Genomics of esophageal squamous cell carcinoma in African Americans.

Abstract

e16552 Background: Esophageal cancer (EC) is one of the most lethal cancers with 90% mortality rate. Uneven Worldwide geographical distribution and varying etiologic factors contribute to the heterogenic nature of EC worldwide. In the US, 75% esophageal squamous cell carcinoma (ESCC) is diagnosed in African Americans (AA). However, despite comprehensive and multi-geographical efforts to understand the genomic basis of ESCC, the knowledge of molecular and genetic mechanisms leading to genomic subtyping of AA has been limited due to the underrepresentation of AAs in these studies. We hypothesized that the differences in mutational events in AA ESCC might, in part, cause the disparity in outcome and the mutational events may determine treatment options. Methods: Whole exome sequencing (WES) of matched- tumor and normal-cell DNA from late-stage ESCC of ten AA patients were performed by using Agilent SureSelect XT Human All Exon V6+UTR. Somatic variants per tumor samples called by two or more methods (Mutect2, VarScan2, and Strelka2) were combined and used for downstream population filtering. Somatic copy number changes were determined by using CNVKit in SevenBridges Genomics. Results: Somatic variants called by two or more algorithms filtered and sorted for rare mutations (equal to or less than 1% African originated population frequency) demonstrated an average of 23 nonsynonymous mutations per MB in high mutation rate AA ESCC. The remaining four samples had two or fewer nonsynonymous mutations per MB. TP53 was one of the most frequently mutated gene with 50% of mutation frequency. ARID2 mutated in 30%, EP300 in 20%, and RB1 in 10% of our cohort. Multiple amplified and deleted regions ranging from 94 to 46 were observed in seven samples in contrast to three samples that were silent in terms of copy number variations ranging from 29 to 9. Significant CNV were mostly seen in proliferation, cell cycle and checkpoint genes, squamous cell homeostasis, epithelial to mesenchymal transition, invasion and metastasis, receptor tyrosine kinase and signaling pathways, chromatin remodeling, detoxification, RNA/DNA editing and angiogenesis. Conclusions: WES of ten AA ESCC samples demonstrated a higher mutation rate in a group of patients with many passenger mutations and complex and recurrent copy number changes that affect oncogenic driver genes, which might suggest enhanced subtyping of ESCC in AA.