Abstract 2703: Extraskeletal myxoid chondrosarcoma: a clinicopathologic and molecular study reveals novel genetic aberrations by targeted next-generation sequencing
Authors: Trautmann Marcel , Cyra Magdalene , Isfort Ilka , Grünewald Inga , Steinestel Konrad , Huss Sebastian , Büttner Reinhard , Wardelmann Eva , Hartmann Wolfgang 
Published: July 2017

Background: Extraskeletal myxoid chondrosarcomas (EMCs) are rare mesenchymal neoplasms comprising approx. 3% of all soft tissue tumors. EMCs arise mainly from the deep soft tissues of the extremities, accompanied with high rates of recurrence and metastases. The molecular hallmarks of EMCs are various cytogenetic NR4A3 rearrangements, generating chimeric -NR4A3 proteins. The most common reciprocal translocation t(9;22)(q22;q12), results in a fusion of the EWS RNA-binding protein 1 gene (EWSR1) to the nuclear receptor subfamily 4, group A, member 3 gene (NR4A3 or TEC; approximately 75% of cases). Further cytogenetic t(9;17)(q22;q11) rearrangements involve TAF15 RNA polymerase II, TATA box binding protein (TBP)-associated factor (TAF15; approximately 15% of cases). The less frequent reciprocal translocations t(9;15)(q22;q21) and t(9;3)(q22;q12), result in transcription factor 12 (TCF12)-NR4A3 and TRK-fused gene (TFG)-NR4A3 fusion proteins. Although the oncogenic -NR4A3 fusion transcripts seem to have a crucial role in EMC tumorigenesis and progression, the specific biological function and the mechanism of action remain to be defined.

Methods: We characterized the cytogenetic rearrangements of 25 comprehensive EMC tumors by RT-PCR and/or fluorescence in situ hybridization (FISH). Next generation sequencing (NGS) was performed (Illumina MiSeq platform) to reveal additional genetic alterations besides the known chromosomal translocation. Therefore, a comprehensive cancer panel was designed, comprising 27 cancer-related genes known to be frequently mutated across various malignancies.

Results: Overall, fusion transcripts were detected in 22 of 25 samples (88%). Sixteen were positive for the EWSR1-NR4A3 and six for the TAF15-NR4A3 fusion gene. The t(9;15) and t(9;3) translocations, resulting in TCF12-NR4A3 and TFG-NR4A3 fusion proteins were not identified in any EMC case. In Addition, several known oncogenic mutations were detected which have not been previously reported in EMC.

Conclusions: The combination of RT-PCR and FISH on paraffin-embedded tissue is a sensitive and specific method for the molecular detection of the pathogenic translocations to be applied in the differential diagnosis of extraskeletal myxoid chondrosarcomas. Our results emphasize that cytogenetic NR4A3 rearrangements are the initiating events in the pathogenesis of EMC. Furthermore, our results indicate the occurrence of additional genetic aberrations providing a rational base for novel targeted therapeutic approaches.

Citation Format: Marcel Trautmann, Magdalene Cyra, Ilka Isfort, Inga Grünewald, Konrad Steinestel, Sebastian Huss, Reinhard Büttner, Eva Wardelmann, Wolfgang Hartmann. Extraskeletal myxoid chondrosarcoma: a clinicopathologic and molecular study reveals novel genetic aberrations by targeted next-generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2703. doi:10.1158/1538-7445.AM2017-2703