Whole-exome sequencing and genome-wide methylation analyses identify novel disease associated mutations and methylation patterns in idiopathic hypereosinophilic syndrome.
A thorough understanding of the idiopathic hypereosinophilic syndrome (IHES) and further optimization of diagnostic work-up procedures are warranted. We analyzed purified eosinophils from patients with IHES by next-generation whole-exome sequencing and compared DNA methylation profiles from reactive eosinophilic conditions to known clonal and suspected clonal eosinophilia. Somatic missense mutations in cancer-related genes were detected in three IHES patients. These included the spliceosome gene PUF60 and the cadherin gene CDH17. Furthermore, reactive eosinophilia samples could be differentiated from known- and suspected clonal eosinophilia samples based on 285 differentially methylated CpG sites corresponding to 128 differentially methylated genes. Using Ingenuity pathway analysis, we found that differentially methylated genes were highly enriched in functional pathways such as cancer, cell death and survival, and hematological disease. Our data show that a subset of IHES may be of clonal origin not related to the classical molecular aberrations of FGFR, PDGFRA/B, or T-cells, and that the initiating hits could be point mutations in a variety of genes, including spliceosome mutations or hypermethylated tumor suppressor genes. In addition, we identified a DNA methylation signature that is relevant for distinguishing clonal and suspected clonal eosinophilia from reactive eosinophilia per se, which may be useful in daily clinical work.
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.|Department of Hematology, Roskilde University Hospital, Roskilde, Denmark.
Christen Lykkegaard
CL
Andersen
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Helene Myrtue
HM
Nielsen
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Lasse Sommer
LS
Kristensen
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Alexandra
A
Søgaard
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Jonas
J
Vikeså
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Lars
L
Jønson
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Finn Cilius
FC
Nielsen
Department of Hematology, Roskilde University Hospital, Roskilde, Denmark.
Hans
H
Hasselbalch
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Ole Weis
OW
Bjerrum
Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Vasu
V
Punj
Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Kirsten
K
Grønbæk
D015415:Biomarkers / Q000378:metabolism*; D002454:Cell Differentiation; D019175:DNA Methylation; D059472:Exome / Q000235:genetics*; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015415:Biomarkers; D012333:RNA, Messenger
diagnosis; eosinophilia; genome-wide DNA methylation analysis; idiopathic hypereosinophilic syndrome; next-generation sequencing