Abstract 6054: Genomic and transcriptomic remodeling of esophageal squamous cell carcinoma by neo-adjuvant radiochemotherapy

Abstract Objective: To identify genetic and clinicopathological factors that affect the response of patients with esophageal squamous cell carcinoma (ESCC) to neoadjuvant chemoradiotherapy (nCRT), profile the genomic and transcriptomic alterations after nCRT and relate the alterations to patient’s prognosis. Methods: A total of 137 samples from 57 ESCC patients undergoing nCRT were collected. 82 samples including 54 pre-treatment samples and 28 post-treatment samples were subjected to whole-exome sequencing, and 55 samples including 26 pre-treatment samples and 29 post-treatment samples were subjected to RNA-seq analysis. Genetic and clinicopathological factors associated with patient’s response to nCRT were identified by comparing baseline features of patients achieving pathological response (pCR) and patients not achieving pCR. Genomic and transcriptomic profiles before and after nCRT were compared to identify features acquired during nCRT and the association of identified features with patient’s recurrence-free survival (RFS) and overall survival (OS) were investigated. Results: Co-deficiency of DDR and HIPPO pathway at baseline synergistically sensitized ESCC to nCRT. The arachidonic acid metabolism pathway was upregulated at baseline in patients with pCR. The proportion of small deletion and insertion (INDEL %) significantly increased in acquired mutations (p<0.001) and was positively correlated with focal chromosomal loss (Spearman's ρ=0.52, p=0.005) and negatively correlated with broad chromosomal gain (Spearman's ρ=-0.61, p<0.001) after nCRT. Acquired INDEL% was associated with tumor regression grade (TRG) (p=0.06) and predicted the worse RFS (p=0.16) and OS (p=0.067). The degree of clonal expansion during nCRT was associated with patient’s RFS (p=0.0087) and OS (p=0.023), and negative correlated with acquired INDEL % (Spearman's ρ=-0.45, p=0.02). The expression profile of tumor tissue was changed after nCRT and displayed upregulation of cell adhesion and stromal related pathways and downregulation of DNA replication and cell cycle pathways, and the alteration of expression profile was associated with patient’s prognosis. Conclusions: nCRT remodels the genome and transcriptome of ESCC. Small deletion/insertion and focal chromosomal loss may be characteristic genomic alterations imposed by radiation. Acquired INDEL proportion is a biomarker to indicate the efficacy of nCRT and predict patient’s prognosis. The degree of clonal expansion during nCRT reflects the treatment resistance and associated with patient’s prognosis. Citation Format: Yang Yang, TingTing Feng, Xiaojun Fan, Xia Zhou, Wu'an Bao, Danhong Zhang, Hua Bao, Junrong Yan, Xue Wu, Yang Shao, Guoqin Qiu, Dan Su, Qixun Chen. Genomic and transcriptomic remodeling of esophageal squamous cell carcinoma by neo-adjuvant radiochemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6054.