uniquely and significantly altered in African-American ESCC. Down-regulation of TP53 pathway components represented the most common feature in ESCC of all ethnic groups. Importantly, this analysis revealed a potential distinctive molecular property of African-American ESCC a widespread and prominent involvement of NRF2 pathway. Conclusion: Taken together, these findings highlight the remarkable interplay of genetic and environmental factors in the pathogenesis of African-American ESCC. Citation Format: Hayriye Verda Erkizan, Jack Lichy, Vincente Notario, Robert Wadleigh. African American esophageal squamous cell carcinoma expression profile reveals dysregulation of stress response and detox networks [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5566. doi:10.1158/1538-7445.AM2017-5566