Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm.
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.
Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
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J
Menezes
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.
F
F
Acquadro
NIMGenetics, R&D Department, Tres Cantos, Madrid, Spain.
M
M
Wiseman
Bioinformatic Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
G
G
Gómez-López
Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
R N
RN
Salgado
Servicio de Hematología y Hemoterapia, Complejo Hospitalario Ntra. Sra. de Candelaria, Santa Cruz de Tenerife, Spain.
J G
JG
Talavera-Casañas
Laboratorio de Genética Hematológica, Servicio de Hematología, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
I
I
Buño
Hematology Department, Hospital Universitario La Fe, Valencia, Spain.
J V
JV
Cervera
Pathology Department, Hospital Universitario Marqués de Valdecilla, Fundación IFIMAV, Santander, Spain.
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S
Montes-Moreno
IBSAL, IBMCC, Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC, Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain.
J M
JM
Hernández-Rivas
Hematology Department, Hospital Universitario 12 de octubre, Madrid, Spain.
R
R
Ayala
Departamento de Genética, Universidad de Navarra, Pamplona, Spain.
M J
MJ
Calasanz
Departamento de Genética, Universidad de Navarra, Pamplona, Spain.
M J
MJ
Larrayoz
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
LF
Brichs
Unidad de Trasplante Hematopoyético, Hospital Niño Jesus, Madrid, Spain.
M
M
Gonzalez-Vicent
Bioinformatic Unit, Structural Biology and Biocomputing Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
D G
DG
Pisano
Pathology Department, Hospital Universitario Marqués de Valdecilla, Fundación IFIMAV, Santander, Spain.
M A
MA
Piris
Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
S
S
Álvarez
Molecular Cytogenetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre-CNIO, Madrid, Spain.
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Cigudosa
D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D003713:Dendritic Cells / Q000473:pathology*; D049308:Dioxygenases; D059472:Exome; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D000074165:Zinc Finger E-box Binding Homeobox 2
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C106285:IKZF3 protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D051740:Ikaros Transcription Factor; D049308:Dioxygenases; C541081:TET2 protein, human