Whole exome sequencing identifies novel somatic variants in Xinjiang Kazak esophageal squamous cell carcinoma

The incidence of esophageal squamous cell carcinoma (ESCC) is increasing globally. Notably, in Xinjiang, China, ESCC patients have garnered significant attention due to their unique epidemiological characteristics. Specifically, the mortality rate of Xinjiang Kazakh ESCC (referred to as XK ESCC) is substantially higher than the national average in China. This alarming disparity underscores the critical need for identifying new therapeutic targets. In this study, we aimed to elucidate the underlying genomic abnormalities in XK ESCC by conducting whole-exome sequencing on four matched pairs of esophageal squamous cell tumors and adjacent control tissues from Xinjiang Kazakh individuals. Comprehensive statistical analysis of the exome data revealed multiple somatic mutations, copy number variations (CNVs), and 14 potential cancer driver genes harbouring missense mutations. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses were performed on 75 significantly mutated genes (SMGs). Intriguingly, we identified IFNA17 and NLRP6 as significantly mutated genes enriched in the NOD-like receptor signaling pathway. Subsequent functional studies on ESCC-derived IFNA17 and NLRP6 mutants demonstrated that these mutations enhance cellular invasion. To the best of our knowledge, this study represents the first comprehensive exome sequencing analysis specifically targeting XK ESCC. Our findings highlight novel mutation loci that may explain the aggressive nature of XK ESCC. These insights could contribute to the development of early diagnostic and prognostic markers, as well as therapeutic targets, tailored for XK ESCC.