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Idiopathic hypereosinophilia is clonal disorder? Clonality identified by targeted sequencing
Idiopathic hypereosinophilia (IHE)/idiopathic hypereosinophilic syndrome (IHES) has been defined by a persistent elevation of the blood eosinophil count exceeding 1.5×10(3)/μL, without evidence of reactive or clonal causes. While T-cell clonality assessment has been recommended for unexplained hyper...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663336/ https://www.ncbi.nlm.nih.gov/pubmed/29088303 http://dx.doi.org/10.1371/journal.pone.0185602 |
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author | Lee, Jee-Soo Seo, Heewon Im, Kyongok Park, Si Nae Kim, Sung-Min Lee, Eun Kyoung Kim, Jung-Ah Lee, Joon-hee Kwon, Sunghoon Kim, Miyoung Koh, Insong Hwang, Seungwoo Park, Heung-Woo Kang, Hye-Ryun Park, Kyoung Soo Kim, Ju Han Lee, Dong Soon |
author_facet | Lee, Jee-Soo Seo, Heewon Im, Kyongok Park, Si Nae Kim, Sung-Min Lee, Eun Kyoung Kim, Jung-Ah Lee, Joon-hee Kwon, Sunghoon Kim, Miyoung Koh, Insong Hwang, Seungwoo Park, Heung-Woo Kang, Hye-Ryun Park, Kyoung Soo Kim, Ju Han Lee, Dong Soon |
author_sort | Lee, Jee-Soo |
collection | PubMed |
description | Idiopathic hypereosinophilia (IHE)/idiopathic hypereosinophilic syndrome (IHES) has been defined by a persistent elevation of the blood eosinophil count exceeding 1.5×10(3)/μL, without evidence of reactive or clonal causes. While T-cell clonality assessment has been recommended for unexplained hypereosinophilia, this approach is not often applied to routine practice in the clinic. We hypothesized that the clonality would exist in a subset of IHE/IHES patients. We aimed to investigate the candidate mutations and T-cell clonality in IHE/IHES and to explore the role of mutations in eosinophil proliferation. We performed targeted capture sequencing for 88 genes using next-generation sequencing, T-cell receptor (TCR) gene rearrangement assays, and pathway network analysis in relation to eosinophil proliferation. By targeted sequencing, 140 variants in 59 genes were identified. Sixteen out of 30 patients (53.3%) harbored at least one candidate mutation. The most frequently affected genes were NOTCH1 (26.7%), SCRIB and STAG2 (16.7%), and SH2B3 (13.3%). Network analysis revealed that our 21 candidate genes (BIRC3, BRD4, CSF3R, DNMT3A, EGR2, EZH2, FAT4, FLT3, GATA2, IKZF, JAK2, MAPK1, MPL, NF1, NOTCH1, PTEN, RB1, RUNX1, TET2, TP53 and WT1) are functionally linked to the eosinophilopoietic pathway. Among the 21 candidate genes, five genes (MAPK1, RUNX1, GATA2, NOTCH1 and TP53) with the highest number of linkages were considered major genes. A TCR assay revealed that four patients (13.3%) had a clonal TCR rearrangement. NOTCH1 was the most frequently mutated gene and was shown to be a common node for eosinophilopoiesis in our network analysis, while the possibility of hidden T cell malignancy was indwelling in the presence of NOTCH1 mutation, though not revealed by aberrant T cell study. Collectively, these results provide new evidence that mutations affecting eosinophilopoiesis underlie a subset of IHE/IHES, and the candidate genes are inferred to act their potential roles in the eosinophilopoietic pathway. |
format | Online Article Text |
