Pathway-centric multi-omics and functional precision medicine reveal shared drug vulnerabilities in heterogeneous adult Wilms tumor

Abstract

Wilms tumor, i.e., nephroblastoma, is rare in adults and lacks standardized treatment, complicating clinical decision-making. Within the functional precision medicine study (DEDUCER), we profiled two spatially distinct tumor regions (T1 and T2) of an adult Wilms tumor patient using integrated histopathology, whole-exome sequencing, FFPE transcriptomics, and ex vivo drug screening of short-term cultured patient-derived cancer cells (PDCs) with 528 compounds. Genomic profiling revealed a truncal ASXL1 frameshift and shared F7, UBA1, COL21A1, and ATM variants alongside region-specific alterations: a TP53 mutation and broad copy-number (CN) gains in T1, versus ARID1A and KMT2D stop-gains in copy-neutral T2. Transcriptomics of tumor areas identified convergent activation of the G2/M checkpoint, E2F targets, and mitotic spindle programs across regions, consistent with high proliferation and partially comparable biomarker signatures to those observed in an open-source pediatric Wilms tumor dataset (n = 130). Functional assays uncovered distinct and shared drug vulnerabilities: although ATM alterations were present in both tumors, T1 PDCs showed selective sensitivity to topoisomerase I and BCL-2 inhibition in the context of an additional T1-specific TP53 alteration, while broader single-agent sensitivity and stronger drug synergies were observed in T2. Pathway-centric data integration indicated that differential gene expression and copy-number gains, rather than single mutations alone, better predicted ex vivo drug responses, revealing actionable shared dependencies despite pronounced spatial heterogeneity and establishing a translational framework for individualized management in this rare disease. HIGHLIGHTS- In the adult Wilms tumor, multi-region genomics revealed a truncal ASXL1 frameshift together with F7, UBA1, COL21A1 and ATM mutations across two tumor regions (T1 and T2), as well as region-specific alterations: TP53 mutation and widespread copy-number gains in T1, versus ARID1A and KMT2D stop-gains in copy-neutral T2, illustrating spatial heterogeneity. - Transcriptomics showed convergent activation of E2F targets, G2/M checkpoint, and mitotic spindle programs in both regions, consistent with high proliferation and aligning with Wilms tumor signatures (TARGET dataset); these pathways were associated with higher ex vivo drug sensitivity scores. - Functional drug sensitivity testing of patient -derived cancer cells ex vivo uncovered distinct and shared vulnerabilities: Although both tumors shared an ATM mutation, T1-specific TP53 alteration and death-pathway/stress-response alterations may underlie selective sensitivity to topoisomerase I inhibitors and BCL-2 inhibition. - Clinically relevant combinations, including vincristine plus dactinomycin and doxorubicin plus dactinomycin, showed ex vivo synergy. These findings are consistent with the patients more than five-year relapse-free outcome following vincristine, doxorubicin, and dactinomycin treatment combined with surgery, supporting the translational relevance of the ex vivo drug testing approach. - Pathway-centric integration (copy-number gains and differential expression) predicted drug response better than single-gene biomarkers. Overall, pathway-level dependencies provide robust, actionable targets despite genomic and phenotypic heterogeneity in adult Wilms tumor.