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1754 Somatic Mutational Landscape of Hereditary Hematopoietic Malignancies Associated with Germline Variants in RUNX1, GATA2 and DDX41

Program: Oral and Poster Abstracts
Session: 636. Myelodysplastic Syndromes—Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Anna Brown, PhD1, Claire Homan, PhD1*, Michael W. Drazer, MD, PhD2,3*, Kai Yu, PhD4*, David Lawrence5*, Jinghua Feng, PhD6*, Luis Arriola-Martinez7*, Matthew Pozsgai8*, Kelsey McNeely8*, Thuong Ha, PhD9*, Parvathy Venugopal, PhD1, Peer Arts, PhD10*, Sarah King-Smith11*, Jesse JC Cheah1*, Mark Armstrong, MSc12*, Csaba Bödör, PhD13*, Paul Wang1*, Alan B. Cantor, MD14, Mario Cazzola, MD15, Erin Degelman, MSc, BSc16*, Courtney D. DiNardo, MD, MSCE17, Nicolas Duployez, PharmD, PhD18,19*, Remi Favier20*, Stefan Fröhling, MD21, Ana Rio-Machin, PhD22*, Jeffery M. Klco, MD, PhD23, Alwin Krämer, MD24*, Mineo Kurokawa25*, Joanne Lee, MBBS26*, Luca Malcovati, MD27, Neil V Morgan28*, Georges Natsoulis, Ph.D.29*, Carolyn Owen, MD30, Keyur P. Patel, MBBS, PhD31, Claude Preudhomme, PharmD, PhD32, Hana Raslova33*, Hugh Young Rienhoff Jr., MD29, Tim Ripperger, MD, PhD34*, Rachael Schulte, MD, MS35*, Kiran Tawana, MD36*, Elvira Deolinda Rodrigues Pereira Velloso, MD, PhD37, Benedict Yan, MBBS38*, Raman Sood, PhD39*, Amy Hsu40*, Steven M. Holland, MD41*, Kerry Phillips42*, Nicola Poplawski, MD42*, Milena Babic, BMPharBio (Hons)10*, Erika M Kwon Kim, PhD43*, Andrew H. Wei, MBBS, FRACP, FRCPA, PhD44, Cecily Forsyth, MBBS, FRACP, FRCPA45, Helen Mar Fan, MD46*, Ian D Lewis, MBBS, PhD47, Julian Cooney, MBBS, FRACP, FRCPA48, Rachel Susman49*, Lucy C. Fox, MBBS50, Piers Blombery, MBBS51, Deepak Singhal, MBBS, MD, FRCPA, FRACP52*, Devendra Hiwase, MD, MBBS, PhD, FRACP, FRCPA52, Andreas W Schreiber, PhD53*, Christopher N Hahn, PhD1, Hamish S Scott, PhD1, Paul P. Liu, MD, PhD54 and Lucy A. Godley, MD, PhD3

1Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia
2Section of Hematology/Oncology, The University of Chicago, Chicago, IL
3The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago
4NHGRI, NHGRI, Bethesda, MD
5ACRF Cancer genomics facility, Centre for Cancer Biology, SA Pathology, Adelaide, Australia
6ACRF Cancer Genomics Facility, SA Pathology, Adelaide, Australia
7Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, AUS
8Department of Medicine, Section of Hematology-Oncology, The University of Chicago, Chicago, IL
9Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, AUS
10Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia
11Centre For Cancer Biology, SA Pathology and University of South Australia, Adelaide, AUS
12Molecular Oncology, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia
13HCEMM-SE Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
14Division of Pediatric Hematology-Oncology, Boston Childrens Hospital, Boston, MA
15University of Pavia, University of Pavia, Pavia, Italy
16Division of Hematology and Hematological Malignancies, Foothills Medical Centre, Calgary, Canada
17Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
18University of Lille, Lille, France
19Cancer Research Institute, INSERM Unité Mixte de Recherche (UMR)-S 1172, F-59000 Lille, CHU Lille, Laboratory of Hematology, F-59000 Lille, Lille, France
20Assistance Publique ? Hôpitaux De Paris, Paris, FRA
21National Center for Tumor Diseases (NCT), Heidelberg, Germany
22Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
23Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
24Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, Heidelberg, Germany
25Graduate School of Medicine, The University of Tokyo, Bunkyo-Ku, Tokyo, JPN
26National University Health System, National University Cancer Institute, Singapore, Singapore
27Department of Molecular Medicine, University of Pavia, Pavia, Italy, Pavia, Italy, Pavia, Italy
28Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom
29Imago BioSciences, San Carlos, CA
30Foothills Medical Centre Division of Hematology and Hematological Malignancies, Calgary, AB, Canada
31Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
32Laboratory of Hematology, Centre Hospitalier Universitaire Lille, Lille, France
33INSERM, UMR1287, Gustave Roussy, Université Paris-Saclay, Equipe labellisée Ligue Nationale Contre le Cancer, Equipe GRex, Villejuif, France
34Department of Human Genetics, Hannover Medical School, Hannover, Germany
35Monroe Carell Jr. Children’s Hospital, Vanderbilt University Medical Center, Nashville, TN
36Department of Haematology, Addenbrooke’s Hospital, Cambridge, United Kingdom
37Division of Hematology, Hospital das Clínicas , São Paulo Medical School, University of São Paulo, São Paulo, Brazil
38Molecular Diagnosis Centre, Department of Laboratory Medicine, National University Hospital, Singapore, Singapore, Singapore
39NHGRI, NIH, Bethesda, MD
40National Institutes of Health, Bethesda, MD
41National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
42Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, Australia
43NCI, NIH, Rockville, MD
44The Alfred Hospital and Monash University, Melbourne, VIC, Australia
45Central Coast Haematology, North Gosford, Australia
46Genetic Health Queensland, Brisbane, Australia
47Adelaide Oncology and Haematology, North Adelaide, Australia
48Department of Haematology, Fiona Stanley Hospital, Perth, Australia
49Queensland Genetic Health, Brisbane, Australia
50Peter MacCallum Cancer Centre, Melbourne, Australia
51Peter MacCallum Cancer Centre, Peter Maccallum Cancer Centre, East Melbourne, VIC, Australia
52Department of Haematology, SA Pathology, Adelaide, Australia
53ACRF Cancer Genomics Facility, Adelaide, Australia
54Translational and Functional Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD

BACKGROUND: Germline variants in RUNX1, GATA2 and DDX41 may confer a predisposition to hereditary haematopoietic malignancies (HHMs) such as MDS and AML yet have distinct age ranges of malignancy diagnosis and a highly variable overall risk for leukemogenesis. The increased awareness and identification of carriers of these germline variants, particularly before development of malignancy, has changed the way in which individuals and families need to be managed in the clinic. Individuals need lifelong monitoring and may also need modification to treatments when malignancy does develop, compared to sporadic counterparts. Gaps in understanding pre-malignant states in HHM syndromes have hampered efforts to design effective clinical surveillance regimes, provide personalized pre-emptive treatments, and appropriate counselling to patients.

METHODS: We have addressed some of these knowledge gaps using the largest known international comparative cohort of germline RUNX1, GATA2, or DDX41 variant carriers, which includes carriers both without a malignancy diagnosis “unaffected-carriers” and those with a malignancy “affected-carriers”. Our cohort included 245 patient samples evenly distributed between unaffected-carrier (n=122) and affected-carrier (n=123) samples. We utilized a uniform bioinformatics approach, to identify somatic variants from next generation sequencing data provided by our network of investigators.

RESULTS: We identified clonal hematopoiesis (CH) in 34% and 38% of RUNX1 and GATA2 unaffected-carriers, respectively (Figure 1A top), with overlap in the ages of observation CH and malignancy in different individuals observed (Figure 1A bottom). In contrast CH was seen in only 4% of DDX41 unaffected-carriers, significantly less frequently than RUNX1 or GATA2 (p=0.002). RUNX1- and GATA2 variant carriers were at an increased risk of early onset CH (0-29 years) present in 19% of RUNX1 carriers and 25% of GATA2 variant carriers compared to 0.2% of the general population (PMID: 25426837; PMID: 25426838). RUNX1 unaffected-carriers had an increased prevalence of CH at all ages compared to population controls, with BCOR being the most frequently mutated gene in RUNX1 carriers, present across the entire age spectrum from as young as 16 years to 76 years (Figure 1B). In RUNX1-driven CH specifically we detected “high-risk” variants in TET2, PHF6 and most frequently in BCOR, all of which were also recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy. Consistent with a multi-step process towards leukaemia, we found both an increase in clone size (variant allele frequency, VAF) and the number of variants present per sample, as the age of carriers increased (Figure 1B).

