(P 132) MOLECULAR LANDSCAPE AND CLINICAL HETEROGENEITY OF BRAZILIAN CHONDROSARCOMAS: INSIGHTS FROM IDH, TERT, AND GENOME-WIDE ANALYSIS

Objective: Chondrosarcomas (CS) account for ~30% of malignant bone tumors, with 90% being conventional subtype. Mutations in IDH1/IDH2 and the TERT promoter occur in ~50% and 23–60% of cases, respectively. These alterations have been linked to high-grade or metastatic tumors and poorer prognosis, though findings remain conflicting. Alone, they do not fully explain the clinical heterogeneity of CS. This study aims to characterize somatic genomic alterations associated with CS development and behavior.

Methods: We expect to include 100 Brazilian patients (pts) diagnosed with conventional CS between 2002–2024. Hotspot mutations in IDH1 (R132), IDH2 (R172), and TERT (c.-124C>T, c.-146C>T) were assessed via targeted next-generation sequencing (NGS). Associations between mutation status and clinical variables were evaluated using non-parametric tests, χ² or Fisher’s exact test. Additionally, whole-exome sequencing (WES), methylation profiling, and optical genome mapping are underway in a subset of 30 pts with conventional or dedifferentiated CS showing extreme phenotypes (indolent vs. aggressive disease).

Results: This interim analysis includes 88 pts (54% male, 45% female), with median age 43 years (range: 11–81). Only 3.4% of patients had metastases at diagnosis, which increased to 20% during follow-up, and an additional 20% had local recurrences. IDH1 mutations were found in 33% of cases, IDH2 in 8%, and TERT in 32%. Co-occurring IDH+TERT mutations were seen in 19% and were significantly associated with higher tumor grade (p=0.005), older age (p=0.002; mean 55 vs. 45 years), and larger lesions (p=0.008; mean 14 vs. 9 cm). Somatic WES in 10 pts identified driver mutations in half of them, affecting genes such as TP53, PTCH1, KRAS, CDKN2A, CREBBP, and PBRM1. One case exhibited a high tumor mutational burden (40 mut/Mb).

Conclusion: One case exhibited a high tumor mutational burden (40 mut/Mb).

Conclusion: Preliminary findings suggest lower frequencies of IDH1, IDH2, and TERT mutations in this Brazilian cohort compared to previous studies. Co-mutated IDH+TERT tumors were linked to features of poor prognosis. Continued analysis aims to refine the molecular landscape of CS and identify therapeutic targets and prognostic biomarkers.