Unique ethnic features of <I>DDX41</I> 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). 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.

Integrating germline variant assessment into routine clinical practice for myelodysplastic syndrome and acute myeloid leukaemia: current strategies and challenges

“…Interestingly, a strong founder effect has been noted across different populations; for example, Korean and Japanese patients exhibit variants such as p.Y259C, p.A500fs and p.E7* [Clinical Genome Resource (ClinGen) Allele identification (ID) numbers: CA3585027, CA3584730, CA362378171], in contrast to Western patients, where p.M1?, p.D140fs and p.G173R (ClinGen Allele IDs:CA358661, CA280919, CA3585177) prevail. 42,43 This finding is consistent with the late, post-reproductive onset of malignancy phenotype in DDX41 carriers, allowing pathogenic alleles to persist and be propagated in populations over time; unlike paediatric onset malignancy disorders, where alleles are likely to extinguish from the population over time. This is also supported by the increased prevalence of pathogenic DDX41 alleles in population databases such as the Genome Aggregation Database (gnomAD) compared to other HHMSs.…”

Clinical implications and genetic features of clonal cytopenia of undetermined significance compared to lower‐risk myelodysplastic syndrome

“…In our previous study, DDX41 mutations were observed in 6.7% (5/75) of the patients with ICUS and 11.9% (5/42) of the patients with CCUS. 21 In this study, during follow-up, three of six patients who had both germline and somatic mutations developed MDS or AML (excess blast-1 in two and secondary AML arising from excess blast-2 in one). Regarding the impact on survival outcomes, patients with biallelic DDX41 mutations with both germline and somatic variants showed significantly worse OS and PFS compared to those without these mutations.…”

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

“…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.…”