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Leukemia. 2014 Apr;28(4):823-9. doi: 10.1038/leu.2013.283. Epub 2013 Sep 27.

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

Author information

1
Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
2
1] Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain [2] NIMGenetics, R&D Department, Tres Cantos, Madrid, Spain.
3
NIMGenetics, R&D Department, Tres Cantos, Madrid, Spain.
4
Bioinformatic Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
5
Servicio de Hematología y Hemoterapia, Complejo Hospitalario Ntra. Sra. de Candelaria, Santa Cruz de Tenerife, Spain.
6
Laboratorio de Genética Hematológica, Servicio de Hematología, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
7
Hematology Department, Hospital Universitario La Fe, Valencia, Spain.
8
Pathology Department, Hospital Universitario Marqués de Valdecilla, Fundación IFIMAV, Santander, Spain.
9
IBSAL, IBMCC, Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain.
10
Hematology Department, Hospital Universitario 12 de octubre, Madrid, Spain.
11
Departamento de Genética, Universidad de Navarra, Pamplona, Spain.
12
Laboratori de Citologia Hematològica, Laboratori de Citogenètica Molecular, Servei de Patologia, Hospital del Mar, GRETNHE, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
13
Unidad de Trasplante Hematopoyético, Hospital Niño Jesus, Madrid, Spain.

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.

PMID:
24072100
DOI:
10.1038/leu.2013.283
[Indexed for MEDLINE]

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