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Comprehensive genomic profiling of early-stage esophageal squamous cell carcinoma

Abstract Background Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers without effective therapy. To explore therapeutic options, the mutational profile of ESCC tumors has to be elucidated to understand the molecular mechanism of its development and explore targetable mutations. In this study, we aim to elucidate the mutational profile of ESCC patients. Methods Capture-based targeted sequencing was performed on tissue samples surgically-removed from 29 early-stage ESCC patients using a 520-gene panel to comprehensively profile the genomic alterations in ESCC. Tumor mutation burden was also estimated for all the samples. Results A total of 421 mutations in 39 genes were detected in all the patients, revealing a mutation detection rate of 100%. The mutation types detected in the cohort included 55% single nucleotide variations, 35% copy number amplification and the remaining 10% were small insertion-deletions and large deletions. Except for 1 patient, all of the patients were TP53 mutant. Copy number amplifications (CNA) in CCND1, FGF3, FGF4 and FGF19 were found in 41% (12/29) of the patients, respectively, with all CNA in 4 genes occurring concurrently in all patients. Interestingly, mutations in NFκB1A, previously unreported in ESCC, were detected in 21% (6/29) of the patients. Further analysis reveals mutations in genes involved in pathways including cell cycle, chromatin modification, Notch and JAK-STAT signaling, suggesting that these may be the most critical pathways involved in the development and progression of ESCC. No actionable mutations in receptor tyrosine kinases were detected in our cohort. Instead, potential therapeutic target analysis identified CDKN2A and PIK3CA, with mutation detection rate of 20.7% and 13.8%, respectively, as candidates for targeted therapy. In addition, the median TMB of the cohort was 5.6 mutations/Mb, ranging from 0.8 to 42.9 mutations/Mb. Conclusions Our study reveals the comprehensive mutation profile of ESCC tumors, shedding light on potential molecular mechanisms associated with its development and possible therapeutic options for ESCC patients. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.