Methylation classifier array and classification of solitary fibrous tumors.

Abstract

e23522 Background: Solitary fibrous tumors (SFTs) are fibroblastic tumors which carry a characteristic NAB2::STAT6 gene rearrangement. SFTs represent a heterogenous group that may arise in multiple locations and have variable risk of progression. Despite a consistent oncogenic driver, there is little biological data explaining this variability. Recently, the German Cancer Research Network (DKFZ) have modified their brain tumor methylation classifier for use in sarcomas. We subjected solitary fibrous tumors diagnosed at our institution to a validated, in-house sarcoma methylation array classifier modeled after that of the DKFZ in order to assess for differences in methylation patterns that may account for biological or clinical variances. Methods: Twenty-eight primary site SFTs from 2011-2021 were subjected to the sarcoma methylation classifier. Histologic diagnosis was confirmed by STAT6 immunohistochemistry or by the presence of the NAB2::STAT6 fusion. The methylation classifier was run on the Illumina iScan platform and the resulting IDAT files were analyzed via a custom bioinformatics pipeline. The sarcoma classifier was trained using the same samples and normalization strategies used by the DKFZ group and validated using the same publicly available samples. Results: Methylation data for each tumor was collected, given a classification score, and visualized by t-distributed stochastic neighbor embedding (t-SNE). We noted three distinct groups of SFTs on the t-SNE plot. Group 1 was comprised of all eight intracranial SFTs and were correctly classified as SFT (classifier score ≥0.9). Group 2 contained nine pleural-based tumors and one SFT each from the mediastinum and bladder wall. Classification was successful in only seven of eleven tumors. Group 3 SFTs predominantly arose in the soft tissues or bone (two pelvis, four extremity, and one mediastinum) and all failed accurate classification. Finally, two orbital SFTs stratified separately from all groups on t-SNE plot but did achieve an appropriate classification. There were no significant differences in grade or risk stratification among the three groups. Conclusions: Our preliminary data show differential clustering based on tumor location, suggesting biological differences between intracranial, pleural/visceral, and connective tissue locations. These results highlight the heterogeneity of these tumors and the inadequacy of the current methylation classification scheme for SFT. Future directions will include analysis of additional cases, gene expression patterns, and outcome data.