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.
Highlights
In healthy individuals, eosinophilic granulocytes constitute less than five percent of all white blood cells [1], and in clinical practice blood eosinophilia is defined as an eosinophil count ≥ 0.5x109/l
Peripheral eosinophil levels ranged from 0.8–5.8x109/L where the highest concentration was noted in a newly diagnosed idiopathic hypereosinophilic syndrome (IHES) patient receiving prednisolone
Within recent years multiple point mutations have been detected in the genes encoding the mRNA splicing machinery in hematological malignancies including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and chronic lymphocytic leukemia [25] as well as in several solid tumors [26]
Summary
Eosinophilic granulocytes (eosinophils) constitute less than five percent of all white blood cells [1], and in clinical practice blood eosinophilia is defined as an eosinophil count ≥ 0.5x109/l. A plethora of distinct disease entities with concomitant eosinophilia has been known for many years, whereas the primary eosinophilic conditions were only introduced in 1968 [1, 5, 6]. Chromosomal aberrations of FGFR and PDGFRB, point mutations in PDFGRA, and T-cell clonality have been identified in rare cases of primary eosinophilia. This leaves a very small subgroup of patients with idiopathic hypereosinophilia (IHE) and idiopathic hypereosinophilic syndrome (IHES), [3, 4, 7, 8] where clonality is often www.impactjournals.com/oncotarget suspected, neither genomic aberrations nor other triggering stimuli can be demonstrated
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
