Novel DDX41 variants in Thai patients with myeloid neoplasms

Polprasert, Chantana; Takeda, June; Niparuck, Pimjai; Rattanathammethee, Thanawat; Pirunsarn, Arunrat; Suksusut, Amornchai; Kobbuaklee, Sirorat; Wudhikarn, Kitsada; Lawasut, Panisinee; Kongkiatkamon, Sunisa; Chuncharunee, Suporn; Songserm, Kritanan; Phowthongkum, Prasit; Bunworasate, Udomsak; Nannya, Yasuhito; Yoshida, Kenichi; Makishima, Hideki; Ogawa, Seishi; Rojnuckarin, Ponlapat

doi:10.1007/s12185-019-02770-3

Cited by 23 publications

(17 citation statements)

References 11 publications

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“…Second, the patterns of germline DDX41 mutations in our Korean population were distinct from those in Western populations 10 , 11 or even other Asian populations. 22 , 23 The germline DDX41 mutations (p.V152G, p.Y259C, p.A500fs, p.E7*, and p.L328R) in our study are totally different from those reported in Western populations (p.M1I, p.D140fs, p.G173R, and Q41*). Korean and Japanese patients shared three major germline DDX41 variants (p.Y259C, p.A500fs, p.E7*),22 but p.V152G was only found in Koreans and not in Japanese or other ethnic populations.…”

Section: Discussioncontrasting

confidence: 96%

“… 22 Therefore, there seems to be an ethnic difference in the incidence of DDX41 mutations in patients with myeloid neoplasms between Asian and Western patients. In contrast, the clinical features of our DDX41 -mutated patients, such as male predominance, old age at presentation, 5 , 6 , 10 , 11 , 23 hypocellular marrow, 3 , 4 , 6 leukopenia, 6 and frequent normal cytogenetics 3-6 , 11 were similar to those reported in other ethnic populations. The DDX41 mutations did not show significant associations with survival outcomes.…”

Section: Discussionsupporting

confidence: 68%

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Unique ethnic features of <I>DDX41</I> mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia

et al. 2021

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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 incidence, 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). The 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 who performed germline-based testing. Of the germline DDX41 mutations, p.V152G (n=10) was most common, followed by p.Y259C (n=8), p.A500fs (n=6), and p.E7* (n=3). Compared with non-mutated patients, DDX41-mutated patients showed male predominance, old age, normal karyotype, low leukocyte count, and hypocellular marrow at diagnosis. Three of the 4 ICUS patients with germline DDX41 mutations progressed to MDS. DDX41 mutations in Korean patients showed a high incidence and distinct mutation patterns, 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 the patients with myeloid malignancies.

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Section: Discussioncontrasting

confidence: 96%

Section: Discussionsupporting

confidence: 68%

Unique ethnic features of <I>DDX41</I> mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia

et al. 2021

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“…We excluded 77 publications, including 41 animal studies, 20 about irrelevant subjects, 13 reviews, and three in languages other than English and Chinese. The remaining 30 were next given full-text reviews and all were considered eligible for this study, including nine case series, 12 , 14 – 21 11 case reports, 22 – 32 four reports about DDX41 -related solid cancers, 33 – 36 and six rare case reports 37 – 42 ( Figure 1 ). No extra study was identified from the references listed in the relevant reviews and the included studies.…”

Section: Resultsmentioning

confidence: 99%

Clinical features of DDX41 mutation-related diseases: a systematic review with individual patient data

