Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

MYELODYSPLASTIC SYNDROME

Germline variants drive myelodysplastic syndrome in young adults

Leukemia volume 35, pages 2439–2444 (2021)Cite this article

Subjects

Inherited pathogenic (P)/likely pathogenic (LP) variants are recognized increasingly as predisposing patients to myelodysplastic syndrome (MDS) and aplastic anemia (AA) [1,2,3], and germline susceptibility to myeloid malignancies is included in the latest World Health Organization (WHO) classification of hematopoietic malignancies [4]. Moreover, clinical guidelines now call for assessment of germline predisposition at MDS diagnosis [5]. Prior studies of the frequency of germline predisposition in patients with AA/bone marrow failure (BMF) and MDS or acute myeloid leukemia (AML) focused on those diagnosed in infancy, with clinical suspicion, or positive family history, found that 18% of individuals had deleterious variants in BMF syndromes [6] and 19–29% had deleterious variants in hereditary MDS/AML genes [1, 2]. Pediatric groups have screened MDS patients younger than 18 years old (yo) based solely on age at diagnosis and found that 17% have deleterious variants in SAMD9 or SAMD9L [7], and 7% in GATA2, with 37% in those who also have monosomy 7 [8]. In patients up to 45 yo who underwent hematopoietic stem cell transplant (HSCT), 13% of MDS and 5% of AA cases had a germline predisposition syndrome [3]. Importantly, deleterious germline DDX41 variants are associated with developing a myeloid malignancy at a median age of 69 [9], similar to sporadic MDS.

Patient characteristics, including gender, age at diagnosis, diagnosis and subtype according to revised WHO classifications in 2008 or 2016, and source of germline DNA, are shown in Supplementary Tables S1 and S2. Distribution of MDS subtypes was consistent with the reported literature, whereas non-severe AA was overrepresented in our study compared to the reported incidence in the young adult age group (Supplementary Table S2). Germline DNA was obtained from cultured skin fibroblasts (n = 13), direct skin biopsies with variants either confirmed in peripheral blood at the same variant allele frequency or found in multiple individuals within the family (n = 17), bone marrow-derived non-hematopoietic mesenchymal stromal cells (MSCs, n = 68), paraffin-embedded tissues (n = 2), saliva (n = 4), or bone marrow (n = 2) with variant confirmation in germline material, and peripheral CD3 + T-cells with purity confirmed by flow cytometry (n = 1, Supplementary Fig. S2). MSCs were characterized in passage four based on minimal essential criteria for MSCs showing plastic adherence, a specific immunophenotype, and multipotent differentiation potential (Supplementary Fig. S3). Targeted next-generation panel-based sequencing (NGS) or whole-exome sequencing (WES) was performed locally to screen for single-nucleotide variants (SNVs) or small indels. Copy number variants (CNVs) were assessed using either NGS or custom high-density gene-targeted array comparative genomic hybridization (Supplementary Table S3, Supplementary Fig. S4).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Incidence and variation in age of onset by causal gene.

References

  1. Churpek JE, Pyrtel K, Kanchi K-L, Shao J, Koboldt D, Miller CA, et al. Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood. 2015;126:2484–90.

    Article  CAS  Google Scholar 

  2. Guidugli L, Johnson AK, Alkorta-Aranburu G, Nelakuditi V, Arndt K, Churpek JE, et al. Clinical utility of gene panel-based testing for hereditary myelodysplastic syndrome/acute leukemia predisposition syndromes. Leukemia. 2017;31:1226–9.

    Article  CAS  Google Scholar 

  3. Keel SB, Scott A, Sanchez-Bonilla M, Ho PA, Gulsuner S, Pritchard CC, et al. Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients. Haematologica. 2016;101:1343–50.

    Article  CAS  Google Scholar 

  4. Peterson LC, Bloomfield CD, Niemeyer CM, Döhner HGL. Myeloid neoplasms with germline predisposition. In: Swerdlow SH, Campo E, Harris NL, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues (Revised 4th ed) Lyon, IARC. 2017.

  5. Myelodysplastic Syndromes, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.

  6. Ghemlas I, Li H, Zlateska B, Klaassen R, Fernandez CV, Yanofsky RA, et al. Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes. J Med Genet. 2015;52:575–84.

    Article  CAS  Google Scholar 

  7. Schwartz JR, Ma J, Lamprecht T, Walsh M, Wang S, Bryant V, et al. The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun. 2017;8:1557.

    Article  Google Scholar 

  8. Wlodarski MW, Hirabayashi S, Pastor V, Starý J, Hasle H, Masetti R, et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood. 2016;127:1387–97.

    Article  CAS  Google Scholar 

  9. Sébert M, Passet M, Raimbault A, Rahmé R, Raffoux E, Sicre de Fontbrune F, et al. Germline DDX41 mutations define a significant entity within adult MDS/AML patients. Blood. 2019;134:1441–4.

    Article  Google Scholar 

  10. Vaht K, Göransson M, Carlson K, Isaksson C, Lenhoff S, Sandstedt A, et al. Incidence and outcome of acquired aplastic anemia: real-world data from patients diagnosed in Sweden from 2000–2011. Haematologica. 2017;102:1683–90.

    Article  Google Scholar 

  11. Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes. Cancer. 2007;109:1536–42.

    Article  Google Scholar 

  12. Trottier AM, Druhan LJ, Kraft IL, Lance A, Feurstein S, Helgeson M, et al. Heterozygous germ line CSF3R variants as risk alleles for development of hematologic malignancies. Blood Adv. 2020;4:5269–84.

    Article  Google Scholar 

  13. Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015;125:591–9.

