Page 172 - 2022_02-Haematologica-web

E.-J. Choi et al.
Table 2. Comparison of clinical features according to the presence of germline DDX41 mutations.
Sex, n(%) Male
Female
Median age (range), years Chromosome, n(%)
Normal
Abnormal
WBC, × 109/ L, median (range)
Hb, g/dL, median (range)
Platelets, × 109/ L, median (range) BM cellularity, %, median (range) BM blasts, %, median (range)
N. of mutated genes, median (range) MDS, n(%)
MDS with SLD/MLD/del(5q)/U MDS with EB-1/EB-2 Unknown
Risk stratification, n(%) MDS
IPSS-R ≤ 3.5 (%)
IPSS-R > 3.5 (%) AML
Favorable Intermediate Adverse Unknown
DDX41 mutations (+) (n=28)
27 (96.4) 1 (3.6) 66 (41-79)
21 (75.0)
7 (25.0) 1.8 (1.0-3.3) 10.1 (5.2-13.2) 90 (13-174) 30 (5-60) 6.2 (0.8-65.2) 3 (2-6)
7 (4.8) 12 (19.0) 0
6 (31.6) 13 (68.4)
0 (0) 2 (50.0) 2 (50.0) 0 (0)
DDX41 mutations (-) (n=429)
245 (57.1) 184 (42.9) 57 (16-89)
209 (48.7)
220 (51.3) 3.7 (0.7-313.1) 9.1 (2.3-16.4) 68 (3-638) 60 (3-100) 5.2 (0-98.8) 2 (0-12)
138 (95.2) 51 (81.0) 2 (100)
69 (36.1) 122 (63.9)
63 (37.5) 33 (19.6) 71 (42.3) 1 (0.6)
P
< 0.001a
< 0.001c
0.007a
0.047c 0.113c 0.689c < 0.001c 0.016c 0.036c
0.001aa*
0.693a 0.215b
WBC: white blood cells, Hb: hemoglobin; BM, bone marrow; MDS: myelodysplastic syndrome; SLD: single lineage dysplasia; MLD: multilineage dysplasia; EB: excess blasts; IPSS- R, International Prognostic Scoring System-Revised; AML: acute myeloid leukemia. aby the χ2 test; bby the Fisher exact test; cby t-test; *SLD/MLD/del(5q)/U vs. EB-1/EB-2.
patients (7 ICUS, 55 MDS, and 54 AML) died. The 5-year overall survival rate was 60.8% in the overall population and 84.6%, 62.2%, and 38.9% in patients with ICUS, MDS, and AML, respectively. There was no significant correlation between overall survival and the presence of DDX41 mutations in each disease category of ICUS, MDS, and AML (Figure 3) as well as in the total study pop- ulation (Online Supplementary Figure S1).
Online Supplementary Table S7 shows the clinical course of each patient with a DDX41 mutation. Clinical courses could be followed up in four of the five ICUS patients with probable germline DDX41 mutations, and notably, three of these four patients showed disease progression to MDS EB-1 (n=2; 77.9 and 17.6 months after ICUS diagno- sis) or MDS EB-2 with a gain of PTPN11 mutation (n=1; 9 months after ICUS diagnosis) during the follow-up. Another ICUS patient with a germline DDX41 mutation had a son with Hodgkin lymphoma.
Discussion
In our cohort of 457 patients with ICUS, MDS, or AML, 6.1% of the patients carried causal germline DDX41 muta- tions, which is a higher incidence than those found in pre- vious studies which ranged between 0.8% and 3.9% in patients with myeloid malignancies (mostly MDS and
AML).5,6,10,11,22 In a study comparing the clinical and genet- ic characteristics of DDX41 mutations in AML and MDS patients between two ethnically distinct populations, germline DDX41 mutations were found in 3.9% of a Japanese cohort and in 0.8% of a Caucasian cohort.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 con- trast, the clinical features of our DDX41 -mutated patients, such as male predominance, old age at presenta- tion,5,6,10,11,23 hypocellular marrow,3,4,6 leukopenia,6 and fre- quent normal cytogenetics3-6,11 were similar to those reported in other ethnic populations. The DDX41 muta- tions did not show significant associations with survival outcomes.
There are several noteworthy findings in our study regarding the genetic characteristics of DDX41 muta- tions. First, the germline mutations were mostly N-termi- nal variants (78.6%), whereas somatic mutations were mostly C-terminal variants (66.7%). This finding is con- sistent with the observations in two recent studies.10,11 The N-terminal region of DDX41 has the helicase ATP binding domain,24,25 and the structural rearrangement in the N-terminal region may change the conformation of the ATP-binding site and eventually decrease ATP-bind- ing ability.24 In contrast, the helicase C-terminal domain is involved in ATP hydrolysis.24,25 Therefore, genetic alter-
514
haematologica | 2022; 107(2)