Multiomic Landscape of Esophageal Squamous Cell Carcinoma: Molecular Profiles and Predictors of Neoadjuvant Chemoradiotherapy Responsiveness and Resistance

Background In neoadjuvant chemoradiotherapy (NCRT), only 1/3 of patients with esophageal squamous cell carcinoma (ESCC) achieve pathologic complete response (pCR). Here, we aimed to depict the biological landscape of ESCC with different responses to neoadjuvant chemoradiotherapy and identify biomarkers to facilitate clinical decision-making. Method Tumor specimens before NCRT were obtained for whole exosome sequencing, RNA sequencing, and DIA mass spectrometry. Genomic data were analyzed for significantly mutated genes, copy number alterations, MSI, TMB, and mutational signatures. Transcriptomic and proteomic data were used to examine differentially activated pathways. GSEA and ActivePathways were used for single omics and joint multiomics analyses, respectively. Treatment-resistance biomarkers were identified and confirmed in a separate cohort using IHC. Result FBXW7 mutation (Fisher exact test p =0.029) and 9p21.3 cytoband loss(q-value=0.001) are the significant genetic variations in the pCR group. Combined transcriptomic and proteomic analyses revealed that the type I interferon signaling pathways and RIG-I-like receptor signaling pathways were enriched in non-pCR tumors. A biomarker panel of 12 proteins predictive of non-pCR tumors was identified, 10 of which were verified using mIHC in an independent cohort. Conclusion We described the multiomic biological characteristics of ESCC with distinct responses to neoadjuvant chemoradiotherapy and proposed a panel of proteins as predictive biomarkers for non-pCR patients.