The genetic landscape of germlineDDX41variants predisposing to myeloid neoplasms

Abstract

Germline DDX41 variants are the most common mutations predisposing to acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) in adults, but the causal variant (CV) landscape and clinical spectrum of hematologic malignancies (HM) remain unexplored. Here, we analyzed the genomic profiles of 176 HM patients carrying 82 distinct presumably germline DDX41 variants among a group of 9,821 unrelated patients. Using our proposed DDX41 specific variant classification, we identified features distinguishing 116 HM patients with CV from 60 HM patients with variant of uncertain significance (VUS): an older age (median 69 years), male predominance (74% in CV versus 60% in VUS, P=0.03), frequent concurrent somatic DDX41 variants (79% in CV versus 5% in VUS, p<0.0001), a lower somatic mutation burden (1.4 ± 0.1 in CV versus 2.9 ± 0.04 in VUS, P=0.012), near exclusion of canonical recurrent genetic abnormalities including mutations in NPM1, CEBPA and FLT3 in AML, and favorable overall survival (OS) in AML/MDS patients. This superior OS was determined independent of blast count, abnormal karyotypes, and concurrent variants, including TP53 in AML/MDS patients, regardless of patient's sex, age or specific germline CV, suggesting that germline DDX41 variants define a distinct clinical entity. Furthermore, unrelated patients with myeloproliferative neoplasm (MPN) and B-cell lymphoma were linked by DDX41 CV, thus expanding the known disease spectrum. This study outlines the CV landscape, expands the phenotypic spectrum in unrelated DDX41-mutated patients, and underscores the urgent need for gene-specific diagnostic and clinical management guidelines.

Unique role of DDX41, a DEAD-box type RNA helicase, in hematopoiesis and leukemogenesis

“…DDX41 mutations occur at a rate of 2 to 5% in AML (9,10). Most affected patients are in their 60s and are therefore not markedly different to non-DDX41 mutant sporadic AML cases with regard to peak age of disease diagnosis.…”

“…There does not appear to be a bias toward a specific AML subtype, but the disease is often characterized by low peripheral WBC counts and bone marrow hypoplasia, and a less differentiated tumor cell phenotype. However, there have been no reports of specific mutations in other genes that could contribute to these features of DDX41 mutant AML (9). DDX41 mutations are also observed in acute erythroid leukemia and lymphoid malignancies (23)(24)(25).…”

“…DDX41 performs these roles by converting RNA structure and changing interactions between RNA and proteins in an ATP-dependent manner (6)(7)(8). Several recent large clinical studies, including a prospective investigation, have established the clinical characteristics of myeloid malignancies with DDX41 mutations (9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Of note, heterozygous germline DDX41 variants cause mild defects in hematopoiesis; subsequent acquisition of a somatic mutation in the remaining wild-type allele at a different location from that of germline variants results in biallelic alteration, which is a requirement for a disease-developing driver mutation (Figure 1) (9,10).…”

Adult-onset hereditary myeloid malignancy and allogeneic stem cell transplantation

“…In addition, remarkable ethnic deviation was found in the mutation sites in DDX41; however, second hit was predominantly R525H, irrespective of ethnicity (47)(48)(49). TP53 and ASXL1 somatic mutations are recurrently detected (48), although the prognostic impact of concomitant mutations is limited (50).…”

“…AML with germline DDX41 mutations has unique clinical characteristics, such as approximately 3:1 male predominance, frequent absence of family history, and indolent clinical course (18,50,51). Makishima et al reported that the age of progression in individuals with germline DDX41 mutation was solely greater than 40 years, and penetrance of pathogenic DDX41 germline variants was estimated to be 38.5% at the age of 85.…”