Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease that currently lacks genomic and genetic biomarkers to assist in its clinical management. We performed whole-exome sequencing (WES) of three BPDCN cases. Based on these data, we designed a resequencing approach to identify mutations in 38 selected genes in 25 BPDCN samples. WES revealed 37–99 deleterious gene mutations per exome with no common affected genes between patients, but with clear overlap in terms of molecular and disease pathways (hematological and dermatological disease). We identified for the first time deleterious mutations in IKZF3, HOXB9, UBE2G2 and ZEB2 in human leukemia. Target sequencing identified 29 recurring genes, ranging in prevalence from 36% for previously known genes, such as TET2, to 12–16% for newly identified genes, such as IKZF3 or ZEB2. Half of the tumors had mutations affecting either the DNA methylation or chromatin remodeling pathways. The clinical analysis revealed that patients with mutations in DNA methylation pathway had a significantly reduced overall survival (P=0.047). We provide the first mutational profiling of BPDCN. The data support the current WHO classification of the disease as a myeloid disorder and provide a biological rationale for the incorporation of epigenetic therapies for its treatment.
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Acknowledgements
We thank all the co-workers in our laboratory for their excellent technical assistance. We especially thank the help of Manuel Morente and their team from the Tumour Bank Unit, Spanish National Cancer Research Centre. This work was supported in part by grants INTRASALUD PI12/0425 and Red Temática de Investigación Cooperativa en Cáncer (RTICC) RD12/0036/0037 to JCC from Instituto de Salud Carlos III and Ministerio de Economia y Competitividad; and INTRASALUD PI12/01047 to JVC. JM is recipient of a La Caixa International PhD Fellowship.
Author contributions
JM designed and performed the research, analyzed and interpreted the data, and wrote the manuscript. FA and MW performed the targeted next-generation sequencing and sequence data analysis. GGL and DGP performed the analysis of sequence data for whole-exome sequencing. RNS and SA analyzed and interpreted the data. MJL performed the FLT3-ITD screening. JGTC, IB, JVC, SMM, MAP, JMH, RA, MJC, LFB and MGV reviewed the pathologic data and confirmed the diagnosis. JCC designed and directed the research and revised the manuscript, which all authors have approved.
URLS
FastQC: http://www.bioinformatics.bbsrc.ac.uk/projects/fastqc/; VEP: http://www.ensembl.org/tools.html; SIFT: http://sift-jcvi.org; PolyPhen-2: http://genetics.bwh.harvard.edu/pph2/index.shtml; SureDesign Tool: https://earray.chem.agilent.com/suredesign/; SRA database: http://www.ncbi.nlm.nih.gov/sra; IPA: http://www.ingenuity.com/products/ipa; Circos: http://circos.ca/.
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Next-generation sequences have been deposited in the NCBI Sequence Read Archive (SRA), pending accession details.
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Menezes, J., Acquadro, F., Wiseman, M. et al. Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm. Leukemia 28, 823–829 (2014). https://doi.org/10.1038/leu.2013.283
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DOI: https://doi.org/10.1038/leu.2013.283
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