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Esophageal adenocarcinoma: understanding the molecular basis of differential treatment response

Subject Area Pathology
General and Visceral Surgery
Bioinformatics and Theoretical Biology
Term from 2019 to 2026
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 418074181
 
Final Report Year 2024

Final Report Abstract

Esophageal cancer is the sixth most common cause of cancer-related death. The most prevalent subtype of esophageal cancer in Western countries is esophageal adenocarcinoma (EAC). A combination of radio- and chemotherapy (RCT) before surgery is standard of care but the response varies dramatically, ranging from minor response (70% of patients) over major response where <10% vital cancer cells remain (15% of patients) to complete response (15% of patients). The factors that determine the different responses are unknown. In this study, we addressed two clinically relevant questions: a) What distinguishes a cancer cell that is resistant from their sensitive counterpart in the same tumor of a major responder? b) Are there molecular differences between tumors of complete responders who relapse early compared to late? To investigate the molecular nature of resistance, we compared the residual vital (resistant) tumor of major responders after treatment with the paired treatment-naïve primary tumors by whole exome- and RNA-sequencing. In 20% of patients, we observed dramatic differences between the genomic profiles (copy number and point mutations) of preand post-therapy (resistant) EAC. The data suggest that very early, potentially dormant clones survive RCT while cancer cells of the same tumor that acquired many more genomic copy number alterations during tumor evolution died. Post-therapy tumors were characterized by upregulation of extracellular matrix genes MMP2, THY1, POSTN and COL5A1 typical for cancer-associated fibroblasts. We screened 600 EAC specimen and found a significant association between moderate (not high) POSTN expression and long overall survival suggesting POSTN as a marker for late relapse. To determine the molecular characteristics of early relapse we analyzed 122 EAC tumor/normal pairs across different therapy response- and survival groups by whole exome and RNA-sequencing. We identified 15 potential driver genes for EAC, among them are new candidates that have not been described before. Comparing the mutational landscape between long and short survivors, FAT3, RYR3 and MAP2K7 were significantly more frequently mutated in short survivors. Investigating the chromosomal structures for regions that gained or lost copies, we observed two groups, a genomically stable (38%) and instable group (62%). There was a trend of complete/major responders being enriched for genomic instable genomes suggesting that genomic instable EAC might be more vulnerable to RCT. On the transcriptomic level, no significant differences between response groups or survival rates could be identified. Overall, our study reveals dramatic genomic changes of EAC through RCT in 20% of patients, markers in the stroma that are characteristic for treatment response or survival and suggests that the genomic structure might be a predictor for RCT response.

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