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

Yasuo Kubota; Misam Zawit; Jibran Durrani; Wenyi Shen; Waled Bahaj; Tariq Kewan; Ben Ponvilawan; Minako Mori; Manja Meggendorfer; Carmelo Gurnari; Thomas LaFramboise; Simone Feurstein; Mikkael A. Sekeres; Valeria Visconte; Lucy A. Godley; Torsten Haferlach; Jaroslaw P. Maciejewski

doi:10.1038/s41375-022-01729-4

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

Yasuo Kubota, Misam Zawit, Jibran Durrani, Wenyi Shen, Waled Bahaj, Tariq Kewan, Ben Ponvilawan, Minako Mori, Manja Meggendorfer, Carmelo Gurnari, Thomas LaFramboise, Simone Feurstein, Mikkael A. Sekeres, Valeria Visconte, Lucy A. Godley, Torsten Haferlach, Jaroslaw P. Maciejewski^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2827-2834
Number of pages	8
Journal	Leukemia
Volume	36
Issue number	12
DOIs	https://doi.org/10.1038/s41375-022-01729-4
State	Published - Dec 2022

Funding

We thank The Torsten Haferlach Leuk\u00E4miediagnostik 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. 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.

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Kubota, Y., Zawit, M., Durrani, J., Shen, W., Bahaj, W., Kewan, T., Ponvilawan, B., Mori, M., Meggendorfer, M., Gurnari, C., LaFramboise, T., Feurstein, S., Sekeres, M. A., Visconte, V., Godley, L. A., Haferlach, T., & Maciejewski, J. P. (2022). Significance of hereditary gene alterations for the pathogenesis of adult bone marrow failure versus myeloid neoplasia. Leukemia, 36(12), 2827-2834. https://doi.org/10.1038/s41375-022-01729-4

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title = "Significance of hereditary gene alterations for the pathogenesis of adult bone marrow failure versus myeloid neoplasia",

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.",

author = "Yasuo Kubota and Misam Zawit and Jibran Durrani and Wenyi Shen and Waled Bahaj and Tariq Kewan and Ben Ponvilawan and Minako Mori and Manja Meggendorfer and Carmelo Gurnari and Thomas LaFramboise and Simone Feurstein and Sekeres, {Mikkael A.} and Valeria Visconte and Godley, {Lucy A.} and Torsten Haferlach and Maciejewski, {Jaroslaw P.}",

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Kubota, Y, Zawit, M, Durrani, J, Shen, W, Bahaj, W, Kewan, T, Ponvilawan, B, Mori, M, Meggendorfer, M, Gurnari, C, LaFramboise, T, Feurstein, S, Sekeres, MA, Visconte, V, Godley, LA, Haferlach, T & Maciejewski, JP 2022, 'Significance of hereditary gene alterations for the pathogenesis of adult bone marrow failure versus myeloid neoplasia', Leukemia, vol. 36, no. 12, pp. 2827-2834. https://doi.org/10.1038/s41375-022-01729-4

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T1 - Significance of hereditary gene alterations for the pathogenesis of adult bone marrow failure versus myeloid neoplasia

AU - Kubota, Yasuo

AU - Zawit, Misam

AU - Durrani, Jibran

AU - Shen, Wenyi

AU - Bahaj, Waled

AU - Kewan, Tariq

AU - Ponvilawan, Ben

AU - Mori, Minako

AU - Meggendorfer, Manja

AU - Gurnari, Carmelo

AU - LaFramboise, Thomas

AU - Feurstein, Simone

AU - Sekeres, Mikkael A.

AU - Visconte, Valeria

AU - Godley, Lucy A.

AU - Haferlach, Torsten

AU - Maciejewski, Jaroslaw P.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

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

Abstract

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ASJC Scopus subject areas

UN SDGs

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