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

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 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). 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, followed 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.

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.

Figure 2.

Distribution of DDX41 mutations and concurrent mutations in other genes. (A) Distribution of DDX41 mutations detected in the current study and two previous studies (Quesada et al. and Sebert et al.). This figure shows the differences in positional distribution (N-terminal skewed vs. C-terminal skewed) and mutational effects (variable vs. missense-dominated) between germline and somatic mutations. The protein structure of DDX41 was based on the RefSeq accession number of NM_016222.3 and the UniProtKB entry of Q9UJV9: the 622 amino acid long protein comprises the helicase ATP-binding domain (position 212-396), the helicase C-terminal domain (position 407-567), and a zinc finger domain (position 580-597). Different colors indicate different effects of mutations: light blue, missense mutation; light green, inframe indel; purple, nonsense mutation; brown, splicing mutation; red, frameshift mutation; black, start codon loss. Different shapes represent the three studies: square, Sebert et al. diamond, Quesada et al. circle, current study. (B) Concurrent mutations of other genes identified in bone marrow samples from DDX41-mutated patients. The types of genetic alterations and diseases are presented in the legend.

Figure 3.

Overall survival of patients with different hematologic disorders according to DDX41 mutation status. (A-C) Overall survival of patients with idiopathic cytopenia of undetermined significance (A), myelodysplastic syndrome (B) or acute myeloid leukemia (C) according to whether they had DDX41 mutations (red) or not (blue).