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CYTOGENETICS AND MOLECULAR GENETICS

Significance of hereditary gene alterations for the pathogenesis of adult bone marrow failure versus myeloid neoplasia

Leukemia volume 36, pages 2827–2834 (2022)Cite this article

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Abstract

Broader genetic screening has led to the growing recognition of the role of germline variants associated with adult bone marrow failure (BMF) and myeloid neoplasia (MN) not exclusively in children and young adults. In this study, we applied a germline variant panel to 3008 adult BMF and MN cases to assess the importance of germline genetics and its impact on disease phenotype and prognosis. In our cohort, up to 9.7% of BMF and 5.3% of MN cases carried germline variants. Our cohort also included heterozygous carriers of recessive traits, suggesting they contribute to the risk of BMF and MN. By gene category, variants of Fanconi anemia gene family represented the highest-frequency category for both BMF and MN cases, found in 4.9% and 1.7% cases, respectively. In addition, about 1.4% of BMF and 0.19% of MN cases harbored multiple germline variants affecting often functionally related genes as compound heterozygous. The burden of germline variants in BMF and MN was clearly associated with acquisition of monosomy 7. While BMF cases carrying germline variants showed similar overall survival as compared to the wild-type (WT) cases, MN cases with germline variants experienced a significantly shorter overall survival as compared to WT cases.

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Fig. 1: The frequencies of germline variants and associations with clinical characteristics in bone marrow failure and myeloid neoplasia cases.
Fig. 2: The prevalence of germline variants by gene category in bone marrow failure and myeloid neoplasia.
Fig. 3: Clinical impact of germline variants in BMF.
Fig. 4: Clinical impact of germline variants in MN.

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Data availability

All the data that support the findings of this study are available within the Article and Supplementary Files. NGS targeted samples can be requested from the Cleveland Clinic by contacting the corresponding author (maciejj@ccf.org). Whole genome sequencing data can be requested from the Munich Leukemia laboratory (torsten.haferlach@mll.com).

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Acknowledgements

We thank The Torsten Haferlach Leukämiediagnostik Stiftung to support this work. The authors also thank The Cancer Genome Atlas, The Beat AML Master Trial, and The German-Austrian Study Group for data accessibility.

Funding

This work was supported by an R35HL135795 (to JPM) and The Leukemia & Lymphoma Society TRP Award 6645-22 (to JPM). SF receives funding from the Olympia Morata Program of the Medical Faculty Heidelberg.

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Authors and Affiliations

  1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Yasuo Kubota, Misam Zawit, Jibran Durrani, Wenyi Shen, Waled Bahaj, Tariq Kewan, Ben Ponvilawan, Minako Mori, Carmelo Gurnari, Valeria Visconte & Jaroslaw P. Maciejewski

  2. Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Wenyi Shen

  3. MLL Munich Leukemia Laboratory, Munich, Germany

    Manja Meggendorfer & Torsten Haferlach

  4. Department of Biomedicine and Prevention, PhD in Immunology, Molecular Medicine and Applied Biotechnology, University of Rome Tor Vergata, Rome, Italy

    Carmelo Gurnari

  5. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA

    Thomas LaFramboise

  6. Section of Hematology/Oncology, Departments of Medicine and Human Genetics, The University of Chicago, Chicago, IL, USA

    Simone Feurstein & Lucy A. Godley

  7. Department of Internal Medicine, Section of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany

    Simone Feurstein

  8. Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA

    Mikkael A. Sekeres

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  1. Yasuo Kubota
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Contributions

Authorship contributions are as followed: YK designed the study, analyzed and interpreted the data, and wrote the manuscript; MZ, JD, WS analyzed sequencing data and participated in the original data collection; WSB, TK, BP, MM collected clinical data and edited the manuscript; CG, MAS, TLaF, VV provided important feedback to the manuscript; SF, LAG gave expert opinion of variants assessment and edited the manuscript; M.Meggendorfer, TH shared whole genome sequencing data and edited the manuscript; JPM conceived the study, interpreted the data and wrote the manuscript. All authors participated in discussions and interpretation of the data and results.

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Correspondence to Jaroslaw P. Maciejewski.

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Kubota, Y., Zawit, M., Durrani, J. et al. Significance of hereditary gene alterations for the pathogenesis of adult bone marrow failure versus myeloid neoplasia. Leukemia 36, 2827–2834 (2022). https://doi.org/10.1038/s41375-022-01729-4

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