60P - Spindle cell sarcomas with tyrosine kinase rearrangement

Background

A group of spindle cell tumors with characteristic morphologic features and recurrent gene rearrangements has recently been described. Genome-wide DNA methylation profiling has emerged as a powerful tool for both robust classification of known sarcoma entities and identification of novel and clinically relevant subclasses of soft tissue tumors with characteristic alterations.

Methods

Anchored Multiplex polymerase chain reaction amplicons were sequenced on Illumina MiSeq and the data were analyzed using the Archer and Arriba software. Genome-wide DNA methylation profiling was performed using Infinium Methylation EPIC (EPIC) BeadChip (Illumina).

Results

We identified 6 spindle cell sarcoma cases with rearrangement/SNV in BRAF gene, 3 pediatric spindle cell sarcomas with NTRK1 fusion, 1 high-grade sarcoma with ALK fusion and 1 pediatric sarcoma with tyrosine-kinase duplication of EGFR gene. We show that CDKN2A deletion was the most prevalent DNA copy number aberration in spindle cell sarcomas for which this deletion is a typical change and connecting element across different subgroups of spindle cell sarcomas and this change was associated with poor clinical outcome. DNA methylation profiling demonstrated that 5 of our BRAF altered spindle cell sarcomas clustered within MPNST-like methylation class, but methylation analysis classified the next BRAF rearranged case (with CUX1::BRAF fusion) near to angiomatoid fibrous histiocytomas or inflammatory myofibroblastic tumors. Our patients with LMNA::NTRK1 fusion gene clustered within dermatofibrosarcoma protuberans methylation class. Methylation analysis of the sample with ALK fusion did not classify the sample in any of the defined class of methylation classifier.

Conclusions

The current study demonstrates, that all detected rearrangements in our spindle cell cohort are potentially therapeutically targetable. We provide evidence for the pathobiological and epigenetical heterogeneity of spindle cell sarcomas generally, and also of spindle cell sarcomas that shows alteration of the tyrosin-kinase genes.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Ministry of Health, Czech Republic - Conceptual Development of Research Organization, Motol University Hospital, Prague, Czech Republic 00064203.

Disclosure

All authors have declared no conflicts of interest.