Molecular profile and clinical behavior of chondrosarcomas

• Grant number: 24/11519-1
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: March 01, 2025
• End date: November 30, 2026
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Giovana Tardin Torrezan
• Grantee: Mariana Amélia Silva de Souza
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil

Abstract

Chondrosarcomas (CS) are rare and heterogeneous tumors, characterized by the formation of hyaline cartilaginous neoplastic tissue, and represent around 30% of malignant bone tumors. Around 90% of CS are conventional and the other 10% are rarer subtypes. The most common point mutations in these tumors occur in the IDH1 and IDH2 genes, present in approximately 52-59% of cases, and in the TERT gene promoter. Alterations in these genes have been linked to high-grade or metastatic tumors, as well as worse prognosis and survival. The objective of the study is to characterize somatic changes associated with the development and clinical behavior of chondrosarcomas. To do this, we included 150 Brazilian patients diagnosed with CS between 2002 and 2024 and with fresh frozen tumor or formalin-fixed paraffin-embedded (FFPE) tumor available at Biobanco A.C. Camargo Cancer Center / Department of Pathological Anatomy. The evaluation of hotspot mutations in IDH1 genes (R132), IDH2(R172) and TERT (c.-124C>T and c.-146C>T) will be performed through multiplex PCR of tumor DNA, followed by next generation sequencing (NGS) on the Ion S5 platform and data analysis in the IGV software. Additionally, we will perform whole exome sequencing (WES) and methylation analysis on a subset of patients with conventional and dedifferentiated CS with and without hotspot mutations and extreme phenotypes (indolent x aggressive disease). Somatic WES will be permormed using the xGen® Exome Research kit on the NextSeq500 equipment, and variant analyzes using the Varseq and Franklin Genoox software. Methylation analysis will be performed with the Infinium MethylationEPIC v2.0 kit (Illumina) and the DKFZ/Heidelberg sarcoma classifier. We will correlate the molecular findings with the clinical outcome (overall, relapse-free survival and progression-free survival). So far, were sequenced samples from 44 patients diagnosed with CS. Of these, 8 patients (18%) were positive for the IDH1 R132 mutation, 5 for IDH2 R172 (11%) and 14 for TERT c.-124C>T (31%). Somatic WES has already performed in 5 patients and 2 of them had driver mutations (TP53, PTCH1 e CREBBP). Our Preliminary results show a frequency below what is described in the literature in cohorts that generally include a higher proportion of high-grade cases. With the continuation and expansion of this study, we intend to collaborate with the characterization of the genetic alterations of CS and their clinical associations, being able to contribute to the identification of potential therapeutic targets and prognostic markers for this disease. (AU)