Whole-exome sequencing and genome-wide methylation analyses identify novel disease associated mutations and methylation patterns in idiopathic hypereosinophilic syndrome

Christen Lykkegaard Andersen; Helene Myrtue Nielsen; Lasse Sommer Kristensen; Alexandra Søgaard Helbo; Jonas Vikeså; Lars Jønson; Finn Cilius Nielsen; Hans Hasselbalch; Ole Weis Bjerrum; Vasu Punj; Kirsten Grønbæk

doi:10.18632/oncotarget.5845

Whole-exome sequencing and genome-wide methylation analyses identify novel disease associated mutations and methylation patterns in idiopathic hypereosinophilic syndrome

Christen Lykkegaard Andersen, Helene Myrtue Nielsen, Lasse Sommer Kristensen, Alexandra Søgaard Helbo, Jonas Vikeså, Lars Jønson, Finn Cilius Nielsen, Hans Hasselbalch, Ole Weis Bjerrum, Vasu Punj, Kirsten Grønbæk

Department of Clinical Medicine

9 Citations (Scopus)

Abstract

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.

Original language	English
Journal	OncoTarget
Volume	6
Issue number	38
Pages (from-to)	40588-97
Number of pages	10
ISSN	1949-2553
DOIs	https://doi.org/10.18632/oncotarget.5845
Publication status	Published - 2015

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.18632/oncotarget.5845

Cite this

Andersen, C. L., Nielsen, H. M., Sommer Kristensen, L., Helbo, A. S., Vikeså, J., Jønson, L., Nielsen, F. C., Hasselbalch, H., Bjerrum, O. W., Punj, V., & Grønbæk, K. (2015). Whole-exome sequencing and genome-wide methylation analyses identify novel disease associated mutations and methylation patterns in idiopathic hypereosinophilic syndrome. OncoTarget, 6(38), 40588-97. https://doi.org/10.18632/oncotarget.5845

Whole-exome sequencing and genome-wide methylation analyses identify novel disease associated mutations and methylation patterns in idiopathic hypereosinophilic syndrome. / Andersen, Christen Lykkegaard; Nielsen, Helene Myrtue; Sommer Kristensen, Lasse et al.
In: OncoTarget, Vol. 6, No. 38, 2015, p. 40588-97.

Research output: Contribution to journal › Journal article › Research › peer-review

Andersen, CL, Nielsen, HM, Sommer Kristensen, L, Helbo, AS, Vikeså, J, Jønson, L, Nielsen, FC , Hasselbalch, H, Bjerrum, OW, Punj, V & Grønbæk, K 2015, 'Whole-exome sequencing and genome-wide methylation analyses identify novel disease associated mutations and methylation patterns in idiopathic hypereosinophilic syndrome', OncoTarget, vol. 6, no. 38, pp. 40588-97. https://doi.org/10.18632/oncotarget.5845

@article{e26d9d19a33145e390195bc80627a6e8,

title = "Whole-exome sequencing and genome-wide methylation analyses identify novel disease associated mutations and methylation patterns in idiopathic hypereosinophilic syndrome",

abstract = "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.",

author = "Andersen, {Christen Lykkegaard} and Nielsen, {Helene Myrtue} and {Sommer Kristensen}, Lasse and Helbo, {Alexandra S{\o}gaard} and Jonas Vikes{\aa} and Lars J{\o}nson and Nielsen, {Finn Cilius} and Hans Hasselbalch and Bjerrum, {Ole Weis} and Vasu Punj and Kirsten Gr{\o}nb{\ae}k",

year = "2015",

doi = "10.18632/oncotarget.5845",

language = "English",

volume = "6",

pages = "40588--97",

journal = "OncoTarget",

issn = "1949-2553",

publisher = "Impact Journals LLC",

number = "38",

}

TY - JOUR

T1 - Whole-exome sequencing and genome-wide methylation analyses identify novel disease associated mutations and methylation patterns in idiopathic hypereosinophilic syndrome

AU - Andersen, Christen Lykkegaard

AU - Nielsen, Helene Myrtue

AU - Sommer Kristensen, Lasse

AU - Helbo, Alexandra Søgaard

AU - Vikeså, Jonas

AU - Jønson, Lars

AU - Nielsen, Finn Cilius

AU - Hasselbalch, Hans

AU - Bjerrum, Ole Weis

AU - Punj, Vasu

AU - Grønbæk, Kirsten

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.18632/oncotarget.5845

DO - 10.18632/oncotarget.5845

M3 - Journal article

C2 - 26497854

SN - 1949-2553

VL - 6

SP - 40588

EP - 40597

JO - OncoTarget

JF - OncoTarget

IS - 38

ER -

Whole-exome sequencing and genome-wide methylation analyses identify novel disease associated mutations and methylation patterns in idiopathic hypereosinophilic syndrome

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this