Dados do Resumo

Título

Molecular characterization of Ollier disease and Maffucci syndrome

Introdução

Ollier disease (OD) and Maffucci syndrome (MS) are rare non-familial diseases characterized by the formation of multiple intramedullary cartilaginous tumors (enchondromas). These diseases are considered tumor predisposition syndromes, with enchondromas being the most prevalent tumor with an overall incidence of approximately 30% and a risk of malignant transformation for chondrosarcoma (CS) of 40% in DO and more than 50% in MS. While OD is primarily characterized by the presence of enchondromas, MS is distinguished by the additional presence of soft tissue hemangiomas. Both OD and MS are associated with postzygotic somatic mutations, which result in genetic mosaicism. The most common somatic mosaic variants in these syndromes occur in the IDH1 and IDH2 genes, in approximately 80% of cases. Germline mutations in other genes associated with the HIF1 pathway are also found in these syndromes, such as HIF1A, VHL, KDM4C or CDKN2A.

Objetivo

To identify the mutational profile of Ollier disease and Maffucci syndrome and associate it with the disease phenotype and malignant transformation.

Métodos

The data of this study is part of a larger cohort from the study entitled “molecular profile and clinical behavior of chondrosarcomas” approved by the CEP under number 3326/22. The cohort includes 5 patients diagnosed with CS or uncertain diagnosis between enchondroma and CS, 3 patients with Ollier disease and 2 with Maffucci syndrome, diagnosed from 2015 to 2022 and with fresh frozen or formalin-fixed paraffin-embedded (FFPE) tumor available at the A.C. Camargo Cancer Center Biobank/Department of Pathological Anatomy. The hotspot mutations in IDH1 (R132) and IDH2 (R172) were 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. Cases that are negative for mutations in these genes will undergo sequencing of a 409-gene panel (Comprehensive Cancer Panel- Thermo Fisher, USA) of 1,300kb, which covers 409 oncogenes and tumor suppressor genes related to cancer. The approach is based on amplification of the coding region of the target genes followed by sequencing on the Ion S5 analysis platform. Variant calling and selection will be performed in TorrentSuite software. Finally, the VCF files will be imported into VarSeq software (Golden Helix) for additional annotation and variant filtering.

Resultados

To date, hotspot sequencing for the IDH1 (R132) and IDH2 (R172) genes has been performed for 3 patients. Two with Ollier's disease in a diagnostic state for chondrosarcoma/enchondroma were positive for IDH1 R132 mutation (variant allele frequencies of 12% and 39%), and one case of Maffucci syndrome was negative for both genes and did not present any clinically relevant variants in the sequencing of the 409-gene panel.

Conclusões

We intend to perform amplicon and panel sequencing for the remaining patients, in order to identify the mutations present in these tumors to investigate their role in the formation of cartilaginous tumors, as well as their influence on the disease phenotype, somatic mosaicism pattern and malignant transformation.

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

Ollier disease; Maffucci Syndrome; IDH