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.

Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified

“…Recently, Anderson and colleagues 26 isolated eosinophils and performed whole genome sequencing in five patients with idiopathic hypereosinophilic syndrome. Somatic missense mutations were found in three patients, Figure 2 Patients with chronic eosinophilic leukemia, not otherwise specified showed a median disease-specific survival of 14.4 months (1.0-120.1 months), significantly inferior to patients with idiopathic hypereosinophilic syndrome with no identifiable mutations (median disease-specific survival: not reached, 0.6-405.3 months, P o0.001), but not statistically different from idiopathic hypereosinophilic syndrome patients with mutations (not reached, 1.0-223.9 months, P = 0.117).…”

“…Although this may be due to the relatively small number of patients with mutations that limited the statistical power, several other explanations are also plausible. The nextgeneration sequencing assays used in this study targeted genes that are known to be mutated with relatively high frequency in myeloid neoplasms; although with good gene coverage, some relevant genes were either not included, such as abovementioned PUF60 and CDH17, 26 or only tested in a subset of patients, such as SETBP1 and CSF3R. We may have found mutations in idiopathic hypereosinophilic syndrome/next-generation sequencingnegative patients if whole genome sequencing or a more extensive next-generation sequencing panel had been performed.…”

Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD)

“…The eosinophil proteome has been preliminarily mapped out, and eosinophils have been shown to regulate the intestinal microbiome . De novo mutations and genome wide methylation patterns responsible for HES have been initiated . The EoE transcriptome has been uncovered, providing new insight into disease pathogenesis and providing the framework for a diagnostic PCR‐based diagnostic panel .…”

“…18 De novo mutations and genome wide methylation patterns responsible for HES have been initiated. 116 The EoE transcriptome has been uncovered, providing new insight into disease pathogenesis and providing the framework for a diagnostic PCR-based diagnostic panel. 108,117 Such an approach has facilitated new drug development such as anti-Type 2 cytokine therapy.…”

Chronic Eosinophilic Leukemia-Not Otherwise Specified (CEL-NOS) - Idiopathic Hypereosinophilic Syndrome (IHES)

“…Somatic missense mutations were found in three patients, including spliceosome gene PUF60 and the cadherin gene CDH17. In addition, they showed that aberrant DNA methylation patterns can distinguish clonal from reactive eosinophilia, which may be very useful in daily clinical work (Andersen et al, 2015). Other study used targeted nextgeneration sequencing panels designed for myeloid neoplasms to bone marrow specimens from a cohort of 51 idiopathic HES patients and 17 CEL-NOS patients (Wang et al, 2016).…”