(P 137) GENOMIC ALTERATIONS IN RARE CARTILAGINOUS TUMOR SYNDROMES ASSOCIATED WITH CHONDROSARCOMA DEVELOPMENT

Objective: Chondrosarcomas (CS) may arise de novo or secondarily from benign cartilaginous lesions, frequently associated with syndromes such as Ollier disease (OD), Maffucci syndrome (MS), and hereditary multiple exostoses (HME). OD and MS are rare, non-hereditary tumor predisposition syndromes caused by post-zygotic somatic mutations, primarily in IDH1 and IDH2, and carry a high risk of malignant transformation to CS (40% and >50%, respectively). In contrast, HME is a rare autosomal dominant disorder caused by germline pathogenic variants in EXT1 or EXT2, with a lower risk of malignization (~3.9%). This study aimed to characterize germline and somatic alterations in patients (pts) with these syndromes, correlating molecular data with clinical phenotype and CS development.

Methods: A cohort of 168 CS cases from A.C.Camargo Cancer Center was analyzed. Clinical data were extracted from electronic records, and germline data for 23 pts were available from a previous study (Carvalho et al., 2023 – PMID: 37536918). Tumor samples (fresh or FFPE) were analyzed for IDH1 (R132) and IDH2 (R172) mutations via targeted next generation sequencing; negative cases proceeded to Oncomine Comprehensive Assay Plus (517 genes) or whole-exome sequencing.

Results: Ten pts were identified with OD (n=3), MS (n=2), or HME (n=5). Median age of CS diagnosis was 41 years, 50% were female, 5/10 had disease recurrence, with 20% developing metastasis. Among HME cases, 3 had pathogenic EXT2 variants and 2 in EXT1, and 4/4 tested tumors were negative for IDH mutations. IDH1 R132 was found in 2/3 OD cases (VAF 12% and 39%), and IDH2 R172 in one (VAF 5%). One MS patient had IDH1 R132 (VAF 5%), and one was negative. Extended genomic analysis is ongoing in IDH-negative cases.

Conclusion: Most patients showed somatic and/or germline alterations in genes known to drive these syndromes, reinforcing their role in tumor predisposition, mosaicism, and malignant transformation to CS. Our findings contribute to the genomic characterization of rare cartilaginous tumor syndromes and will help to expand our understanding of the molecular mechanisms underlying their development and malignant progression.