Background: Esophageal cancer ranks as the sixth most common cause of cancer-related deaths worldwide. The occurrence and development of esophageal cancer is a complex process that involves multiple genetic variants, including changes in gene function, which could be a crucial factor in its development. Hence, studying the molecular genetic changes specific to esophageal cancer is essential for understanding its mechanism and guiding clinical treatment. In this study, we analyzed and documented genetic variations and clinical information of 82 esophageal cancer patients to provide new insights into the correlation between genes and clinical symptoms. Methods: The tissue and blood-based DNA samples from 82 patients were analyzed using 680-gene targeted capture sequencing for CNV, fusion, SNV, indel, MSI, and TMB. Coverage of tissue with 2200X, cfDNA 20000X, and control gDNA 10000X. Additionally, the level of PD-L1 expression was assessed in the tissue samples. TMB was classified as TMB-H ( > 10 mutations/megabase) and TMB-L ( < 10). MSI-H was determined with instability ≥20% of 117 sites for detection, while < 20% was determined as MSS. Results: The analysis revealed 786 SNV/indel mutations in 82 patients, of which 346 (44.02%) mutations were detected in both tissue and plasma, 296 (37.66%) only found in tissue, and 144 (18.32%) only found in plasma. 378 mutations were detected in CNV, with 181 mutations (47.88%) in tissue and blood, 186 mutations only found in tissue (49.21%), and 11 mutations only in plasma (2.91%). The high-frequency mutation genes identified in this study were TP53, CCND1, FGF19, FGF3/4, NOTCH1, and PIK3CA, which are also listed as high frequency mutated genes in the IntoGen database (7 cohorts, 945 samples). However, the genes CCND1, FGF19, FGF3/4, and PIK3CA in the CNV results were not in the IntoGen high frequency mutated gene list. The results of tTMB vs bTMB were consistent in 80 out of 82 patients (97.56%). Among the 82 samples, 79 had low expression of PD-L1, while 3 had high PD-L1 expression and TMB-L, MSS. Conclusions: Fibroblast growth factor (FGF) signaling system may plays an important role in tumorigenesis and progression. Increase in the expression of FGFs and fibroblast growth factor receptor genes, might lead to genetic alterations in their protein structures and activation of the FGFs-FGFR signaling pathway, which may contribute to the onset of esophageal cancer. In conclusion, the results of our study suggest that the detection of tissue mutations in the blood of esophageal cancer patients is challenging and cannot be reliably determined by a single blood sample. The incidence of PD-L1 expression was low in all esophageal cancer tissues. Further investigation into the correlation between CCND1, FGF19, FGF3/4, and PIK3CA genes and esophageal cancer is warranted.