Abstract 7499: Genetic evolution of sarcomatoid/rhabdoid de differentiation in renal cancers

Abstract Background: The presence of sarcomatoid and rhabdoid (SR) differentiation is associated withpoor prognosis in renal cell carcinomas (RCCs), yet molecular underpinnings of SR patterns areunderstudied. While advances in cancer genomics have shed light on substantial intratumoralheterogeneity (ITH) in RCC, the evolutionary dynamics fueling disease progression, andemergence 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 46RCC patients. Somatic variant and copy number analysis was performed to identify distinctsubclonal populations within each sample. Using PyClone and ClonEvol, we modeled thetrajectories of subclonal evolution within each patient, capturing the emergence and progressionof shared and site-specific subclones across tumor regions and metastatic sites. Results: We observed significant ITH across RCC subtypes. Each individual sample exhibitedseveral cell populations with distinct profiles of subclonal somatic mutations. Temporal orderingof subclones revealed the emergence of new subclonal cell populations during the transition to S/Rdifferentiation. We constructed phylogenetic trees for each individual patient, in which theemergence of subclones driving S/R features exhibited both monoclonal and polyclonal seedingpatterns, suggesting that there may be several evolutionary routes to these changes. Significance: Monoclonal tumors showed a more uniform path of evolution, while polyclonaltumors exhibited greater genetic complexity, reflecting the diversity of tumor progressionpatterns. These findings underscore the importance of targeting truncal mutations in early-stagetumors and monitoring subclonal evolution in aggressive phenotypes. Disclosures: The authors have no conflicts to disclose. Citation Format: Natalie R. Abuelsamen, Kate I. Glennon, Mustafa Soytas, Madeleine Arseneault, Peixi Liu, eleonora scarlata, fadi brimo, Simon Tanguay, Yasser Riazalhosseini. Genetic evolution of sarcomatoid/rhabdoid de differentiation in renal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7499.