(P 231) COMPREHENSIVE MOLECULAR PROFILING OF FOLLICULAR DENDRITIC CELL SARCOMA

Objective: Follicular dendritic cells (FDCs) reside in the primary follicles and germinal centers of secondary and tertiary lymphoid organs. They play a crucial role in B cell activation and antibody affinity maturation, thereby shaping the B cell anti-genome, i.e., the sum of all B cell antigens. Follicular dendritic cell sarcoma (FDCS) is a malignant tumor originating from FDCs. FDCS is difficult to diagnose, especially when occurring at extra-nodal sites, due to histologic similarities to epithelial, mesenchymal, meningeal, or lymphoid malignancies. FDCS patients have a poor prognosis and are frequently treated with a lymphoma chemotherapy regimen despite evidence of a mesenchymal origin of FDCs. The limited knowledge of FDCS biology and the unmet medical need in FDCS patients support comprehensive molecular profiling of this ultra-rare sarcoma type.

Methods: We analyzed a cohort of FDCS tumors by whole-exome sequencing (WES, n = 34) and RNA sequencing (RNA-seq, n = 5) to identify recurrent and potentially clinically relevant genomic and transcriptomic alterations. Specifically, WES data were used to detect mutations, copy number alterations, and structural variants. In addition to assessing the expression level of genes of interest, RNA-seq data were used to extract immune profiles by transcriptional signature-based deconvolution.

Results: Interrogation of the genomic landscape revealed TP53 pathway alterations in 41% of tumors, affecting TP53 (hotspot mutations), CDKN2A (homozygous deletions), and MDM2 (amplification). Furthermore, we detected NF-kB pathway alterations in 38% of cases, involving NFKBIA (various mutations), BIRC3, CYLD (homozygous deletions), and MAP3K14 (amplification). The overall genomic landscape revealed a complex karyotype, displaying frequent gains, e.g., on chromosomes 5p, 12, 19, and 20, and losses, e.g., on chromosomes 6, 9p, 11, 13q, 14q, 18, and 22q, of large genomic regions in 85% of cases. Interestingly, we also observed a focal gain in chromosome 9p harboring PD-L1 and PD-L2, which translated to high expression of these genes compared to their median expression in the pan-cancer cohort of the NCT/DKFZ MASTER precision oncology program (Horak et al. Cancer Discovery 2021). Analysis of structural variants revealed gene fusions affecting the cytokine oncostatin M in two of five cases analyzed by RNA-seq. In addition, we observed structural rearrangements upstream of TERT that correlated with increased expression of this gene and a TERT promoter mutation, suggesting telomerase activation as a mechanism whereby FDCS cells escape replicative senescence. Finally, deconvolution of immune cell types revealed enrichment of regulatory T cells in primary and metastatic FDCS tumors.

Conclusion: Our study represents an in-depth molecular characterization of the largest FDCS cohort to date. We confirmed the recurrence of NF-kB and TP53 pathways detected previously by panel sequencing approaches and individual case studies and uncovered additional alterations likely contributing to FDCS development. High PD-L1 and PD-L2 expression and enrichment of regulatory T cells indicate the role of immunosuppression in FDCS pathobiology and represent entry points for therapeutic intervention. Further studies are being conducted to assess the interplay of tumor cells and their immune microenvironment in the lymph node/germinal center and metastatic niches.