Figure 4.
Genetic characteristics of patients with AML/MDS with germline variants in DDX41. (A) The occurrence of somatic DDX41 variants in patients with AML is closely linked to the presence of germline DDX41 CV (79%; 52 of 66), in comparison with patients with VUS (5.6%, 1 of 18, P < .0001) or patients not carrying germline DDX41 variants (DDX41−, 0.2%; 3 of 1365, P < .0001). A similar trend is seen in patients with MDS (79% in CV, 0% in VUS, and 0.1% in DDX41−, P < .0001). (B) A lower somatic mutation burden, calculated by the number of total concomitant somatic variants (excluding somatic DDX41 variants) per case, is seen in patients with AML with CV (mean ± standard error of the mean: 1.6 ± 0.2) compared with patients with AML with wild-type DDX41 (DDX41−, 3.7 ± 0.07, P < .0001) and those with VUS (2.6 ± 0.4, P = .03). Similarly, in MDS, a lower somatic mutation burden is seen in patients with CV (0.7 ± 0.1) in contrast to those with wild-type DDX41 (DDX41−, 2.7 ± 0.06, P < .0001) or VUS (3.2 ± 0.5, P < .0001). (C-D) Circos plot diagrams illustrate the pairwise co-occurrence of somatic variants and cytogenetic abnormalities in 94 patients with AML/MDS with germline CV (C) and 30 with VUS (D). Genetic variants and cytogenetic events listed in Figure 3 appear in descending order clockwise, starting at 12 o’clock. Each link (ribbon) indicates pairwise co-occurrence of mutational events, and the width of the ribbons indicates the frequency of the co-occurrent events. The occurrence of germline and somatic DDX41 variants is indicated in red and yellow ribbons, respectively. Variants in signaling and RAS/MAPK pathways are labeled in pink; NPM1 and TP53 variants are labeled in black and green, respectively; the remaining variants are labeled in gray. s (yellow) in D, somatic DDX41; SF (purple), RNA splicing factors; TF (orange), transcription factors; S (pink) in panel C, signaling; O (gray), others; # (blue), cohesin; ! (black), NPM1; @ (green), TP53; nl CG, normal cytogenetics; a CG, abnormal cytogenetics. (E) Frequencies of somatic DDX41 and other concurrent variants in AML/MDS patients. For each gene or genetic category, the percentage of mutations is displayed, associated with either germline CV (red bars, gl DDX41+ CV), VUS (blue bars, gl DDX41+ VUS), or wild-type DDX41 (green bars, gl DDX41−). s DDX41, somatic DDX41 variants; epigenetics, genes involving DNA methylation or histone acetylation and deacetylation; signaling transduction, molecules in tyrosine kinase pathway or RAS/MAPK pathways; RCA, recurrent cytogenetic abnormalities in AML. *P < .05; ****P < .0001.

Genetic characteristics of patients with AML/MDS with germline variants in DDX41. (A) The occurrence of somatic DDX41 variants in patients with AML is closely linked to the presence of germline DDX41 CV (79%; 52 of 66), in comparison with patients with VUS (5.6%, 1 of 18, P < .0001) or patients not carrying germline DDX41 variants (DDX41−, 0.2%; 3 of 1365, P < .0001). A similar trend is seen in patients with MDS (79% in CV, 0% in VUS, and 0.1% in DDX41−, P < .0001). (B) A lower somatic mutation burden, calculated by the number of total concomitant somatic variants (excluding somatic DDX41 variants) per case, is seen in patients with AML with CV (mean ± standard error of the mean: 1.6 ± 0.2) compared with patients with AML with wild-type DDX41 (DDX41−, 3.7 ± 0.07, P < .0001) and those with VUS (2.6 ± 0.4, P = .03). Similarly, in MDS, a lower somatic mutation burden is seen in patients with CV (0.7 ± 0.1) in contrast to those with wild-type DDX41 (DDX41−, 2.7 ± 0.06, P < .0001) or VUS (3.2 ± 0.5, P < .0001). (C-D) Circos plot diagrams illustrate the pairwise co-occurrence of somatic variants and cytogenetic abnormalities in 94 patients with AML/MDS with germline CV (C) and 30 with VUS (D). Genetic variants and cytogenetic events listed in Figure 3 appear in descending order clockwise, starting at 12 o’clock. Each link (ribbon) indicates pairwise co-occurrence of mutational events, and the width of the ribbons indicates the frequency of the co-occurrent events. The occurrence of germline and somatic DDX41 variants is indicated in red and yellow ribbons, respectively. Variants in signaling and RAS/MAPK pathways are labeled in pink; NPM1 and TP53 variants are labeled in black and green, respectively; the remaining variants are labeled in gray. s (yellow) in D, somatic DDX41; SF (purple), RNA splicing factors; TF (orange), transcription factors; S (pink) in panel C, signaling; O (gray), others; # (blue), cohesin; ! (black), NPM1; @ (green), TP53; nl CG, normal cytogenetics; a CG, abnormal cytogenetics. (E) Frequencies of somatic DDX41 and other concurrent variants in AML/MDS patients. For each gene or genetic category, the percentage of mutations is displayed, associated with either germline CV (red bars, gl DDX41+ CV), VUS (blue bars, gl DDX41+ VUS), or wild-type DDX41 (green bars, gl DDX41−). s DDX41, somatic DDX41 variants; epigenetics, genes involving DNA methylation or histone acetylation and deacetylation; signaling transduction, molecules in tyrosine kinase pathway or RAS/MAPK pathways; RCA, recurrent cytogenetic abnormalities in AML. *P < .05; ****P < .0001.

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