Integrated Clinical Genotype-Phenotype Characteristics of Blastic Plasmacytoid Dendritic Cell Neoplasm

Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive neoplasm derived from plasmacytoid dendritic cells. While advances in understanding the pathophysiology of the disease have been made, integrated systematic analyses of the spectrum of immunophenotypic and molecular alterations in real-world clinical cases remain limited. We performed mutation profiling of 50 BPDCN cases and assessed our findings in the context of disease immunophenotype, cytogenetics, and clinical characteristics. Patients included 42 men and 8 women, with a median age of 68 years (range, 14–84) at diagnosis. Forty-two (84%) patients had at least one mutation, and 23 (46%) patients had ≥3 mutations. The most common mutations involved TET2 and ASXL1, detected in 28 (56%) and 23 (46%) patients, respectively. Co-existing TET2 and ASXL1 mutations were present in 17 (34%) patients. Other recurrent mutations included ZRSR2 (16%), ETV6 (13%), DNMT3A (10%), NRAS (10%), IKZF1 (9%), SRSF2 (9%), IDH2 (8%), JAK2 (6%), KRAS (4%), NOTCH1 (4%), and TP53 (4%). We also identified mutations that have not been reported previously, including ETNK1, HNRNPK, HRAS, KDM6A, RAD21, SF3A1, and SH2B3. All patients received chemotherapy, and 20 patients additionally received stem cell transplantation. With a median follow-up of 10.5 months (range, 1–71), 21 patients achieved complete remission, 4 had persistent disease, and 24 died. Patients younger than 65 years had longer overall survival compared to those who were ≥65 years (p = 0.0022). Patients who had ≥3 mutations or mutations in the DNA methylation pathway genes had shorter overall survival (p = 0.0119 and p = 0.0126, respectively). Stem cell transplantation significantly prolonged overall survival regardless of mutation status. In conclusion, the majority of patients with BPDCN have somatic mutations involving epigenetic regulators and RNA splicing factors, in addition to ETV6 and IKZF1, which are also frequently mutated. Older age, multiple mutations, and mutations in the DNA methylation pathway are poor prognostic factors.

Integrative molecular profiling identifies two molecularly and clinically distinct subtypes of blastic plasmacytoid dendritic cell neoplasm

“…In this hitherto most comprehensive, paired genomic and transcriptomic study of BPDCN, supplemented by CNA analysis, we systematically defined recurrent mutations, CNAs, and gene fusions alongside predominant mutation and transcriptional signatures beyond the scope of previous efforts 5,[11][12][13][14]18,51,52,55,56 . The present study hereby made three novel and essential observations.…”

“…An oncoplot integrating clinical features and mutational status of all putative oncogenic driver genes according to our MUTSIGCV analysis is provided in Figure 1A. The list of significant candidate driver genes included several genes previously implicated in BPDCN and further expanded on these 5,11,14,18,20,37,38 .…”

“…Given molecularly tailored treatments increasingly outperforming non-biomarker stratified therapies in patients with advanced cancers, an entity-specific in-depth molecular definition has become a vital prerequisite in precision oncology 10 . Panel or whole-exome sequencing (WES) studies on small cohorts of patients and RNA-sequencing (RNA-Seq) of selected cases have reported a limited number of potential genetic drivers and transcriptional mechanisms in BPDCN 5,[11][12][13][14][15][16][17][18] . Molecular and pathogenetic similarities between BPDCN and several other blood cancers have been proposed, as both syn-and metachronous myeloid neoplasms such as chronic myelomonocytic leukemia (CMML), AML and even myelodysplastic syndromes (MDS) have been reported in up to 20% of cases 19 .…”

Clinical Insights into the Management of Blastic Plasmacytoid Dendritic Cell Neoplasm

“…Like other myeloid malignancies, the mutational landscape of BPDCN is characterized by recurrent mutations in epigenetic modifiers, transcriptional regulators, and splicing factors. 34 , 35 Concurrent manifestation of BPDCN and MDS or AML has been described; this suggests a common pathogenesis, with initiating mutations in pluripotent myeloid stem cells. 36 The 2 most frequently mutated epigenetic genes in BPDCN are AXSL1 and TET2 , and these mutations are associated with poor OS in BPDCN.…”

Integrative molecular profiling identifies two molecularly and clinically distinct subtypes of blastic plasmacytoid dendritic cell neoplasm

“…Recent observations proposed a subset of BPDCN to originate from AXL1 + SIGLEC6 + DCs (AS-DCs), suggesting a heterogeneous cellular ontogeny [ 5 ]. Panel and whole-exome sequencing (WES) on small cohorts and transcriptome sequencing (RNA-seq) of selected patients have reported a limited number of potential genetic drivers and transcriptional mechanisms underlying BPDCN [ 6 , 7 ]. Syn- and metachronous myeloid neoplasms (CMML, AML and MDS) have been reported in up to 20% of cases [ 8 ].…”