Abstract PR013: Genetic evolution of sarcomatoid/rhabdoid de-differentiation in renal cancers

Abstract Background: The presence of sarcomatoid and rhabdoid (SR) differentiation is associated with poor prognosis in renal cell carcinomas (RCCs), yet molecular underpinnings of SR patterns are understudied. While advances in cancer genomics have shed light on substantial intratumoral heterogeneity (ITH) in RCC, the evolutionary dynamics fueling disease progression, and emergence of SR dedifferentiation has remained poorly understood. Methods: We conducted multi-region whole-exome sequencing (WES) of 156 tumor samples, representing S/R histological features and matched clear-cell or papillary tumor areas from 46 RCC patients. Somatic variant and copy number analysis was performed to identify distinct subclonal populations within each sample. Using PyClone and ClonEvol, we modeled the trajectories of subclonal evolution within each patient, capturing the emergence and progression of shared and site-specific subclones across tumor regions and metastatic sites. Results: We observed significant ITH across RCC subtypes. Each individual sample exhibited several cell populations with distinct profiles of subclonal somatic mutations. Temporal ordering of subclones revealed the emergence of new subclonal cell populations during the transition to S/R differentiation. We constructed phylogenetic trees for each individual patient, in which the emergence of subclones driving S/R features exhibited both monoclonal and polyclonal seeding patterns, suggesting that there may be several evolutionary routes to these changes. Significance: Monoclonal tumors showed a more uniform path of evolution, while polyclonal tumors exhibited greater genetic complexity, reflecting the diversity of tumor progression patterns. These findings underscore the importance of targeting truncal mutations in early-stage tumors and monitoring subclonal evolution in aggressive phenotypes. Citation Format: Natalie R. Abuelsamen. Genetic evolution of sarcomatoid/rhabdoid de-differentiation in renal cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr PR013.