Abstract
Acute myeloid leukemia with germline CEBPA mutation is a subtype of acute myeloid leukemia that is associated with a favorable prognosis. Most of the reported cases of acute myeloid leukemia with CEBPA germline variants involve a germline variant in the N-terminus and a somatic variant in the C-terminus. There are only a few reported cases where the CEBPA germline variant has been identified in the C-terminus and the somatic variant in the N-terminus. This case report and review of the literature illustrates that, although acute myeloid leukemia with CEBPA N- or C-terminal germline variants have certain similarities such as atypically young age at diagnosis, frequent relapse, and favourable overall prognosis, there are also significant differences such as lower life-time penetrance of acute myeloid leukemia and shorter time to relapse for germline C-terminal cases. These findings add important information on the natural history and clinical outcomes of acute myeloid leukemia with germline CEBPA C-terminal variants and these findings should be considered in the management of patients and their family members.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The authors declare that data supporting the findings of this study are available within the article.
References
Pathak A, Seipel K, Pemov A et al (2016) Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family. Haematologica 101:846. https://doi.org/10.3324/HAEMATOL.2015.130799
Brown AL, Hahn CN, Scott HS (2020) Secondary leukemia in patients with germline transcription factor mutations (RUNX1, GATA2, CEBPA). Blood 136:24–35. https://doi.org/10.1182/BLOOD.2019000937
Arber DA, Orazi A, Hasserjian RP et al (2022) International consensus classification of myeloid neoplasms and acute leukemia: integrating morphological, clinical, and genomic data. Blood. https://doi.org/10.1182/BLOOD.2022015850/485730/INTERNATIONAL-CONSENSUS-CLASSIFICATION-OF-MYELOID
Döhner H, Wei AH, Appelbaum FR et al (2022) Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 140:1345–1377. https://doi.org/10.1182/BLOOD.2022016867
Taskesen E, Bullinger L, Corbacioglu A et al (2011) Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood 117:2469–2475. https://doi.org/10.1182/BLOOD-2010-09-307280
Tawana K, Rio-Machin A, Preudhomme C, Fitzgibbon J (2017) Familial CEBPA-mutated acute myeloid leukemia. Semin Hematol 54:87–93. https://doi.org/10.1053/J.SEMINHEMATOL.2017.04.001
Tawana K, Wang J, Renneville A et al (2015) Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood 126:1214–1223. https://doi.org/10.1182/BLOOD-2015-05-647172
Simon L, Spinella JF, Yao CY et al (2020) High frequency of germline RUNX1 mutations in patients with RUNX1-mutated AML. Blood 135:1882–1886. https://doi.org/10.1182/BLOOD.2019003357
Zhang Y, Wang F, Chen X et al (2020) Companion gene mutations and their clinical significance in AML with double mutant CEBPA. Cancer Gene Ther 27:599–606. https://doi.org/10.1038/S41417-019-0133-7
Kim HS, Han E, Jang W et al (2019) Germline CEBPA mutations in Korean patients with acute myeloid leukemia. Leuk Res 76:84–86. https://doi.org/10.1016/J.LEUKRES.2018.12.003
Rio-Machin A, Vulliamy T, Hug N et al (2020) (2020) The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants. Nat Commun 11:1–12. https://doi.org/10.1038/s41467-020-14829-5
Gutman JA, Hoffner B (2012) A novel CCAAT/enhancer binding protein α germline variant in a case of acute myeloid leukemia. Leuk Lymphoma 53:1006–1007. https://doi.org/10.3109/10428194.2011.638718/SUPPL_FILE/DISCLOSURE.ZIP
Richards S, Aziz N, Bale S et al (2015) 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 17:405–424. https://doi.org/10.1038/GIM.2015.30
Godley LA, Shimamura A (2017) Genetic predisposition to hematologic malignancies: management and surveillance. Blood 130:424–432. https://doi.org/10.1182/BLOOD-2017-02-735290
Xiao H, Shi J, Luo Y et al (2011) First report of multiple CEBPA mutations contributing to donor origin of leukemia relapse after allogeneic hematopoietic stem cell transplantation. Blood 117:5257–5260. https://doi.org/10.1182/BLOOD-2010-12-326322
Acknowledgements
None.
Author information
Authors and Affiliations
Contributions
AT identified the cases and obtained written informed consent for the case report as well as supervised and revised the manuscript. AH performed the literature review, wrote the manuscript, and participated in the revisions of the manuscript. All authors edited, read, and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors of this case report and literature review do not have any conflict of interest to disclose.
Informed consent
As per our institution’s Research and Ethics Board policy, written informed consent was obtained from all individuals whose personal medical information was included in the case report prior to submission of the manuscript.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Harrigan, A.M., Trottier, A.M. Hereditary acute myeloid leukemia associated with C-terminal CEBPA germline variants. Familial Cancer 22, 331–339 (2023). https://doi.org/10.1007/s10689-023-00329-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10689-023-00329-0