-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

85 Germline Risks and Clinical Impacts of DDX41 Mutations in Myeloid MalignanciesClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 636. Myelodysplastic Syndromes—Basic and Translational: Clonal Trajectories and Novel Therapies
Hematology Disease Topics & Pathways:
Research, Translational Research
Saturday, December 10, 2022: 9:30 AM

Hideki Makishima, MD, PhD1, Ryunosuke Saiki2*, Yasuhito Nannya, M.D., Ph.D.2,3, Sophia C. Korotev4*, Carmelo Gurnari, MD5,6, June Takeda, MD1*, Yukihide Momozawa, DVM, Ph.D7*, Steve Best, PhD8*, Pramila Krishnamurthy, MD9*, Tetsuichi Yoshizato, MD, PhD2,10, Yoshiko Atsuta11,12*, Yusuke Shiozawa, MD, PhD13,14*, Yuka Iijima-Yamashita, PhD15*, Kenichi Yoshida2,16, Yuichi Shiraishi, PhD17*, Yasunobu Nagata, MD, PhD2*, Nobuyuki Kakiuchi, MD, PhD2*, Makoto Onizuka, MD, PhD18, Kenichi Chiba, PhD19*, Hiroko Tanaka, B.A.20*, Ayana Kon, MD, PhD2*, Yotaro Ochi, MD, PhD21*, Masahiro Marshall Nakagawa, MD, PhD2, Rurika Okuda, MSc, BS13*, Takuto Mori, MD2*, Akinori Yoda, PhD13*, Hidehiro Itonaga, MD, PhD22, Yasushi Miyazaki, MD23, Masashi Sanada, MD, PhD15, Takayuki Ishikawa24, Shigeru Chiba, MD, PhD25, Hisashi Tsurumi, MD, PhD26, Senji Kasahara27, Carsten Müller-Tidow, MD28*, Akifumi Takaori-Kondo, MD, PhD29, Kazuma Ohyashiki, MD, PhD30, Toru Kiguchi, MD, PhD31*, Fumihiko Matsuda, MD, PhD32*, Joop H. Jansen, PhD33, Chantana Polprasert, MD34*, Piers Blombery, MBBS35, Yoichiro Kamatani, MD, Ph.D36*, Satoru Miyano, PhD20*, Luca Malcovati, MD37, Torsten Haferlach, MD38, Michiaki Kubo, MD, Ph.D39*, Mario Cazzola, MD40, Austin Kulasekararaj, MD, MBBS, FRCPath, MRCP41, Lucy A. Godley, MD, PhD42, Jaroslaw P. Maciejewski, MD, PhD, FACP43 and Seishi Ogawa, MD, PhD10,13,44

1Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, KYO, Japan
2Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
3Department of Hematology/Oncology, IMSUT Hospital, The University of Tokyo, Tokyo, Japan
4Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
5Department of Biomedicine and Prevention, Ph.D. in Immunology, Molecular Medicine and Applied Biotechnology, University of Rome Tor Vergata, Rome, Italy
6Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH
7Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
8King's College Hospital, London, United Kingdom
9King's College Hospital NHS Foundation Trust, London, United Kingdom
10Center for Hematology and Regenerative Medicine, Department of Medicine (MedH), Karolinska Institutet, Huddinge, Sweden
11The Japanese Data Center for Hematopoietic Cell Transplantation, Nagakute, Japan
12Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Nagakute, Japan
13Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto City, Japan
14Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan
15Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
16Wellcome Trust Sanger Institute, Hinxton, United Kingdom
17Laboratory of Sequence Data Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
18Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan
19Center for Cancer Genomics and Advanced Therapeutics, National Cancer Center Research Institute, Tokyo, Japan
20M&D Data Science Center, Tokyo Medical and Dental University, Tokyo, Japan
21Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, HYO, Japan
22Department of Hematology, Nagasaki University Hospital, Nagasaki city, NSK, Japan
23Department of Hematology, Atomic Bomb Disease Institute, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
24Department of Hematology, Kobe City Medical Center General Hospital, Kobe, Japan
25Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
26Hematology, Gifu University Graduate School of Medicine, Gifu, Japan
27Department of Hematology, Gifu Pharmaceutical University, Gifu, Japan
28Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
29Department of Hematology, Kyoto University, Kyoto, Japan
30Department of Advanced Cellular Therapy, Tokyo Medical University, Tokyo, Japan
31Department of Hematology, Chugoku Central Hospital, Fukuyama, HIR, Japan
32Kyoto University Graduate School of Medicine, Kyoto, JPN
33Radboud Institute Molecular Studies, Radboud University Medical Center, Nijmegen, Netherlands
34Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
35Peter MacCallum Cancer Centre, Peter Maccallum Cancer Centre, East Melbourne, VIC, Australia
36Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
37Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Pavia, Italy
38MLL Munich Leukemia Laboratory, Munich, Germany
39Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan
40University of Pavia, University of Pavia, Pavia, Italy
41King’s College Hospital, National Institute for Health and Care Research/Wellcome King’s Clinical Research Facility, London, ENG, United Kingdom
42University of Chicago Medical Center, Chicago, IL
43Translational Hematology and Oncology Research, Cleveland Clinic Foundation/ Taussig Cancer Institute, Cleveland, OH
44Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan

