A Genomic Analysis of Squamous Cell Carcinoma of the Oesophagus Following Neoadjuvant Chemotherapy

Background Esophageal carcinoma is a common upper gastrointestinal (GI) malignancy predominantly in East Asian countries. There is a lack of effective molecular markers and therapeutic, esophageal squamous cell carcinoma (ESCC) shows a poor 5 years survival rate. The primary purpose of this study is to identify a clinically relevant genomic and transcriptomic alteration in squamous cell carcinoma of esophagus and their ability to predict a response to NACT. Methods A total of 130 patients with squamous cell carcinoma of the esophagus treated with neoadjuvant chemotherapy followed by surgery were taken for this study. Both pre-operative and postoperative biopsy (operated patients) samples were collected. The genomic variations were interpreted as single nucleotide variations (SNV), small insertions/deletions (INDEL), gene fusion and tumor mutational burden. Fold change was used in the analysis of gene expression data for RNA-Sequencing. Results Out of 130 preoperative samples, 84 passed DNA-QC and 32 passed RNA-QC. SNV was found in 92.5%, while CNV was present in 24.4% of preoperative samples but absent postoperatively. Common CNV-altered genes included CADM4, MEN1, CTNNB1, NTRK1, and FLCN. Fusion occurred in 44% of samples, and P53 mutations were detected in 73%. Cell cycle and protein metabolism were the most altered pathways. Mutations in GDF3, MPL, FLG, NFE2L2, and CAPOX were linked to poor NACT response and survival, while ABCA4, CFHR5, FUT1, HBD, and INCENP were not clinically significant. Conclusion This study identified key genomic and transcriptomic alterations in esophageal squamous cell carcinoma (ESCC) affecting response to neoadjuvant chemotherapy (NACT). Mutations in GDF3, MPL, FLG, NFE2L2, and CAPOX correlated with poor response and survival, while cell cycle dysregulation was the most altered pathway. These findings highlight the potential of molecular profiling to guide personalized treatment, improving patient selection and therapeutic outcomes in ESCC.