Tumor profiling similarly highlighted differences in the pathways to myeloid malignancy development for the three syndromes. Leukemogenesis in both RUNX1 and DDX41 carriers was often driven by second-hit variants in RUNX1 and DDX41 respectively. Somatic RUNX1 variants were not seen in germline RUNX1 unaffected-carriers, only in tumors, therefore this likely represents a “late” leukemogenic event. This was not able to be inferred for somatic DDX41 variants in DDX41 related predisposition where mutations before malignancy were rarely seen. In contrast, GATA2 germline driven malignancy was not associated with somatic mutation of GATA2, instead this process favored mutations in ASXL1. Both germline RUNX1 and DDX41 cohorts presented with a sex bias for HM development, but in opposite directions (AML 1:2.5 (RUNX1) and HM 3:1 (DDX41), Male:Female). Disruption of RUNX1 regulation of estrogen signalling, and DDX41 mediated exaggeration of the known sex difference in innate immunity, are postulated as mechanisms worth investigation to explain these observed sex biases (PMID: 25479752; PMID:28223406).

CONCLUSIONS: This study lays the foundation for developing novel-preventative therapies and the implementation of gene-specific clinical monitoring requirements for carriers of germline variants in RUNX1, DDX41 and GATA2. Individuals with RUNX1 variants will require regular monitoring for somatic variants in several genes throughout their lifetime, while DDX41 carriers are likely to benefit from monitoring throughout adulthood for driver DDX41 variants using sensitive technology to detect low-frequency initiating events.

Disclosures: Bödör: Abbvie: Research Funding; Janssen: Speakers Bureau; Roche: Research Funding; Astra-Zeneca: Speakers Bureau; Epizyme: Speakers Bureau; Takeda: Speakers Bureau; Astellas Pharma: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau. DiNardo: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Astellas: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Jazz: Honoraria; Astex: Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees; Cleave: Research Funding; AbbVie: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Research Funding; LOXO: Research Funding; Takeda: Honoraria; Forma: Research Funding; ImmuneOnc: Honoraria, Research Funding; Gilead: Honoraria; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kurokawa: SANWA KAGAKU KENKYUSHO CO., LTD.: Consultancy, Honoraria; Astellas Pharma Inc: Research Funding; Eisai Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Takeda Pharmaceutical Company Limited: Honoraria, Research Funding; Chugai Pharmaceutical Company: Honoraria, Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Nippon Shinyaku Co., Ltd.: Honoraria, Research Funding; Daiichi Sankyo Company .: Honoraria, Research Funding; AbbVie GK: Research Funding; Teijin Limited: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria, Research Funding; Asahi Kasei Pharma Corporation.: Research Funding; Shionogi & Co., Ltd.: Research Funding; AstraZeneca K.K.: Honoraria; Amgen Inc: Honoraria; SymBio Pharmaceuticals Limited: Honoraria; Sanofi K.K.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; MOCHIDA PHARMACEUTICAL CO.,LTD.: Honoraria. Natsoulis: Imago BioSciences: Current Employment. Owen: AbbVie: Honoraria; Novartis: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria; Merck: Honoraria; Roche: Honoraria; GIlead: Honoraria; Incyte: Honoraria; BeiGene: Honoraria. Rienhoff: Imago BioSciences: Current Employment, Current equity holder in publicly-traded company. Wei: Amgen: Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, and Expenses, Research Funding, Speakers Bureau; Roche: Honoraria; BMS: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding; Shoreline: Honoraria; Gilead: Honoraria; Astellas: Honoraria, Speakers Bureau; Astex: Research Funding; Syndax: Research Funding; BeiGene: Consultancy; Macrogenics: Honoraria; Janssen: Honoraria, Research Funding; Pfizer: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Other: Travel, Accommodations, and Expenses, Patents & Royalties: Filing Date: 21/07/2017. Combination of a BCL-2 inhibitor and a MCL-1 inhibitor, uses and pharmaceutical compositions thereof. A. Wei, D. Moujalled, G. Pomilio, A.L. Maragno, O. Geneste, A. Claperon, H. Maacke, E. Halilovic, D. Porter, E. Morris, Y. Wang,, Research Funding, Speakers Bureau; Agios: Honoraria; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties. Forsyth: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other. Blombery: Adaptive Biotechnologies: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Servier: Honoraria. Hiwase: AbbVie: Speakers Bureau; Novartis: Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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