237. DIFFERENTIAL CLONAL EVOLUTION IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA IN RESPONSE TO NEO-ADJUVANT CHEMORADIOTHERAPY

As a major component of esophageal squamous cell carcinoma (ESCC) treatment regimen, neo-adjuvant chemoradiotherapy (NCRT) affects ESCC genome is largely unknown. Deciphering the evolutionary history of ESCC following NCRT would reveal dynamic mutational processes and enable us identify the key molecular features associated with NCRT-resistance. We performed whole exome sequencing (WES) on matched pre-NCRT endoscopic biopsy tissue (n = 29), post-NCRT cystectomy tumor tissue (n = 30). On the basis of a rigorous evaluation of estimated percentage of the estimated percentage of vital residual tumor cells, 29 pre-NCRT cases were classified into two groups: major response (n = 20) and minor response (n = 9). The computational method PyClone was used to define subclones within each tumor. The method Clonality Inference in Tumors Using Phylogeny (CITUP) was subsequently used to infer phylogenetic relationships among subclones. By comparing the subclonal composition of each patient before and after NCRT, we found that resistant subclones were polyclonal and driver mutations improved the fitness of resistant subclones. The number of driver mutations existed in resistant subclones was positively related to the size of subclones. The most frequent driver genes in resistant subclones identified in our research included TP53, NOTCH1 and a novel gene RYR3. Multi resistant subclones result in the resistance of ESCC genome to NCRT. The fitness of resistant subclones is relevant to the number of driver mutations.