id | pubmed-5663336 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-56633362017-11-09 Idiopathic hypereosinophilia is clonal disorder? Clonality identified by targeted sequencing Lee, Jee-Soo Seo, Heewon Im, Kyongok Park, Si Nae Kim, Sung-Min Lee, Eun Kyoung Kim, Jung-Ah Lee, Joon-hee Kwon, Sunghoon Kim, Miyoung Koh, Insong Hwang, Seungwoo Park, Heung-Woo Kang, Hye-Ryun Park, Kyoung Soo Kim, Ju Han Lee, Dong Soon PLoS One Research Article Idiopathic hypereosinophilia (IHE)/idiopathic hypereosinophilic syndrome (IHES) has been defined by a persistent elevation of the blood eosinophil count exceeding 1.5×10(3)/μL, without evidence of reactive or clonal causes. While T-cell clonality assessment has been recommended for unexplained hypereosinophilia, this approach is not often applied to routine practice in the clinic. We hypothesized that the clonality would exist in a subset of IHE/IHES patients. We aimed to investigate the candidate mutations and T-cell clonality in IHE/IHES and to explore the role of mutations in eosinophil proliferation. We performed targeted capture sequencing for 88 genes using next-generation sequencing, T-cell receptor (TCR) gene rearrangement assays, and pathway network analysis in relation to eosinophil proliferation. By targeted sequencing, 140 variants in 59 genes were identified. Sixteen out of 30 patients (53.3%) harbored at least one candidate mutation. The most frequently affected genes were NOTCH1 (26.7%), SCRIB and STAG2 (16.7%), and SH2B3 (13.3%). Network analysis revealed that our 21 candidate genes (BIRC3, BRD4, CSF3R, DNMT3A, EGR2, EZH2, FAT4, FLT3, GATA2, IKZF, JAK2, MAPK1, MPL, NF1, NOTCH1, PTEN, RB1, RUNX1, TET2, TP53 and WT1) are functionally linked to the eosinophilopoietic pathway. Among the 21 candidate genes, five genes (MAPK1, RUNX1, GATA2, NOTCH1 and TP53) with the highest number of linkages were considered major genes. A TCR assay revealed that four patients (13.3%) had a clonal TCR rearrangement. NOTCH1 was the most frequently mutated gene and was shown to be a common node for eosinophilopoiesis in our network analysis, while the possibility of hidden T cell malignancy was indwelling in the presence of NOTCH1 mutation, though not revealed by aberrant T cell study. Collectively, these results provide new evidence that mutations affecting eosinophilopoiesis underlie a subset of IHE/IHES, and the candidate genes are inferred to act their potential roles in the eosinophilopoietic pathway. Public Library of Science 2017-10-31 /pmc/articles/PMC5663336/ /pubmed/29088303 http://dx.doi.org/10.1371/journal.pone.0185602 Text en © 2017 Lee et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Lee, Jee-Soo Seo, Heewon Im, Kyongok Park, Si Nae Kim, Sung-Min Lee, Eun Kyoung Kim, Jung-Ah Lee, Joon-hee Kwon, Sunghoon Kim, Miyoung Koh, Insong Hwang, Seungwoo Park, Heung-Woo Kang, Hye-Ryun Park, Kyoung Soo Kim, Ju Han Lee, Dong Soon Idiopathic hypereosinophilia is clonal disorder? Clonality identified by targeted sequencing |
title | Idiopathic hypereosinophilia is clonal disorder? Clonality identified by targeted sequencing |
title_full | Idiopathic hypereosinophilia is clonal disorder? Clonality identified by targeted sequencing |
title_fullStr | Idiopathic hypereosinophilia is clonal disorder? Clonality identified by targeted sequencing |
title_full_unstemmed | Idiopathic hypereosinophilia is clonal disorder? Clonality identified by targeted sequencing |
title_short | Idiopathic hypereosinophilia is clonal disorder? Clonality identified by targeted sequencing |
title_sort | idiopathic hypereosinophilia is clonal disorder? clonality identified by targeted sequencing |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663336/ https://www.ncbi.nlm.nih.gov/pubmed/29088303 http://dx.doi.org/10.1371/journal.pone.0185602 |
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