Abstract C007: Age-Stratified Causal Reconstruction of Ewing Sarcoma Reveals Three Molecular Subtypes With Distinct Clinical Trial Implications
Tiara S. JamisonAbstract
Background:
Ewing sarcoma is traditionally classified as a single EWSR1-ETS fusion-defined malignancy, yet patients demonstrate substantial heterogeneity in age at presentation, genomic complexity, treatment response, and relapse risk. Current treatment paradigms remain largely uniform, suggesting that clinically relevant biological heterogeneity may be obscured by fusion-based classification alone. We applied age-stratified causal reconstruction to determine whether Ewing sarcoma contains reproducible molecular architectures with direct implications for pediatric cancer stratification and clinical trial design.
Methods:
We analyzed two independent Memorial Sloan Kettering Ewing sarcoma cohorts comprising 473 patients, including a discovery cohort of 295 patients and an independent validation cohort of 178 patients. Clinical and genomic features, including age, mutation burden, tumor mutational burden, loss of heterozygosity, fraction genome altered, structural variants, copy number alterations, STAG2, TP53, EWSR1-ETS fusions, and chromatin remodeling alterations, were integrated using CASCADE, an AI-enabled Biology-First Intelligence causal reconstruction system designed to infer disease architecture from multidimensional cancer data without disease-specific configuration.
Results:
Three reproducible, age-stratified molecular subtypes were identified across both cohorts. ES-C, or Canonical Pediatric Ewing, represented the largest group and was characterized by younger age, low mutation burden, low genomic instability, and fusion-dominant biology. ES-L, or Late-Onset Ewing, showed the oldest age at presentation, relatively few point mutations, and disproportionate structural/genomic instability, consistent with a distinct late-onset trajectory. ES-H, or Hypermutated Ewing, demonstrated intermediate age, the highest mutation burden, and extensive genome alteration, including markedly elevated fraction genome altered. Subtype reproducibility was supported by consistent cluster proportions, age gradients, mutation burden gradients, STAG2 and TP53 alteration frequencies, and chromatin remodeling disruption across cohorts. Near-universal chromatin remodeling alteration was observed, suggesting a shared epigenetic vulnerability across distinct Ewing architectures.
Conclusions:
These findings suggest that Ewing sarcoma is not a single biological entity, but a fusion-associated disease family composed of distinct age-stratified molecular architectures. This classification provides a clinically actionable framework for pediatric cancer trial design: standard therapy optimization for ES-C, structurally informed or intensified strategies for ES-L, and evaluation of immune or DNA damage response-based approaches for ES-H. Prospective validation in outcome-linked cohorts is warranted. Causal architecture reconstruction may provide a scalable path from molecular discovery to clinically meaningful pediatric cancer stratification.
Citation Format:
Tiara S. Jamison. Age-Stratified Causal Reconstruction of Ewing Sarcoma Reveals Three Molecular Subtypes With Distinct Clinical Trial Implications [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Bridging Discovery and Clinical Impact in Pediatric Cancer; 2026 Sep 22-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_1):Abstract nr C007.