• AML/MDS defined by germline DDX41 CV represents a unique entity with favorable outcome.

  • Germline DDX41 CVs predisposing patients to MN are often associated with somatic DDX41 mutations.

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 (HMs) remain unexplored. Here, we analyzed the genomic profiles of 176 patients with HM carrying 82 distinct presumably germline DDX41 variants among a group of 9821 unrelated patients. Using our proposed DDX41-specific variant classification, we identified features distinguishing 116 patients with HM with CV from 60 patients with HM with variant of uncertain significance (VUS): an older age (median 69 years), male predominance (74% in CV vs 60% in VUS, P = .03), frequent concurrent somatic DDX41 variants (79% in CV vs 5% in VUS, P < .0001), a lower somatic mutation burden (1.4 ± 0.1 in CV vs 2.9 ± 0.04 in VUS, P = .012), near exclusion of canonical recurrent genetic abnormalities including mutations in NPM1, CEBPA, and FLT3 in AML, and favorable overall survival (OS) in patients with AML/MDS. This superior OS was determined independent of blast count, abnormal karyotypes, and concurrent variants, including TP53 in patients with AML/MDS, 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 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.

1.
Klco
JM
,
Mullighan
CG
.
Advances in germline predisposition to acute leukaemias and myeloid neoplasms
.
Nat Rev Cancer.
2021
;
21
(
2
):
122
-
137
.
2.
Cannon-Albright
LA
,
Thomas
A
,
Goldgar
DE
, et al
.
Familiality of cancer in Utah
.
Cancer Res.
1994
;
54
(
9
):
2378
-
2385
.
3.
Kerber
RA
,
O’Brien
E
.
A cohort study of cancer risk in relation to family histories of cancer in the Utah population database
.
Cancer.
2005
;
103
(
9
):
1906
-
1915
.
4.
Arber
DA
,
Orazi
A
,
Hasserjian
R
, et al
.
The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia
.
Blood.
2016
;
127
(
20
):
2391
-
2405
.
5.
Zhang
J
,
Walsh
MF
,
Wu
G
, et al
.
Germline mutations in predisposition genes in pediatric cancer
.
N Engl J Med.
2015
;
373
(
24
):
2336
-
2346
.
6.
Huang
KL
,
Mashl
RJ
,
Wu
Y
, et al;
Cancer Genome Atlas Research Network
.
Pathogenic germline variants in 10,389 adult cancers
.
Cell.
2018
;
173
(
2
):
355
-
370.e14
.
7.
Sébert
M
,
Passet
M
,
Raimbault
A
, et al
.
Germline DDX41 mutations define a significant entity within adult MDS/AML patients
.
Blood.
2019
;
134
(
17
):
1441
-
1444
.
8.
Li
P
,
White
T
,
Xie
W
, et al
.
AML with germline DDX41 variants is a clinicopathologically distinct entity with an indolent clinical course and favorable outcome
.
Leukemia
.
2022
;
36
(
3
):
664
-
674
.
9.
Yang
F
,
Long
N
,
Anekpuritanang
T
, et al
.
Identification and prioritization of myeloid malignancy germline variants in a large cohort of adult patients with AML
.
Blood.
2022
;
139
(
8
):
1208
-
1221
.
10.
Polprasert
C
,
Schulze
I
,
Sekeres
MA
, et al
.
Inherited and somatic defects in DDX41 in myeloid neoplasms
.
Cancer Cell.
2015
;
27
(
5
):
658
-
670
.
11.
Cardoso
SR
,
Ryan
G
,
Walne
AJ
, et al
.
Germline heterozygous DDX41 variants in a subset of familial myelodysplasia and acute myeloid leukemia
.
Leukemia.
2016
;
30
(
10
):
2083
-
2086
.
12.
Alkhateeb
HB
,
Nanaa
A
,
Viswanatha
D
, et al
.
Genetic features and clinical outcomes of patients with isolated and comutated DDX41-mutated myeloid neoplasms
.
Blood Adv.
2021
;
6
(
2
):
528
-
532
.
13.
Chlon
TM
,
Stepanchick
E
,
Hershberger
CE
, et al
.
Germline DDX41 mutations cause ineffective hematopoiesis and myelodysplasia
.
Cell Stem Cell.
2021
;
28
(
11
):
1966
-
1981.e6
.
14.
Berger
G
,
van den Berg
E
,
Sikkema-Raddatz
B
, et al
.
Re-emergence of acute myeloid leukemia in donor cells following allogeneic transplantation in a family with a germline DDX41 mutation
.
Leukemia.
2017
;
31
(
2
):
520
-
522
.
15.
Kobayashi
S
,
Kobayashi
A
,
Osawa
Y
, et al
.
Donor cell leukemia arising from preleukemic clones with a novel germline DDX41 mutation after allogenic hematopoietic stem cell transplantation
.
Leukemia.
2017
;
31
(
4
):
1020
-
1022
.
16.
Bannon
SA
,
Routbort
MJ
,
Montalban-Bravo
