2026 Proffered Presentations
S114: METHYLATION AND PROTEOMIC SIGNATURES OF RADIOSENSITIVITY IN CHORDOMA
Andrew Ajisebutu1; Chloe Gui1; Jeff Zuccato1; Gelareh Zadeh2; 1University of Toronto; 2Mayo Clinic
Introduction: Chordomas are rare, aggressive primary bone malignancies of the skull base and spine that remain therapeutically challenging. Despite radical surgical resection and adjuvant radiotherapy representing the current standard of care, long-term outcomes remain poor, with a 10-year overall survival of approximately 40% and frequent disease recurrence. Although radiotherapy is a cornerstone of treatment, its clinical benefit is variable, and prior studies have yielded inconsistent evidence regarding its impact on survival. To clarify the molecular determinants of radiotherapy response, we investigated the role of DNA methylation-defined subtypes and complementary proteomic alterations in chordoma.
Methodology: We analyzed a multi-institutional cohort of n =102 patients spanning a 20-year period, comprised of a discovery cohort of our previously published cohort as well as n = 32 newly analysed samples in our validation cohort. Genome-wide DNA methylation profiling was performed using the Illumina EPIC array Clinical outcomes were assessed in relation to molecular subtype and treatment exposures using Kaplan–Meier analysis and multivariable Cox proportional hazards modeling. In a subset of cases, mass spectrometry–based proteomic profiling was performed to interrogate subtype-associated protein-level changes and to identify pathways potentially underlying treatment sensitivity.
Results: Patients classified within the cellular molecular subtype who received radiotherapy demonstrated significantly improved overall survival (median 17.3 years, p=0.0208) compared with those harboring the immune-infiltrative subtype (median 6.0 years). Notably, the favorable prognosis of the cellular subtype was largely seen in the absence of radiotherapy, suggesting a subtype-specific enhancement of radiosensitivity. Progression-free survival did not differ significantly between irradiated cellular and immune-infiltrative tumors (p=0.65), indicating that improved survival was not attributable solely to delayed recurrence. Proteomic analysis reinforced these findings, identifying distinct protein expression patterns related to DNA damage repair and immune signaling that aligned with methylation-derived subtypes and provided mechanistic support for differential radiotherapy responses.
Conclusion: We validate and extend the utility of a DNA methylation–based chordoma classifier, demonstrating that subtype assignment has significant prognostic and predictive implications for radiotherapy benefit. Integration of proteomic profiling further highlights candidate biological mechanisms of radiosensitivity. These results support the incorporation of molecular stratification into clinical decision-making for chordoma and underscore the promise of integrative, multi-omic approaches to guide precision therapy in this rare malignancy.