Whole-exome sequencing and genome-wide methylation analyses identify novel disease associated mutations and methylation patterns in idiopathic hypereosinophilic syndrome
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Christen Lykkegaard Andersen1,2, Helene Myrtue Nielsen1, Lasse Sommer Kristensen1, Alexandra Søgaard1, Jonas Vikeså3, Lars Jønson3, Finn Cilius Nielsen3, Hans Hasselbalch2, Ole Weis Bjerrum1, Vasu Punj4, Kirsten Grønbæk1
1Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
2Department of Hematology, Roskilde University Hospital, Roskilde, Denmark
3Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
4Keck School of Medicine, University of Southern California, Los Angeles, California, USA
Christen Lykkegaard Andersen, e-mail: [email protected]
Keywords: eosinophilia, idiopathic hypereosinophilic syndrome, diagnosis, next-generation sequencing, genome-wide DNA methylation analysis
Received: September 13, 2015 Accepted: September 22, 2015 Published: October 19, 2015
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.
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