The RUNX1 database (RUNX1db): establishment of an expert curated RUNX1 registry and genomics database as a public resource for familial platelet disorder with myeloid malignancy

Claire C Homan¹, Sarah L King-Smith¹, David M Lawrence², Peer Arts¹, Jinghua Feng³, James Andrews¹, Mark Armstrong¹, Thuong Ha¹, Julia Dobbins¹, Michael W Drazer⁴, Kai Yu⁵, Csaba Bödör⁶, Alan Cantor⁷, Mario Cazzola⁸, Erin Degelman⁹, Courtney D DiNardo¹⁰, Nicolas Duployez¹¹, Remi Favier¹², Stefan Fröhling¹³, Jude Fitzgibbon¹⁴, Jeffery M Klco¹⁵, Alwin Krämer¹⁶, Mineo Kurokawa¹⁷, Joanne Lee¹⁸, Luca Malcovati⁸, Neil V Morgan¹⁹, Georges Natsoulis²⁰, Carolyn Owen⁹, Keyur P Patel¹⁰, Claude Preudhomme¹¹, Hana Raslova²¹, Hugh Rienhoff²⁰, Tim Ripperger²², Rachael Schulte²³, Kiran Tawana²⁴, Elvira Velloso²⁵, Benedict Yan¹⁸, Paul Liu⁵, Lucy A Godley⁴, Andreas W Schreiber²⁶, Christopher N Hahn²⁷, Hamish S Scott²⁸, Anna L Brown²⁹

Affiliations

¹ Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA.
² Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; Australian Cancer Research Foundation (ACRF) Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, SA.
³ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; Australian Cancer Research Foundation (ACRF) Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, SA.
⁴ Section of Hematology/Oncology, Departments of Medicine and Human Genetics, Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL.
⁵ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
⁶ HCEMM-SE Molecular Oncohematology Research Group, 1st Department of P athology and E xperimental Cancer R esearch, Semmelweis U niversity, B udapest, H ungary.
⁷ Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.
⁸ Department of Molecular Medicine, University of Pavia, Pavia, Italy; Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia.
⁹ Division of Hematology and Hematological Malignancies, Foothills Medical Centre, Calgary, AB.
¹⁰ Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
¹¹ Laboratory of Hematology, Biology and Pathology Center, Centre Hospitalier Regional Universitaire de Lille, Lille, France; Jean-Pierre Aubert Research Center, INSERM, Universitaire de Lille, Lille.
¹² Assistance Publique- Hôpitaux de Paris, Armand Trousseau children's Hospital, Paris.
¹³ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
¹⁴ Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London.
¹⁵ St Jude Children's Research Hospital, Memphis, Tennessee, United States.
¹⁶ Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
¹⁷ Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan.
¹⁸ Department of Haematology-Oncology, National University Cancer Institute, National University Health System.
¹⁹ Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham.
²⁰ Imago Biosciences, Inc., San Francisco, CA.
²¹ Institut Gustave Roussy, Université Paris Sud, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villejuif.
²² Department of Human Genetics, Hannover Medical School, Hannover, Germany.
²³ Department of Pediatrics, Division of Pediatric Hematology and Oncology, Monroe Carell Jr. Children's Hospital, Vanderbilt University Medical Center, Nashville, TN.
²⁴ Department of Haematology, Addenbrooke's Hospital. Cambridge, CB2 0QQ.
²⁵ Service of Hematology, Transfusion and Cell Therapy and Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31) HCFMUSP, University of Sao Paulo Medical School, Sao Paulo, Brazil; Genetics Laboratory, Hospital Israelita Albert Einstein, Sao Paulo, Brazil.
²⁶ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; Australian Cancer Research Foundation (ACRF) Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia; School of Biological Sciences, University of Adelaide, Adelaide, SA.
²⁷ Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; School of Medicine, University of Adelaide, Adelaide, SA.
²⁸ Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia; School of Medicine, University of Adelaide, Adelaide, SA.
²⁹ Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; School of Medicine, University of Adelaide, Adelaide, SA. anna.brown@sa.gov.au.

PMID: 34233450
PMCID: PMC8561292
DOI: 10.3324/haematol.2021.278762

The RUNX1 database (RUNX1db): establishment of an expert curated RUNX1 registry and genomics database as a public resource for familial platelet disorder with myeloid malignancy

Claire C Homan et al. Haematologica. 2021.

. 2021 Nov 1;106(11):3004-3007.

doi: 10.3324/haematol.2021.278762.

