Discovery of potential predictive marker and targeted therapy to overcome chemotherapy resistance in an advanced stage Wilms' tumor

Wilms tumor (WT) is the most prevalent type of renal cancer in children. Although the overall survival rates of WT are greater than 90%. chemotherapy resistance, chemotherapy resistance remains a major challenge for the treatment of advanced stage WT, which accounts for 10% of all WT cases. In this study, we aimed to discover potential mutation markers and drug targets for chemotherapy resistance in advanced stage WT. We conducted exome sequencing to detect somatic mutations and molecular targets in 43 WT samples, comparing 26 advanced stage WTs of which 7 cases are chemotherapy-resistant. We identified four genes (ALPK2, C16orf96, PRKDC, and SVIL) that were correlated with chemotherapy resistance and reduced disease-free survival in advanced stage WT. We also detected driver mutations in 55 genes in the chemotherapy-resistant group of advanced stage WT, among which 14 were druggable cancer driver genes. Based on the mutation profile of the resistant WT samples, we suggested possible therapeutic strategies, such as platinum-based agents, PARP inhibitors, and antibiotic/antineoplastic agents. Our results uncover the genetic landscape and the potential drug targets of WT, particularly for the group with chemotherapy resistance.