Abstract 2280: Comparison of somatic mutations of whole exome sequencing data from black and white patients with esophageal adenocarcinoma
Authors: Zhao Jing , Tsavachidis Spiridon , Amos Christopher , Thrift Aaron P. 
Published: June 2022

Abstract
Introduction: Esophageal adenocarcinoma (EAC) is the most common histological subtype of esophageal cancer in western countries and shows poor prognosis and rapid growth. EAC is characterized by a strong male predominance and racial disparity. EAC is up to five-fold more common among whites than Blacks, yet Black patients with EAC have poorer survival rates. The reason for the racial disparity is still largely unknown. Knowledge of somatic mutations in EAC from recent DNA sequencing studies have shown EAC has a high mutation burden and distinct mutational signatures. However, knowledge of mutations in EAC regarding racial disparities is limited.
Methods: In this study, we performed whole-exome sequencing of tumors obtained from 10 Black patients and 8 White patients with EAC. We performed Principal Component Analysis (PCA) by using subset of SNPs with FST&gt;0.2. We performed mutational signature analysis using non-negative matrix factorization (NMF) and R package MutationalPatterns. We used the Wilcoxon rank-sum test to compare mutational signature contributions between racial groups and performed Fisher’s exact test to compare the gene-level somatic mutation counts between racial groups. All p-values were two sided and the significant level was 0.05.
Results: We identified 5,281 variants for the PCA and found principal component 1 (PC1) was strongly associated with race. We identified 94,482 somatic mutations and found 3 mutational signatures (A, B and C). “Signature A” was strongly correlated with Signature 19 (cosine-similarity: 0.80, unknown etiology), “Signature B” was strongly correlated with Signatures 4 and 29 (cosine-similarity: 0.78 and 0.80 respectively, etiology: smoking and chewing tobacco), and “Signature C” was strongly correlated with Signature 1 (cosine-similarity: 0.82, etiology: aging). There were no statistically significant differences of the 3 mutational signatures between tumors from black and white patients in EAC. When decomposing mutation count matrix into a sum of known components, we identified 25 COSMIC signatures, and found Signature12 (unknown etiology) shows more contribution in Black patients than in White patients and the difference was statistically significant (p=0.0008, q=0.02). For gene-level analysis, we found TP53 was the most frequently mutated in EAC patients and ARID1A and SMAD4 were the second group of driver genes. There was no statistically significant difference between the gene-level mutations among blacks and whites (Fisher exact test, P&gt;0.05).
Conclusion: These results demonstrate that EAC from black patients are similar to cancers from white patients with respect to clinically actionable genomic alterations. Mutational signature 12 might be the characteristic gene mutation that contribute to the racial difference between Black and White EAC patients.
Citation Format: Jing Zhao, Spiridon Tsavachidis, Christopher Amos, Aaron P. Thrift. Comparison of somatic mutations of whole exome sequencing data from black and white patients with esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2280.