Wan

Han

2021

Therapeutic Advances in Hematology

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Background: DDX41 serves as a DNA sensor in innate immunity and mutated DDX41 is pathogenic, mainly for myeloid neoplasms. Methods: In this study, “ DDX41” was searched in PubMed and Web of Science between 1 January 2015 and 29 April 2021 with individual-patient data seeking. A meta-analysis was not valid here due to the absence of a large dataset. Thirty articles were finally included in the qualitative analysis and 277 patients from 20 studies without overlap were involved in the quantitative summary. Results: Pooled incidence was 3.3% (95% confidence interval 2.4–4.2%) of unselected myeloid neoplasms. Patients with hematologic disorders harboring mutated DDX41 were featured as 80% males, median 66 (20–88) years old at diagnosis, 75% acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), 64% with normal karyotype. Eighty-five percent of patients had germline variants which were nationally diverse and more of frameshift type, whereas 64% of patients had somatic DDX41 variants where p.R525H and missense dominated. ASXL1 and TP53 were the top frequent concomitant somatic mutations. Therapeutically, 70% overall response rate was obtained of hypomethylating agents in MDS, 96% complete remission of chemotherapy in AML, and 8% of relapse in hematopoietic stem cell transplant. Neither overall survival nor progression-free survival could be summed. Conclusions: Several significant clinical differences were observed in different diagnosis groups, familial and sporadic cases, and p.R525H compared with other somatic variants. In conclusion, myeloid neoplasms carrying DDX41 mutations were mainly older, male, MDS, and AML patients who had promising responses to treatment. Both germline and somatic DDX41 variants possessed unique characteristics and groups of interest presented certain differences worth further research. (CRD42021228886)

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“…Nevertheless, the rate of TP53 mutation increased to 14% in MDS-EB patients with complex karyotype. The prevalence of TP53 mutation in 19 patients with high-risk MDS was 11% compared with 15% (4 out of 26 patients) in the previous study [ 14 ]. The possible causes of low prevalence of TP53 mutation in our MDS-EB patients might be from the small number of MDS-EB patients in the study (25 patients), low incidence of complex karyotype (7 patients) and/or underestimate the true mutation prevalence since our PCR technique was designed to detect only multiple hotspot mutations that was not the whole gene.…”

Section: Discussionmentioning

confidence: 74%

TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome

et al. 2021

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Objectives TP53 mutation is found frequently in therapy related acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS), AML and MDS patients with monosomy or complex karyotype. However, the prevalence and treatment outcome in TP53 mutated AML/MDS patients in Asian population are scarce. We therefore conducted this study to analyze the prevalence and the treatment outcomes of TP53 mutation in AML and MDS-EB patients. Methods Patients with newly diagnosed AML and MDS-EB were recruited, extraction of deoxyribonucleic acid from bone marrow samples were done and then performing TP53 mutation analysis, using MassArray® System (Agena Bioscience, CA, USA). Results A total of 132 AML/MDS patients were recruited, patients with de novo AML, secondary AML, MDS-EB1, MDS-EB2 and T-AML/MDS were seen in 66, 13, 9, 9 and 3%, respectively. TP53 mutation was found in 14 patients (10.6%), and prevalence of TP53 mutation in T-AML/MDS, secondary AML, de novo AML and MDS-EB patients were 50, 17.6, 9.2 and 8%, respectively. Three patients had double heterozygous TP53 mutation. Mutated TP53 was significantly detected in patients with monosomy and complex chromosome. Common TP53 mutation were R290C, T220C, A249S and V31I which V31I mutation was reported only in Taiwanese patients. Most variant allele frequency (VAF) of TP53 mutation in the study were greater than 40%. Three year-overall survival (OS) in the whole population was 22%, 3y-OS in AML and MDS-EB patients were 22 and 27%, respectively. The 1y-OS in patients with TP53-mutant AML/MDS were shorter than that in TP53 wild-type patients, 14% versus 50%, P = 0.001. In multivariate analysis, factors affecting OS in 132 AML/MDS patients was mutant TP53 (P = 0.023, HR = 1.20–7.02), whereas, WBC count> 100,000/μL (P = 0.004, HR = 1.32–4.16) and complex karyotype (P = 0.038, HR = 1.07–9.78) were associated with shorter OS in AML patients. Discussion In this study, the prevalence of TP53 mutation in de novo AML and MDS-EB patients were low but it had impact on survival. Patients with monosomy or complex karyotype had more frequent TP53 mutation.

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Novel DDX41 variants in Thai patients with myeloid neoplasms

Cited by 23 publications

References 11 publications

Unique ethnic features of <I>DDX41</I> mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia

Unique ethnic features of <I>DDX41</I> mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia

Clinical features of DDX41 mutation-related diseases: a systematic review with individual patient data

TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome

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