Authors

Affiliations

¹ Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA.
² Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; Australian Cancer Research Foundation (ACRF) Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, SA.
³ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; Australian Cancer Research Foundation (ACRF) Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, SA.
⁴ Section of Hematology/Oncology, Departments of Medicine and Human Genetics, Center for Clinical Cancer Genetics, and The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL.
⁵ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892.
⁶ HCEMM-SE Molecular Oncohematology Research Group, 1st Department of P athology and E xperimental Cancer R esearch, Semmelweis U niversity, B udapest, H ungary.
⁷ Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.
⁸ Department of Molecular Medicine, University of Pavia, Pavia, Italy; Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia.
⁹ Division of Hematology and Hematological Malignancies, Foothills Medical Centre, Calgary, AB.
¹⁰ Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
¹¹ Laboratory of Hematology, Biology and Pathology Center, Centre Hospitalier Regional Universitaire de Lille, Lille, France; Jean-Pierre Aubert Research Center, INSERM, Universitaire de Lille, Lille.
¹² Assistance Publique- Hôpitaux de Paris, Armand Trousseau children's Hospital, Paris.
¹³ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
¹⁴ Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London.
¹⁵ St Jude Children's Research Hospital, Memphis, Tennessee, United States.
¹⁶ Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Dept. of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
¹⁷ Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan.
¹⁸ Department of Haematology-Oncology, National University Cancer Institute, National University Health System.
¹⁹ Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham.
²⁰ Imago Biosciences, Inc., San Francisco, CA.
²¹ Institut Gustave Roussy, Université Paris Sud, Equipe Labellisée par la Ligue Nationale Contre le Cancer, Villejuif.
²² Department of Human Genetics, Hannover Medical School, Hannover, Germany.
²³ Department of Pediatrics, Division of Pediatric Hematology and Oncology, Monroe Carell Jr. Children's Hospital, Vanderbilt University Medical Center, Nashville, TN.
²⁴ Department of Haematology, Addenbrooke's Hospital. Cambridge, CB2 0QQ.
²⁵ Service of Hematology, Transfusion and Cell Therapy and Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31) HCFMUSP, University of Sao Paulo Medical School, Sao Paulo, Brazil; Genetics Laboratory, Hospital Israelita Albert Einstein, Sao Paulo, Brazil.
²⁶ Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; Australian Cancer Research Foundation (ACRF) Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia; School of Biological Sciences, University of Adelaide, Adelaide, SA.
²⁷ Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; School of Medicine, University of Adelaide, Adelaide, SA.
²⁸ Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia; School of Medicine, University of Adelaide, Adelaide, SA.
²⁹ Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia; School of Medicine, University of Adelaide, Adelaide, SA. anna.brown@sa.gov.au.

PMID: 34233450
PMCID: PMC8561292
DOI: 10.3324/haematol.2021.278762

No abstract available

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Figures

**Figure 1.**
**Registry of germline *RUNX1* mutations.** Germline *RUNX1* variants currently included in the RUNX1db registry are visualised using the ProteinPaint web application (*https://pecan.stjude.cloud/home*).12 Variants (displayed as protein changes where possible) are colour-coded according to pathogenicity classification as determined by the MM-VCEP RUNX1-specific recommendations. The number of probands for each variant is indicated within the circle where the number is greater than one. All variants are annotated to RUNX1c; NM_001754.4; LRG_ 482.

**Figure 2.**
**RUNX1 database genomics cohort demographic.** (A) Breakdown of the number and types of NGS samples currently stored in the RUNX1db. Pre- Leukemic: thrombocytopenia, asymptomatic Other: includes post-transplant/post-treatment and saliva samples. Both WES and panel data is analysed and stored in the database. (B) Scatter plot displaying the age of the individual when each sample was collected. Major RUNX1db cohorts (malignancy and preleukemic samples) are displayed. The median age for each cohort is represented by the vertical line. Clinical demographics of the malignancy cohort is shown with the number of individuals with different types of FPD-MM malignancy presentation and the (C) gender and (D) age distribution; Adult ≥40years, AYA=15-39 years, children ≤14years. AML: Acute myeloid leukemia; MDS: myelodysplastic syndromes; MDS/MPN: myelodysplastic syndrome/myeloproliferative Neoplasm overlap; MPN: Myeloproliferative Neoplasm; ALL: acute lymphoblastic leukemia; AL: acute undifferentiated leukemia.

See this image and copyright information in PMC

References

1. 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. Blood. 2016;128(3):462-463. - PubMed
1. Brown AL, Hahn CN, Scott HS. Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA). Blood. 2020;136(1):24-35. - PMC - PubMed
1. Song WJ, Sullivan MG, Legare RD, et al. . Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 1999;23(2):166-175. - PubMed
1. Brown AL, Arts P, Carmichael CL, et al. . RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML. Blood Adv. 2020;4(6):1131-1144. - PMC - PubMed
1. Richards S, Aziz N, Bale S, et al. . 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. - PMC - PubMed

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The RUNX1 database (RUNX1db): establishment of an expert curated RUNX1 registry and genomics database as a public resource for familial platelet disorder with myeloid malignancy

Affiliations

The RUNX1 database (RUNX1db): establishment of an expert curated RUNX1 registry and genomics database as a public resource for familial platelet disorder with myeloid malignancy

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