    Article  CAS  Google Scholar 

  14. Dietz AC, Orchard PJ, Baker KS, Giller RH, Savage SA, Alter BP, et al. Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita. Bone Marrow Transpl. 2011;46:98–104.

    Article  CAS  Google Scholar 

  15. Ebens CL, MacMillan ML, Wagner JE. Hematopoietic cell transplantation in Fanconi anemia: current evidence, challenges and recommendations. Expert Rev Hematol 2017;10:81–97.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to gratefully acknowledge all of the individuals who participated in this study and their physicians for submitting the clinical samples. We would also like to thank Michelle Le Beau and Ludmila Hill from the Cancer Cytogenetics Laboratory at The University of Chicago for providing viably frozen bone marrow samples. This study was supported by the Cancer Research Foundation and the Taub Foundation (L.A.G.), the intramural ‘Baustein’ program for Junior Scientists of the Medical Faculty of Ulm University, Ulm, Germany (S.F.), and the German Bundesministerium für Bildung und Forschung ‘MyPred’ (01GM1911B) (B.S., G.G.) and ‘ADDRess’ (01GM1909A) (G.G.) and the Cancer Society of Finland, the Children’s Cancer Foundation Väre, and the Sigrid Juselius Foundation (M.H., O.K., U.W-K.). In addition, the NIH supported this work through: P30CA016056 (use of Roswell Park Comprehensive Cancer Center’s Hematologic Procurement Shared Resource, E.W.), R03HL145253 (J.E.C.), R35CA197458 and R24DK099808 (M-C.K., T.W., S.G., M.L.). We would also like to acknowledge the input of Linda Lutgen-Dunckley, Brandon Martens, and Joseph Moberg from the Roswell Park Hematologic Procurement Shared Resource (CIC 98-05) for providing samples supported by the Cancer Center Support Grant at Roswell Park (2P30CA016056-42). M-C.K. is an American Cancer Society Professor.

Author information

Authors and Affiliations

  1. Department of Medicine, Section of Hematology/Oncology, The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA

    Simone Feurstein & Lucy A. Godley

  2. Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, The University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Jane E. Churpek

  3. Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA

    Tom Walsh

  4. Department of Medicine, Division of Hematology, University of Washington, Seattle, WA, USA

    Sioban Keel

  5. Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland

    Marja Hakkarainen, Outi Kilpivaara & Ulla Wartiovaara-Kautto

  6. Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, University of Helsinki, Helsinki, Finland

    Marja Hakkarainen & Ulla Wartiovaara-Kautto

  7. Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, University of Duesseldorf, Duesseldorf, Germany

    Thomas Schroeder, Ulrich Germing & Stefanie Geyh

  8. Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    Michael Heuser & Felicitas Thol

  9. Munich Leukemia Laboratory, Munich, Germany

    Christian Pohlkamp & Torsten Haferlach

  10. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Juehua Gao

  11. Division of Hematology and Hematological Malignancies, University of Calgary, Calgary, AB, Canada

    Carolyn Owen

  12. Department of Human Genetics, Hannover Medical School, Hannover, Germany

    Gudrun Goehring & Brigitte Schlegelberger

  13. Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Medicine, Frankfurt, Germany

    Divij Verma & Daniela S. Krause

  14. Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA

    Divij Verma

  15. Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA

    Guimin Gao

  16. Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Tara Cronin, Eunice S. Wang & Elizabeth A. Griffiths

  17. Department of Genome Sciences, University of Washington, Seattle, WA, USA

    Suleyman Gulsuner, Ming Lee & Mary-Claire King

  18. Department of Laboratory Medicine, University of Washington, Seattle, WA, USA

    Colin C. Pritchard

  19. Department of Human Genetics, The University of Chicago, Chicago, IL, USA

    Hari Prasanna Subramanian, Daniela del Gaudio & Soma Das

  20. Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital, Houston, TX, USA

    Zejuan Li

  21. Department of Medical and Clinical Genetics/Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland

    Outi Kilpivaara

  22. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

    Konstanze Döhner & Hartmut Döhner

Authors
  1. Simone Feurstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jane E. Churpek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tom Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sioban Keel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marja Hakkarainen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas Schroeder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ulrich Germing
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stefanie Geyh
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael Heuser
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Felicitas Thol
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christian Pohlkamp
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Torsten Haferlach
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Juehua Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Carolyn Owen
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Gudrun Goehring
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Brigitte Schlegelberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Divij Verma
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Daniela S. Krause
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Guimin Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Tara Cronin
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Suleyman Gulsuner
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Ming Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Colin C. Pritchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Hari Prasanna Subramanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Daniela del Gaudio
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Zejuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Soma Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Outi Kilpivaara
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Ulla Wartiovaara-Kautto
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Eunice S. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Elizabeth A. Griffiths
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Konstanze Döhner
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Hartmut Döhner
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Mary-Claire King
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. Lucy A. Godley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lucy A. Godley.

Ethics declarations

Conflict of interest

We declare the following conflicts of interest: TW consults for Color Genomics. TH is part owner of the Munich Leukemia Laboratory. EAG has received honoraria/advisory board payments from Alexion Pharmaceuticals, Celgene/BMS, AbbVie, and Novartis. EAG has also received institutional research funding from Genentech Inc., Appelis pharmaceuticals, Celldex Therapeutics, and Celgene/BMS. CO has received honoraria/advisory board payments from AbbVie, AstraZeneca, Janssen, Roche, and Novartis. LAG and JEC have received honoraria from UptoDate, Inc. LAG has received advisory board payments from Invitae, Inc.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Feurstein, S., Churpek, J.E., Walsh, T. et al. Germline variants drive myelodysplastic syndrome in young adults. Leukemia 35, 2439–2444 (2021). https://doi.org/10.1038/s41375-021-01137-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-021-01137-0

This article is cited by

Search

Advanced search

Quick links