Clinical and molecular correlates of somatic and germline DDX41 variants in patients and families with myeloid neoplasms

Abstract

The diagnosis of germline predisposition to myeloid neoplasms (MN) secondary to DDX41 variants is currently hindered by the long latency period, variable family histories and the frequent occurrence of DDX41 variants of uncertain significance (VUS). We reviewed 4,524 consecutive patients who underwent targeted sequencing for suspected or known MN and analyzed the clinical impact and relevance of DDX41VUS in comparison to DDX41path variants. Among 107 patients (44 [0.9%] DDX41path and 63 DDX41VUS [1.4%; 11 patients with both DDX41path and DDX41VUS]), we identified 17 unique DDX41path and 45 DDX41VUS variants: 24 (23%) and 77 (72%) patients had proven and presumed germline DDX41 variants, respectively. The median age was similar between DDX41path and DDX41VUS (66 vs. 62 years; P=0.41). The median variant allele frequency (VAF) (47% vs. 48%; P=0.62), frequency of somatic myeloid co-mutations (34% vs 25%; P= 0.28), cytogenetic abnormalities (16% vs. 12%; P=>0.99) and family history of hematological malignancies (20% vs. 33%; P=0.59) were comparable between the two groups. Time to treatment in months (1.53 vs. 0.3; P=0.16) and proportion of patients progressing to acute myeloid leukemia (14% vs. 11%; P=0.68), were similar. The median overall survival in patients with high-risk myelodysplastic syndrome/acute myloid leukemia was 63.4 and 55.7 months in the context of DDX41path and DDX41VUS, respectively (P=0.93). Comparable molecular profiles and clinical outcomes among DDX41path and DDX41VUS patients highlights the need for a comprehensive DDX41 variant interrogation/classification system, to improve surveillance and management strategies in patients and families with germline DDX41 predisposition syndromes.

Figure 1.

Flowchart of the study, illustrating germline versus somatic status, and proportion of patients with DDX41_path and D DX41_VUS. In this study, 107 patients with 132 DDX41 variants are identified from 4,524 adult patients screened. The yellow boxes indicate the number of patients, and the white boxes indicate the number of variants. We identified 44 patients with pathogenic DDX41, harboring 56 pathogenic and 11 variants of uncertain significance (VUS) variants. Sixty-three DDX41 VUS only, harboring 65 VUS variants. pts: patients; path: pathogenic; P/LP: pathogenic/likely pathogenic.

Figure 2.

Distribution of DDX41 variants detected, positioned on the DDX41 protein and its functional domains with representation of germline and somatic status. NTD: N-terminal domain; ZFD: zinc finger domain; CTD: C-terminal domain; VUS: variants of uncertain significance.

Figure 3.

Integrated matrix for DDX41_path and DDX41_VUS per case and observed concurrent mutations. *2: second pathogenic (path) DDX41 mutation. VUS: variants of uncertain significance.

Figure 4.

Kaplan Meier curves for overall survival. (A) Overall survival (OS) in high-risk myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML) patients with DDX41_path and DDX41_VUS, (B) isolated vs. co-mutated DDX41, (C) bone marrow (BM) blast 10%-19% vs. ≥20% (D) age <70 years (yrs) vs. ≥70 yrs (E) germline vs. somatic DDX41, and (F) with or without cytogenetic abnormality. VUS: variants of uncertain significance; path: pathogenic.