Abstract
Germ line DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here we performed a comprehensive characterization of DDX41-mutated MNs, enrolling a total of 346 patients with DDX41 pathogenic/likely-pathogenic (P/LP) germ line variants and/or somatic mutations from 9082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients. P/LP DDX41 germ line variants explained ∼80% of known germ line predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n = 4461) compared with the general population of Japan (n = 20 238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years of age but rapidly increased to 49% by 90 years of age. Patients with myelodysplastic syndromes (MDS) along with a DDX41-mutation rapidly progressed to acute myeloid leukemia (AML), which was however, confined to those having truncating variants. Comutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and WT cases, in which none of the comutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multihit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System. Our findings establish that MDS with DDX41-mutation defines a unique subtype of MNs that is distinct from other MNs.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 534-549 |
| Number of pages | 16 |
| Journal | Blood |
| Volume | 141 |
| Issue number | 5 |
| DOIs | |
| State | Published - Feb 2 2023 |
Funding
This work was supported by the Japan Agency for Medical Research and Development (AMED) (JP15cm0106056h0005, JP19cm0106501h0004, JP16ck0106073h0003, JP19ck0106250h0003 to S.O.; JP17km0405110h0005, JP19ck0106470h0001, JP21cm0106586h0001 to H.M.; JP19ck0106353h0003 to Y.N.) and the Core Research for Evolutional Science and Technology (CREST) (JP19gm1110011 to S.O.); the Ministry of Education, Culture, Sports, Science and Technology of Japan; the High Performance Computing Infrastructure System Research Project (hp160219, hp170227, hp180198, and hp190158 to S.O. and S.M.) (this research used computational resources of the K computer provided by the RIKEN Advanced Institute for Computational Science through the HPCI System Research project); the Japan Society for the Promotion of Science (JSPS); Scientific Research on Innovative Areas (JP15H05909 to S.O. and S.M.; JP15H05912 to S.M.) and KAKENHI (JP26221308 and JP19H05656 to S.O.; JP16H05338 and JP19H01053 to H.M.; JP15H05707 to S.M.); the Takeda Science Foundation (S.O. H.M. and T.Y.). S.O. is a recipient of the JSPS Core-to-Core Program A: Advanced Research Networks. DNA samples and subjects\u2019 clinical data were provided by Biobank Japan, the Institute of Medical Science, the University of Tokyo. The supercomputing resource was provided by the Human Genome Center, the Institute of Medical Science, the University of Tokyo. This work was supported by a grant from the Edward P. Evans Foundation (to C.G.). Contribution: H.M. Y. Nannya, Y. Momozawa, M.K. M.C. L.M. A.G.K. L.A.G. J.P.M. and S.O. designed the study; S. Korotev, C.G. Y. Momozawa, S.B. P.K. Y.A. M.O. H.I. Y. Miyazaki, T.I. H. Tsurumi, S. Kasahara, C.M.-T. A.T.-K. K.O. T.K. F.M. J.H.J. C.P. P.B. T.H. M.K. M.C. A.G.K. L.A.G. and J.P.M. provided DNA samples and/or clinical data; Y. Nannya, R.S. T.Y. Y. Shiozawa, K.Y. K.C. H. Tanaka and Y.K. performed copy-number analysis; J.T. Y. Momozawa, Y.I.-Y. K.Y. Y. Shiraishi, Y. Nagata, N.K. A.K. Y.O. M.M.N. R.O. T.M. A.Y. M.S. C.P. and P.B. performed sequencing; H.M. Y. Nannya, R.S. Y. Nagata, K.Y. S.M. and S.O. performed bioinformatics analysis; H.M. R.S. Y. Nannya, M.C. L.A.G. J.P.M. and S.O. prepared the manuscript; and all authors participated in discussions and interpretation of the data and results. This work was supported by the Japan Agency for Medical Research and Development (AMED) ( JP15cm0106056h0005 , JP19cm0106501h0004 , JP16ck0106073h0003 , JP19ck0106250h0003 to S.O.; JP17km0405110h0005 , JP19ck0106470h0001 , JP21cm0106586h0001 to H.M.; JP19ck0106353h0003 to Y.N.) and the Core Research for Evolutional Science and Technology (CREST) ( JP19gm1110011 to S.O.); the Ministry of Education, Culture, Sports, Science and Technology of Japan ; the High Performance Computing Infrastructure System Research Project ( hp160219 , hp170227 , hp180198 , and hp190158 to S.O. and S.M.) (this research used computational resources of the K computer provided by the RIKEN Advanced Institute for Computational Science through the HPCI System Research project); the Japan Society for the Promotion of Science (JSPS); Scientific Research on Innovative Areas ( JP15H05909 to S.O. and S.M.; JP15H05912 to S.M.) and KAKENHI (JP26221308 and JP19H05656 to S.O.; JP16H05338 and JP19H01053 to H.M.; JP15H05707 to S.M.); the Takeda Science Foundation (S.O., H.M., and T.Y.). S.O. is a recipient of the JSPS Core-to-Core Program A: Advanced Research Networks. DNA samples and subjects\u2019 clinical data were provided by Biobank Japan, the Institute of Medical Science, the University of Tokyo. The supercomputing resource was provided by the Human Genome Center, the Institute of Medical Science, the University of Tokyo. This work was supported by a grant from the Edward P. Evans Foundation (to C.G.).
ASJC Scopus subject areas
- Biochemistry
- Immunology
- Hematology
- Cell Biology