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E.-J. Choi et al.
ations in the N-terminal region may cause greater suscep- tibility to protein hypofunction than those in the C-termi- nal region. Second, the patterns of germline DDX41 mutations in our Korean population were distinct from those in Western populations10,11 or even other Asian pop- ulations.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 popula- tions (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. Third, we observed the exclusive presence of PHF6 p.M1T/V variants in three patients with proba- ble germline DDX41 mutations. These variants potential- ly cause a complete lack of protein production as a conse- quence of start codon loss and are causative germline mutations of the Börjeson-Forssman-Lehmann syndrome.26-28 Thus, our findings suggest that the same genetic mutation can induce both hereditary diseases and sporadic cancer, as exemplified by mutations in ETV6.29 The possible association between PHF6 p.M1T/V vari- ants and germline DDX41 mutations should be investi- gated further.
Germline mutations that predispose an individual to MDS or AML may also contribute to the development of ICUS, but the genetic predisposition to ICUS has not been systematically investigated. In a recent study of germline DDX41 mutations in adult patients with MDS or AML, 45.5% of patients with pathogenic germline DDX41 mutations had a previous history of cytopenia before the diagnosis of MDS or AML, and the preexisting cytopenia might indicate the presence of ICUS in these patients.11 We also observed similar findings. Furthermore, five (6.7%) of 75 ICUS patients had causal germline DDX41 mutations, three of whom progressed to MDS. Our study shows that germline DDX41 mutations are not uncom- mon in ICUS patients. Our findings do not indicate that the germline DDX41 mutations contribute to the progres- sion of ICUS to MDS, but instead do suggest that ICUS patients harboring such variants may be considered as having a hereditary myeloid neoplasm.
Our observations highlight the potential oncogenic role of germline DDX41 mutations in the pathogenesis of ICUS/MDS in comparison with AML. First, the patients with ICUS/MDS carried germline DDX41 mutations more frequently than did AML patients and germline missense mutations were highly enriched in ICUS/MDS rather than in AML. These findings might support the notion that less disruptive variants are associated with a milder phenotype in the disease spectrum. Second, only one (3.6%) of the 28 patients with germline DDX41 mutations carried a muta- tion in the splicing factor gene. This finding is in line with previous observations that splicing factor gene mutations were largely mutually exclusive with DDX41 muta- tions.5,10 DDX41 interacts with core splicing proteins such as SF3B, U2 complex, PRPF8 scaffold protein, and U5 com- plex, indicating that spliceosomal proteins are the top functional group associated with DDX41.5,25 Genetic alter- ations of the splicing components affect the 3’-splice site recognition during pre-mRNA processing and are involved in the pathogenesis of myelodysplasia.30 This indicates that mutant DDX41 can have an oncogenic role in MDS via aberrant mRNA splicing with the assumption that mutations in these splicing factors have an impact on the
pathways of downstream oncogenes and tumor suppres- sor genes.3
Donor-derived leukemia has been reported in several families with germline DDX41 mutations; in all such cases, donors had the same type of germline DDX41 vari- ants as the respective recipients.31,32 In our study, DDX41 mutations (germline p.E7* and somatic p.G228C) were found in a 60-year-old man with high-risk MDS (#12). No
A
B
C
Figure 3. Overall survival of patients with different hematologic disorders according to DDX41 mutation status. (A-C) Overall survival of patients with idio- pathic cytopenia of undetermined significance (A), myelodysplastic syndrome (B) or acute myeloid leukemia (C) according to whether they had DDX41 mutations (red) or not (blue).
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haematologica | 2022; 107(2)