Background Pathogenic/likely-pathogenic (P/LP) germline DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications regarding this gene, many important features of DDX41-mutated (DDX41mut) MNs remain to be elucidated, including disease penetrance.

Methods Here, we enrolled 9,082 cases with various MNs of divergent ethnicity. Tumor-derived DNA was available for all cases at one or more time points. In particular, diagnostic or treatment-naive tumor samples were obtained in 7,697 cases, of which 2,359 had survival data. Germline DNA was available for 1,350 patients. Bone marrow (BM)- or blood-derived tumor DNA was subjected to whole genome, exome and/or targeted sequencing using different driver gene panels, which included DDX41 and an additional 36 genes in common. We also enrolled 20,238 individuals from different Japanese biobanks for population controls.

Results We identified a total of 346 (3.8%) DDX41mut MNs among 9,082 MN cases. Among these, 293 (84.7%) had a germline variant, whereas 53 (15.3%) carried somatic variants alone of which biallelic lesions were suspected for 52%. As many as 66.6% of germline variants are truncating, which was rarely true of somatic variants. Based on the genotyping of known leukemia predisposition genes in consecutively enrolled 1,039 Japanese cases with MNs, DDX41 variants explains ~80% of all known predisposition to adult MNs in Japan. We determined the penetrance of MNs for P/LP DDX41 alleles through a kin-cohort analysis involving a total of 288 and 237 first-degree relatives of patients with MNs with and without P/LP DDX41 germline variants, respectively. The risk is almost negligible (~0%) under the age of 40 years, but rapidly increases to 49.3% (95%CI: 29.8-68.2) by the age of 90. In population analysis, five DDX41 alleles showed a significant enrichment in MNs in Japanese populations and therefore represent P/LP alleles (Odds ratio (OR) of ~10; 95%CI: 4.5-22.8, on average), which was more prominent in female than in male (20.7 vs. 5.0 in OR). Accordingly, the penetrance in males (52.5%) almost double that in females (28.7%). DDX41mut patients with MDS showed a significantly faster progression to AML, which however, confined to those cases having truncating variants, while those with non-truncating variants showed a rather slower progression compared with DDX41WT patients. Co-mutation patterns at diagnosis and at progression to AML are substantially different between DDX41mut and DDX41WT patients. Particularly, CUX1 mutations were overrepresented in DDX41mut cases. Conspicuously, unlike other MDS cases, DDX41mut MDS were not significantly enriched for mutations in AML-related genes, such as RAS and other signaling pathway genes. In contrast to DDX41WT cases, none of the co-mutations significantly affected clinical outcomes. Even biallelic TP53 mutations did not affect overall survival (OS) and as expected, neither IPSS-R nor IPSS-M scores do so. DDX41mut patients showed a significantly better OS than DDX41WT cases with higher-risk MDS and sAML patients and a survival comparable to that of DDX41WT lower-risk MDS cases. OS in patients who received hypomethylating agent (HMA) was significantly better for DDX41mut than DDX41WT patients and so in those who received hematopoietic stem cell transplantation (HSCT), which however, confined to those who received HMA prior to HSCT, highlighting a role of HMA treatment in DDX41mut cases.