G
, et al
.
Next-generation sequencing of DDX41 in myeloid neoplasms leads to increased detection of germline alterations
.
Front Oncol.
2021
;
10
:
582213
.
17.
Aldoss
I
,
Clark
M
,
Marcucci
G
,
Forman
SJ
.
Donor derived leukemia in allogeneic transplantation
.
Leuk Lymphoma.
2021
;
62
(
12
):
2823
-
2830
.
18.
Dietz
AC
,
DeFor
TE
,
Brunstein
CG
,
Wagner
JE
Jr
.
Donor-derived myelodysplastic syndrome and acute leukaemia after allogeneic haematopoietic stem cell transplantation: incidence, natural history and treatment response
.
Br J Haematol.
2014
;
166
(
2
):
209
-
212
.
19.
Lewinsohn
M
,
Brown
AL
,
Weinel
LM
, et al
.
Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies
.
Blood.
2016
;
127
(
8
):
1017
-
1023
.
20.
Richards
S
,
Aziz
N
,
Bale
S
, et al;
ACMG Laboratory Quality Assurance Committee
.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
.
Genet Med.
2015
;
17
(
5
):
405
-
424
.
21.
D’Agostino
M
,
Zaccaria
GM
,
Ziccheddu
B
, et al
.
Early relapse risk in patients with newly diagnosed multiple myeloma characterized by next-generation sequencing
.
Clin Cancer Res.
2020
;
26
(
18
):
4832
-
4841
.
22.
Shah
V
,
Johnson
DC
,
Sherborne
AL
, et al;
National Cancer Research Institute Haematology Clinical Studies Group
.
Subclonal TP53 copy number is associated with prognosis in multiple myeloma
.
Blood.
2018
;
132
(
23
):
2465
-
2469
.
23.
Corre
J
,
Cleynen
A
,
Robiou du Pont
S
, et al
.
Multiple myeloma clonal evolution in homogeneously treated patients
.
Leukemia.
2018
;
32
(
12
):
2636
-
2647
.
24.
Kortüm
KM
,
Mai
EK
,
Hanafiah
NH
, et al
.
Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes
.
Blood.
2016
;
128
(
9
):
1226
-
1233
.
25.
Kelley
GA
,
Kelley
KS
.
Systematic reviews and meta-analysis in rheumatology: a gentle introduction for clinicians
.
Clin Rheumatol.
2019
;
38
(
8
):
2029
-
2038
.
26.
Vinches
M
,
Neven
A
,
Fenwarth
L
, et al
.
Clinical research in cancer palliative care: a metaresearch analysis
.
BMJ Support Palliat Care.
2020
;
10
(
2
):
249
-
258
.
27.
Bernard
E
,
Nannya
Y
,
Hasserjian
RP
, et al
.
Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes [corrections published in Nat Med. 2021;27:921]
.
Nat Med.
2020
;
26
(
10
):
1549
-
1556
.
28.
Qu
S
,
Li
B
,
Qin
T
, et al
.
Molecular and clinical features of myeloid neoplasms with somatic DDX41 mutations
.
Br J Haematol
.
2021
;
192
(
6
):
1006
-
1010
.
29.
Choi
E-J
,
Cho
Y-U
,
Hur
E-H
, et al
.
Unique ethnic features of DDX41 mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia
.
Haematologica
.
2022
;
107
(
2
):
510
-
518
.
30.
Li
R
,
Sobreira
N
,
Witmer
PD
,
Pratz
KW
,
Braunstein
EM
.
Two novel germline DDX41 mutations in a family with inherited myelodysplasia/acute myeloid leukemia
.
Haematologica.
2016
;
101
(
6
):
e228
-
e231
.
31.
Cheah
JJC
,
Hahn
CN
,
Hiwase
DK
,
Scott
HS
,
Brown
AL
.
Myeloid neoplasms with germline DDX41 mutation
.
Int J Hematol.
2017
;
106
(
2
):
163
-
174
.
32.
Quesada
AE
,
Routbort
MJ
,
DiNardo
CD
, et al
.
DDX41 mutations in myeloid neoplasms are associated with male gender, TP53 mutations and high-risk disease
.
Am J Hematol.
2019
;
94
(
7
):
757
-
766
.
33.
Vairo
FPE
,
Ferrer
A
,
Cathcart-Rake
E
, et al
.
Novel germline missense DDX41 variant in a patient with an adult-onset myeloid neoplasm with excess blasts without dysplasia
.
Leuk Lymphoma.
2019
;
60
(
5
):
1337
-
1339
.
34.
Polprasert
C
,
Takeda
J
,
Niparuck
P
, et al
.
Novel DDX41 variants in Thai patients with myeloid neoplasms
.
Int J Hematol.
2020
;
111
(
2
):
241
-
246
.
35.
Bejar
R
,
Stevenson
K
,
Abdel-Wahab
O
, et al
.
Clinical effect of point mutations in myelodysplastic syndromes
.
N Engl J Med.
2011
;
364
(
26
):
2496
-
2506
.
36.
Méndez-Ferrer
S
,
García-Fernández
M
,
de Castillejo
CL
.
Convert and conquer: the strategy of chronic myelogenous leukemic cells
.
Cancer Cell.
2015
;
27
(
5
):
611
-
613
.
37.
Maciejewski
JP
,
Padgett
RA
,
Brown
AL
,
Müller-Tidow
C
.
DDX41-related myeloid neoplasia
.
Semin Hematol.
2017
;
54
(
2
):
94
-
97
.
You do not currently have access to this content.

Sign in via your Institution