P484: whole exome sequencing (wes) characterizes the mutational landscape of blastic plasmacytoid dendritic cell neoplasm (bpdcn)

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and clinically aggressive hematologic malignancy. Due to novel technologies pathogenetic concepts of BPDCN underlie a dynamic process. However, its genomic features including novel therapeutic vulnerabilities remain sparsely characterized. Aims: The present study aimed to illustrate the mutational landscape of BPDCN. Methods: To delineate the mutational landscape of BPDCN, whole-exome sequencing (WES) of 47 cases was performed. Significantly mutated genes, oncogenic drivers and perturbed pathways were compared with data from acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). Results: Median age was 73 years (range 26 – 91) and 72.3% were male. Primary involvement of the skin and the bone marrow was present in 28 (59.6%) and 15 (34.9%) cases, respectively. A median of 98 mutations per sample was detected resulting in a tumor mutational burden (TMB) of 2.57 mutations/Mb/sample. WES and consecutive gene set enrichment analysis revealed an accumulation of oncogenic mutations in epigenetic regulators of gene-expression (95.7% of cases; TET2, DNMT3A, KMT2D, SETD2, IDH2), RTK-RAS (93.6%; NRAS, MET, EGFR), NOTCH (76.6%; NOTCH2, CREBBP, EP300) and WNT signaling pathways (59.6%; CTNNB1, MED12). Moreover, WES identified a subset of shared myeloid drivers across the spectrum of BPDCN, AML and CMML. In the era of precision oncology, exome profiling revealed several potential therapeutic targets such as NOTCH2, NRAS, EGFR or EZH2. Summary/Conclusion: To the best of our knowledge, we provide genomic profiling in the largest WES cohort in BPDCN to date. Current results confirmed previous genomic features associated with myeloid pathogenesis, identified additional significantly mutated drivers and novel potential therapeutic vulnerabilities.