Somatic mutations of esophageal adenocarcinoma: a comparison between Black and White patients
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 mutations in EAC regarding racial disparities is limited.
Methods
We performed whole-exome sequencing of tumors and performed mutational signature analysis using non-negative matrix factorization (NMF) and R package MutationalPatterns. To compare the difference by race, we performed Wilcoxon rank test and then used Bonferroni adjusted significant tests. Somatic single nucleotide variants (SNVs) and short insertion-deletions (InDels) called by at least two of three variant calling algorithms were filtered by a read-depth of 50 × or higher. This analysis included variant allele frequency (VAF)>5% and rare variants with < 1% MAF.
Results
We identified a mutation signature defined by a high prevalence of C>T transversion. By race, the median variant of Black patients was 1.6-fold higher (N=1,017) compared to White patients (N=613). The mutational profile of EAC clustered into three mutational signature groups. Group 1 (Signature A) has shown to be common in the most common cancers. Group 2 (Signature B) is associated with smoking or chewing tobacco. Group 3 (Signature C) is associated unknow etiologic factor, i.e. race. Signature 12 (unknown etiology) shows substantially more contribution in EAC tumors from White patients than in EAC tumors from Black patients (p=0.0008, q=0.02). Four genes (MUC2, MUC3, MUC5AC, and MUC6) were observed in most of samples (78%) and ARID1A, SMAD4 observed in only White patients. These genes have been shown as important genes on EAC progression. Therefore, it could be distinguishing biomarkers for EAC between ethnic groups at early stage.
Conclusion
In summary, our present study, which to our knowledge is the first comprehensive exome sequencing analysis to evaluate the difference of mutations between Black and White EAC patients using mutational signature analysis, is a novel method to provide insight into the biological mechanisms involved in carcinogenesis of EAC. Discovering key genetic changes could generate novel early diagnostic markers and actionable targets for efficacious intervention and drug discovery. Future studies are needed to illuminate and validate these findings that could eventually contribute to Precision Oncology in EAC.