P563: novel genes exhibiting functional relevance in korean patients with blastic plasmacytoid dendritic cell neoplasm

Background: Only two studies on Korean patients with blastic plasmacytoid dendritic cell neoplasm were reported, and none of them analyzed the genetic profile of Korean patients. Aims: We performed a comprehensive study on Korean patients with BPDCN, including cyto- and molecular genetic profiling and treatment outcomes for the first time. Methods: Fourteen patients with BPDCN on primary sites and/or in BM were enrolled. Microscopic examination, conventional karyotyping, next-generation sequencing followed by a network analysis and survival analysis were performed. Results: The median age of patients was 52 years (range 25-75) at the time of diagnosis with 7 patients under 50 years old. The male-to-female ratio was 1.8:1. Eleven had BM involvement at the initial diagnosis and/or during follow-up. Among 12 who had BM karyotype result, 9 had BM karyotype result at the time of BM involvement of BPDCN - 7 patients (77.8%) with complex karyotype, 1 (11.1%) with normal karyotype and 1 (11.1%) with insufficient mitosis. Addition of 1p, 7p, 8q, 12p, and 19p, deletion of 1p, 6q, and 13q, and monosomies 5, 9, 13, 15, and 17 were previously reported abnormalities in Western studies, whereas del(1q), t(1;12), t(2;8), t(3;21), del(4p), inv(5q), t(5;6), der(8;12), dic(9;15), add(12q), t(13;14), del(14q), and del(18q), add(p22), and monosomy 10 and 18 were unique to our patients. In terms of abnormalities, loss of chromosomes 9, 13, 15, and 17, and abnormalities involving 1p13.1, 8q24.1, 12p13, 14q24, 19p13.3 were common in our patients. Candidate affected genes include CDKN2C, NR3C1, PARK2, MAD1L1, MYC, CDC14B, SYK, ETV6, CDKN1B, LASTS2, RB and TP53. Chromosome 12 had the most abnormalities, followed by chromosomes 1 and 9. A total of 32 genes were mutated in 5 patients. Among them, 10 genes (30%) overlapped with the known disease gene set, while the remaining 22 genes (70%) were not previously reported to be relevant to BPDCN. The known genes include ASXL1, IKZF1, KMT2D, KRAS, NF1, NR3C1, NRAS, SRSF2, TET2 and TP53. The novel genes include ABCA13, ANKRD26, CBLB, COL19A1, DDX3X, DOCK8, FANCA, FAT3, FGFR1, FMN1, GNB1, GPRC5A, JMJD1C, MSH4, MUC16, PIGA, RPS28, RUNX1T1, SMARCD2, SPTB, SYNE1 and VPS13B3. Among them, TET2 and KRAS were the most commonly mutated genes. When we only kept the edges between mutated genes and known genes in a network analysis, it yielded a subnetwork of 27 nodes and 51 edges. Among the known genes, TP53, KRAS, and NRAS interacted with most known genes. Among the novel genes SMARCD2, DDX3X, and GNB1 interacted the most with known genes. Excluding 2 patients who did not receive therapy, the median survival duration was 9 months, 26 months, and 54 months in those who underwent chemotherapy only, chemotherapy followed by autologous HSCT, and chemotherapy followed by allogenic HSCT (p=0.039). Summary/Conclusion: Korean patients with BPDCN showed less male predominance. Complex karyotypes were dominant. Loss of chromosomes 9, 13, and 17, and abnormalities involving 1p13.1 and 8q24.1 were common. NGS detected mutations in 10 known genes and 22 novel genes, among which TET2 and KRAS were the most commonly mutated genes. Network analysis suggested among novel genes, SMARCD2, DDX3X, and GNB1 of the most functional significance in BPDCN, and among known genes, TP53, KRAS, and NRAS of the most functional relevance. Korean patients who received allogeneic hematopoietic stem cell transplantation showed longer overall survival than those reported.Keywords: HSCT, Myeloid malignancies