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Cytogenetics and Molecular Genetics

Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm

Leukemia volume 28, pages 823–829 (2014)Cite this article

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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/.

Accession codes

Next-generation sequences have been deposited in the NCBI Sequence Read Archive (SRA), pending accession details.

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Authors and Affiliations

  1. Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre—CNIO, Madrid, Spain

    J Menezes, F Acquadro, R N Salgado, S Álvarez & J C Cigudosa

  2. R&D Department, NIMGenetics, Tres Cantos, Madrid, Spain

    F Acquadro & M Wiseman

  3. Bioinformatic Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Research Centre—CNIO, Madrid, Spain

    G Gómez-López & D G Pisano

  4. Servicio de Hematología y Hemoterapia, Complejo Hospitalario Ntra. Sra. de Candelaria, Santa Cruz de Tenerife, Spain

    J G Talavera-Casañas

  5. Laboratorio de Genética Hematológica, Servicio de Hematología, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain

    I Buño

  6. Hematology Department, Hospital Universitario La Fe, Valencia, Spain

    J V Cervera

  7. Pathology Department, Hospital Universitario Marqués de Valdecilla, Fundación IFIMAV, Santander, Spain

    S Montes-Moreno & M A Piris

  8. IBSAL, IBMCC, Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain

    J M Hernández-Rivas

  9. Hematology Department, Hospital Universitario 12 de octubre, Madrid, Spain

    R Ayala

  10. Departamento de Genética, Universidad de Navarra, Pamplona, Spain

    M J Calasanz & M J Larrayoz

  11. Laboratori de Citologia Hematològica, Laboratori de Citogenètica Molecular, Servei de Patologia, Hospital del Mar, GRETNHE, IMIM (Hospital del Mar Research Institute), Barcelona, Spain

    L F Brichs

  12. Unidad de Trasplante Hematopoyético, Hospital Niño Jesus, Madrid, Spain

    M Gonzalez-Vicent

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  1. J Menezes
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Correspondence to J C Cigudosa.

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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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