Mapping the Clinical and Molecular landscape of childhood renal tumors: with a special focus on relapsed Wilms tumors.

Abstract

Wilms tumors (WT) are the most common renal tumors in children. Although survival after primary WT exceeds 90% in high-income countries, roughly 15% of patients relapse, associated with survival rates of 70-50%, reaching as low as 10% in patients with high-risk primary tumors. In this thesis, we reviewed prognostic factors for recurrence, highlighting biological markers including 1q gain, loss of heterozygosity (LOH) of 1p/16q, and LOH of 11p15, which may contribute to future risk stratification at diagnosis. We subsequently evaluated outcomes of relapsed WT patients treated within the International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG), retrospectively stratified according to the latest treatment protocol. In patients initially treated with vincristine and actinomycin-D (VA), CyCED (cyclophosphamide, carboplatin, etoposide, doxorubicin) at first relapse resulted in five-year event-free survival (EFS) and overall survival (OS) of 74.8% and 73.1%, respectively. Some patients were successfully treated with less intensive VAD (vincristine, actinomycin-D, doxorubicin), although these patients could not be specifically identified. Among patients previously treated with more intensive upfront therapy, five-year EFS and OS were 62.7% and 67.6% for high-risk relapse, compared with only 17.4% and 18.6% for very high-risk relapse. ICE/CyCE regimens were associated with five-year OS rates of 73.9% and 30.9% in high- and very high-risk relapse, respectively. Patients experiencing a second relapse could still be rescued, with five-year OS rates of 41.0% following an initial standard-risk relapse and 21.9% following a high-risk relapse. Outcomes following very high-risk relapse remained poor, emphasizing the need for novel therapeutic strategies. To support personalized treatment approaches, we demonstrated the feasibility of developing tumoroids from internationally collected relapsed WT tissue, enabling high-throughput drug screening within a clinically relevant timeframe. Paired primary-relapse gene expression analyses further suggested that relapse may be associated with impaired immune regulation and activation of cancer stem-cell programs, thereby potentially preserving a stem-like cellular state. We additionally investigated translocation-type renal cell carcinoma (tRCC), applying genomic and transcriptomic analyses to identify molecular drivers and potential therapeutic vulnerabilities. Our findings suggest that tRCC is partly driven by dysregulated epigenetic control, with fusion products affecting distinct transcriptional programs involving apoptosis, immune regulation, extracellular matrix/cell adhesion, tyrosine kinase signaling, and angiogenesis. Overall, this thesis demonstrates how clinical factors combined with genomic and transcriptomic insights can improve relapse-risk identification, patient stratification, and therapeutic target discovery in relapsed WT and tRCC.