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Ethnic features of DDX41 mutations in ICUS/MDS/AML
only these patients were included in further analyses. The frequency of the causal germline DDX41 mutations was 6.1% (28 of 457); 6.7% (5 of 75) in ICUS, 9.0% (19 of 210) in MDS, and 2.3% (4 of 172) in AML (Figure 1). Detailed information on the DDX41 variants, concurrent mutations of other genes, and karyotypes in the 28 patients are pro- vided in Online Supplementary Table S2. Germline origins of the DDX41 mutations were confirmed in all of the 11 patients who underwent germline-based testing (p.V152G in 5, p.Y259C in 3, p.A500fs in 2, and p.L328R in 1).
Of the 55 DDX41 mutations detected in this study, 28 were germline and the other 27 appeared to be somatic. All of the somatic mutations were missense, whereas germline mutations were missense in 19 (67.9%) cases, frameshift in six (21.4%), and nonsense in three (10.7%). The majority of somatic mutations were located in the helicase C or C-terminal domain (n=18, 66.7%), whereas the majority of germline mutations were in the helicase ATP-binding or N-terminal domain (n=22, 78.6%; P=0.001) (Figure 2A). Of the germline DDX41 mutations, p.V152G (n=10, 35.7%) was the most common, followed by p.Y259C (n=8, 28.6%), p.A500fs (n=6, 21.4%), p.E7* (n=3, 10.7%), and p.L328R (n=1, 3.6%).
Two germline variants (p.A500fs and p.E7*) were classi- fied as pathogenic according to the ACMG guideline. The other germline variants (p.V152G, p.Y259C, and p.L328R) were classified as being of uncertain significance, but were considered causal when accompanied by somatic DDX41 mutations (Online Supplementary Table S3). Notably, four mutations (p.V152G, p.Y259C, p.A500fs and p.E7*) were found at a significantly higher frequency in the study patients than in healthy Koreans, as shown by high odds ratios (38.5, 17.3, 49.6 and 26.5, respectively) (Online Supplementary Table S4). Two germline mutations (p.V152G and p.Y259C) were only detected in ICUS/MDS (75.0%) and not in AML (0%), whereas p.A500fs and p.E7* were detected in both ICUS/MDS and AML groups (Online Supplementary Table S5). Of the 27 somatic DDX41 mutations, p.R525H (n=14, 51.9%) was the most com- mon, followed by p.T227M (n=5, 18.5%), and the remain- ing eight somatic DDX41 mutations were detected in one (3.7%) patient each. The somatic p.R525H variant was
less frequently associated with the germline p.V152G vari- ant (3 of 10) than with p.Y259C (6 of 8) or p.A500fs (4 of 6), whereas the somatic p.T227M variant tended to be more frequently associated with p.V152G (4 of 10) than with p.Y259C (1 of 8) or p.A500fs (0 of 6) (Online Supplementary Table S6).
Twenty-two (78.6%) of the 28 patients with mutations in DDX41 had concurrent mutations in other genes. Genes mutated in over 10% of the patients were PHF6 and ASXL1 (5 patients [17.9%] each), followed by CBL and NF1 (4 patients [14.3%] each), and DNMT3A and TP53 (3 patients [10.7%] each) (Figure 2B; Online Supplementary Table S2). We observed six variants of the PHF6 gene in five patients with DDX41 germline muta- tions: p.M1T and p.R116* in one patient, and p.G248D, p.C20F, p.M1T and p.M1V in one patient each. Interestingly, PHF6 p.M1T/V variants were detected in only three patients harboring DDX41 germline mutations among the whole study population of 457 patients.
Clinical features and outcomes of the patients with DDX41 mutations
There was a male predominance among the DDX41-mutated patients (96.4% vs. 57.1%; P<0.001), and the patients with this mutation tended to be older (median 66 vs. 57 years; P<0.001), and were more likely to have a normal karyotype (75.0% vs. 48.7%; P=0.007), lower white blood cell count (median 1.8 vs. 3.7×109/L; P=0.047), and lower marrow cellularity (median 30% vs. 60%; P<0.001) at diagnosis compared with the non-mutated patients (Table 2). Among patients with MDS, the DDX41 mutations were significantly more frequent in the MDS subtypes with excess blasts (EB)-1 and EB-2, compared to other categories with bone marrow blasts <5%, although the mutation frequencies were not significantly different between patients with lower risk or higher risk according to the IPSS-R (Table 2). Of 23 MDS or AML patients with causal germline DDX41 mutations, data regarding blood counts before diagnosis were available for 16 patients, and all 16 patients had a history of cytopenia at least 1 year prior to diagnosis.
During the median follow-up of 25.5 months, 116
Figure 1. Frequency of DDX41 mutations according to the type of hematologic malignancy. ICUS: idiopathic cytopenia of undetermined significance; MDS: myelodysplastic syndrome; AML: acute myeloid leukemia.
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