: Germline 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, enrolling a total of 346 patients with DDX41 pathogenic/likely pathogenic (P/LP) germline variants and/or somatic mutations from 9,082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients, we performed a comprehensive characterization of DDX41-mutated MNs. P/LP DDX41 germline variants explained ~80% of known germline predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n=4,461) compared to a Japanese general population (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 old but rapidly increased to 49% by 90 years of age. DDX41-mutated MDS patients rapidly progressed to AML, which was, however, confined to those having truncating variants. Co-mutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and -WT cases, where none of the co-mutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multi-hit 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 (IPSS-R/M). Our findings establish that DDX41-mutated MDS defines a unique subtype of MNs that is distinct from other MNs.

Makishima, H., Saiki, R., Nannya, Y., Korotev, S.c., Gurnari, C., Takeda, J., et al. (2022). Germline DDX41 mutations define a unique subtype of myeloid neoplasms. BLOOD [10.1182/blood.2022018221].

Germline DDX41 mutations define a unique subtype of myeloid neoplasms

Gurnari, Carmelo
Writing – Review & Editing
;
2022-11-02

Abstract

: Germline 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, enrolling a total of 346 patients with DDX41 pathogenic/likely pathogenic (P/LP) germline variants and/or somatic mutations from 9,082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients, we performed a comprehensive characterization of DDX41-mutated MNs. P/LP DDX41 germline variants explained ~80% of known germline predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n=4,461) compared to a Japanese general population (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 old but rapidly increased to 49% by 90 years of age. DDX41-mutated MDS patients rapidly progressed to AML, which was, however, confined to those having truncating variants. Co-mutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and -WT cases, where none of the co-mutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multi-hit 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 (IPSS-R/M). Our findings establish that DDX41-mutated MDS defines a unique subtype of MNs that is distinct from other MNs.
Online ahead of print
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/15
English
10.1182/blood.2022018221
Makishima, H., Saiki, R., Nannya, Y., Korotev, S.c., Gurnari, C., Takeda, J., et al. (2022). Germline DDX41 mutations define a unique subtype of myeloid neoplasms. BLOOD [10.1182/blood.2022018221].
Makishima, H; Saiki, R; Nannya, Y; Korotev, Sc; Gurnari, C; Takeda, J; Momozawa, Y; Best, S; Krishnamurthy, P; Yoshizato, T; Atsuta, Y; Shiozawa, Y; Iijima-Yamashita, Y; Yoshida, K; Shiraishi, Y; Nagata, Y; Kakiuchi, N; Onizuka, M; Chiba, K; Tanaka, H; Kon, A; Ochi, Y; Nakagawa, Mm; Okuda, R; Mori, T; Yoda, A; Itonaga, H; Miyazaki, Y; Sanada, M; Ishikawa, T; Chiba, S; Tsurumi, H; Kasahara, S; Müller-Tidow, C; Takaori-Kondo, A; Ohyashiki, K; Kiguchi, T; Matsuda, F; Jansen, Jh; Polprasert, C; Blombery, P; Kamatani, Y; Miyano, S; Malcovati, L; Haferlach, T; Kubo, M; Cazzola, M; Kulasekararaj, Ag; Godley, La; Maciejewski, Jp; Ogawa, S
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/311890
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