Dados do Resumo

Título

Molecular profile and clinical behavior of chondrosarcomas

Introdução

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.

Objetivo

The objective of the study is to characterize somatic changes associated with the development and clinical behavior of chondrosarcomas.

Métodos

This project is underway under CEP registration number 3326/22. We included 150 Brazilian patients diagnosed with CS between 2002 and 2023 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 hotspot mutations in IDH1 (R132), IDH2(R172) and TERT (c.-124C>T and c.-146C>T) will be evaluated 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 30 patients with conventional and dedifferentiated CS with and without hotspot mutations and extreme phenotypes (indolent x aggressive disease). Somatic WES will be performed 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. Finally, we will correlate the molecular findings with the clinical outcome (overall, relapse-free survival and progression-free survival).

Resultados

So far, we sequenced hotspot variants for 51 patients diagnosed with CS. The average age was 43 years and the most common histological types were: Conventional (45/51), Myxoid (4/51), Mesenchymal (1/51) and Dedifferentiated (1/51). Most had histological grade 1 tumors (27/51), followed by grade 2 (18/51), grade 3 (3/51) and 3 metastatic tumors (grade 4). Of these, 11 patients (21,5%) were positive for the IDH1 R132 mutation, 6 for IDH2 R172 (11,7%) and 14 for TERT c.-124C>T (27,4%). Somatic WES has already performed in 5 patients and 2 of them had driver mutations in genes already described in chondrosarcoma or sarcomas: TP53, PTCH1 and CREBBP. Overall, the rate of somatic point mutations was low for the tumors evaluated, with 4/5 of the patients having a tumor mutational burden (TMB) of less than 5 per Megabase and 1 having a TMB of 46, being considered a hypermutated tumor.

Conclusões

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 contribute to the characterization of the genetic alterations of CS and their clinical associations, aiming the identification of potential therapeutic targets and prognostic markers for this disease.

Financiador do resumo

This project will be partially funded with resources from the INCITO project (FAPESP 2014/509443-1, CNPq 465682/2014-6) and from a FAPESP Regular project under the responsibility of the advisor.

Palavras Chave

Chondrossarcomas; IDH; TERT