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Ferrata Storti Foundation
Haematologica 2022 Volume 107(2):510-518
Unique ethnic features of DDX41 mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia
Eun-Ji Choi,1* Young-Uk Cho,2* Eun-Hye Hur,1 Seongsoo Jang,2 Nayoung Kim,3 Han-Seung Park,1 Jung-Hee Lee,1 Kyoo-Hyung Lee,1 Si-Hwan Kim,2 Sang-Hyun Hwang,2 Eul-Ju Seo,2 Chan-Jeoung Park2 and Je-Hwan Lee1
1Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine; 2Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine and 3Asan Institution for Life Sciences and Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
*E-JG and Y-UC contributed equally as co-first authors.
ABSTRACT
DDX41 mutations are associated with hematologic malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but the incidence in idiopathic cytopenia of undetermined significance (ICUS) is unknown. We investigated the inci- dence, genetic characteristics, and clinical features of DDX41 mutations in Korean patients with ICUS, MDS, or AML. We performed targeted deep sequencing of 61 genes including DDX41 in 457 patients with ICUS (n=75), MDS (n=210), or AML (n=172). Germline DDX41 mutations with causality were identified in 28 (6.1%) patients, of whom 27 (96.4%) had somatic mutations in the other position of DDX41. Germline origins of the DDX41 mutations were confirmed in all of the 11 patients in whom germline-based testing was performed. Of the germline DDX41 mutations, p.V152G (n=10) was most common, fol- lowed by p.Y259C (n=8), p.A500fs (n=6), and p.E7* (n=3). Compared with non-mutated patients, patients with a DDX41 mutation were more frequently male, older, had a normal karyotype, low leukocyte count, and hypocellular marrow at diagnosis. Three of the four ICUS patients with germline DDX41 mutations progressed to MDS. The incidence of DDX41 mutations in Korean patients was high and there was a distinct mutation pattern, in that p.V152G was a unique germline variant. ICUS harboring germline DDX41 mutations may be regarded as a hereditary myeloid neoplasm. Germline DDX41 mutations are not uncommon and should be explored when treating patients with myeloid malignancies.
Introduction
Inherited hematologic malignancies have been established in well-defined hereditary syndromes, which exhibit a particular phenotype, often present in childhood, or have a strong family history.1 There is also an increasing awareness of additional autosomal dominant genetic aberrations with predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), which are primarily sporadic diseases and typically present in older adults. The recently updated World Health Organization (WHO) classification defined myeloid neo- plasms with germline predisposition2 and categorized familial myeloid neoplasms into three groups: those with an absence of pre-existing disorder or organ dysfunc- tion (e.g., CEBPA or DDX41 mutations), those with a pre-existing platelet disorder (e.g., RUNX1 mutations), and those with dysfunction of other organs (e.g., GATA2 mutations). DDX41 mutations have recently joined the growing list of genetic alterations in familial myeloid malignancies.3,4 MDS or AML with germline DDX41 mutations usually occurs in the sixth decade of life or beyond, whereas
Myeloid Biology
Correspondence:
JE-HWAN LEE
jhlee3@amc.seoul.kr
Received: August 27, 2020. Accepted: February 2, 2021. Pre-published: February 25, 2021.
https://doi.org/10.3324/haematol.2020.270553 ©2022 Ferrata Storti Foundation
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