Conclusion P/LP germline DDX41variants explain the largest risk of adult MNs with very high penetrance. DDX41mut MNs have distinct genetic and clinical/hematological features, representing a unique subset of MNs. IPSS-R/IPSS-M prognostication may not be applied to DDX41mut MDS.

Disclosures: Nannya: Asahi Kasei Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Sumitomo Pharma: Speakers Bureau; Filgen: Speakers Bureau; Janssen Pharmaceutical: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Fuji Pharma: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Speakers Bureau; Takeda Pharmaceutical Company: Speakers Bureau; Kyowa-Kirin: Speakers Bureau; Daiichi Sankyo RD Novare: Research Funding; Otsuka Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Daiichi Sankyo Co., Ltd: Research Funding. Krishnamurthy: Jazz Pharmaceuticals: Consultancy, Honoraria; Astellas: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria. Atsuta: Astellas Pharma Inc.: Honoraria; AbbVie GK: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Mochida Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma KK: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria. Nakagawa: Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding. Yoda: Chordia Therapeutics inc.: Research Funding. Miyazaki: Otsuka Pharmaceutical: Honoraria; Pfizer: Honoraria; Kyowa-Kirin: Honoraria; Bristol-Myers: Honoraria; Chugai: Honoraria; SyinBio: Honoraria; Dainippon-Sumitomo Pharma: Honoraria, Research Funding; Astellas: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Nippon Shinyaku: Honoraria; Takeda: Honoraria; Daiichi-Sankyo: Honoraria; Janssen Pharmaceutical: Honoraria; Celgene: Honoraria. Sanada: Otsuka pharmaceutical: Research Funding. Chiba: Astellas Pharma Inc.: Research Funding; Kyowa Kirin Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Thyas Co., Ltd.: Research Funding; Bayer Yakuhin Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding. Takaori-Kondo: abbVie GK: Research Funding; Asahi Kasei Pharma Corporation: Research Funding; Bristol-Myers Squibb Co: Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Research Funding; COGNANO, Inc.: Patents & Royalties, Research Funding; DKS Co. Ltd.: Research Funding; Eisai: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Japanese Society of Hematology: Research Funding; Kyowa Kirin Co., Ltd.: Research Funding; Megakaryon Co: Consultancy; NextGeM Inc: Patents & Royalties; Nippon Shinyaku Co., Ltd.: Honoraria; OHARA Pharmaceutical Co.,Ltd: Research Funding; Ono Pharma Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Sanofi K.K.: Research Funding; SHIONOGI & Co., Ltd.: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding. Blombery: AstraZeneca: Consultancy, Honoraria; Servier: Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria. Haferlach: Munich Leukemia Laboratory: Current Employment, Other: Part ownership. Kulasekararaj: Apellis: Consultancy, Honoraria, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; F. Hoffmann-La Roche: Consultancy, Honoraria, Speakers Bureau; Samsung: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Speakers Bureau; Akari: Consultancy, Honoraria, Speakers Bureau; Achillion: Consultancy, Honoraria, Speakers Bureau. Maciejewski: Alexion: Consultancy; Apellis Pharmaceuticals: Consultancy. Ogawa: Esai Pharmatheutical: Consultancy; PCT/JP2014/062112 (WO01): Patents & Royalties; 2015-239547: Patents & Royalties; 62/187386 (US01): Patents & Royalties; 2014-191287: Patents & Royalties; 15/353395 (US03): Patents & Royalties; Novartis: Honoraria, Speakers Bureau; ASAHI Genomics: Current equity holder in publicly-traded company; Astellas: Speakers Bureau; Otsuka Pharmatheutical: Research Funding; The Mitsubishi foundation: Honoraria; Chordia Threapeutics: Consultancy, Current equity holder in publicly-traded company, Research Funding; Nanpu Hospital: Research Funding; Sysmex: Honoraria; MSD: Speakers Bureau; Clinical Research Support Center Kyushu: Research Funding; Kirin/Chugai: Speakers Bureau; The Chemo-Sero-Therapeutic Research Institute: Speakers Bureau; Astrazeneca: Speakers Bureau; DaiichiSankyo: Speakers Bureau; 2013-526957 (JP02): Patents & Royalties; 2013-096582 (JP01): Patents & Royalties; Pfaizer: Speakers Bureau.

Previous Abstract | Next Abstract >>
*signifies non-member of ASH