HAEM4Backup:Myeloid Neoplasms with Germline ANKRD26 Mutation
Primary Author(s)*
Fei Yang, MD, FACMG
Oregon Health & Science University, Portland, OR
Cancer Category/Type
Myeloid Neoplasms with Germline Predisposition
Cancer Sub-Classification / Subtype
Myeloid Neoplasms with Germline ANKRD26 Mutation
Definition / Description of Disease
This is a distinct entity in the World Health Organization (WHO) classification system within the section of Myeloid Neoplasms with Germline Predisposition[1].
This entity defines cases of myeloid neoplasms, in particular AML, MDS, and rarely CML and CMML, occur in association with inherited or de novo germline mutations in the ANKRD26 gene.
Synonyms / Terminology
Thrombocytopenia 2; familial myeloid neoplasms with germline ANKRD26 mutation; familial myelodysplastic syndromes/acute leukemias with germline ANKRD26 mutation
Epidemiology / Prevalence
The median age of patients with onset of myeloid neoplasms is not well established. The prevalence of MDS/AML with germline ANKRD26 mutations is currently unknown. There are about 45 affected pedigrees reported in the literature.
Clinical Features
Patients with germline ANKRD26 mutation initially present with mild bleeding and thrombocytopenia at very variable age of onset[2]. The common bleeding symptoms include petechiae, ecchymosis, gum bleeding, epistaxis, and menorrhagia[3]. The risk of developing myeloid neoplasms is estimated 30 times higher than that in the general population.
Sites of Involvement
Blood and bone marrow.
Morphologic Features
Patients with germline ANKRD26 mutation who develop MDS/AML could show markedly hypercellular bone marrow, a high myeloid-to-erythroid ratio, prominent megakaryocytic atypia with an increased number of small hypolobated megakaryocytes, and erythroid and myeloid dysplasia[4].
Immunophenotype
No typical immunophenotype is described in the current literature.
Chromosomal Rearrangements (Gene Fusions)
No typical chromosomal rearrangements/gene fusions are described in the current literature.
Characteristic Chromosomal Aberrations / Patterns
No typical chromosomal aberrations are described in the current literature. It could be non-specific alterations associated with MDS/AML.
Genomic Gain/Loss/LOH
No typical copy number aberrations are described in the current literature.
Gene Mutations (SNV/INDEL)
Most germline mutations in the ANKRD26 gene are single nucleotide variants or small insertions/deletions occurring within the 5' untranslated region, resulting in the disruption of the assembly of RUNX1 and FLI1 on the ANKRD26 promoter[2][5][6]. Truncating mutation in the N-terminus has also been reported[7].
Other Mutations
Co-occurring somatic mutation in ASXL1 has been reported in a patient with germline ANKRD26-related thrombocytopenia and CMML[8].
Epigenomics (Methylation)
Not applicable.
Genes and Main Pathways Involved
The ANKRD26 gene, located on the short arm of chromosome 10 (band 10p12.1), encodes a protein that plays a role in the TOP/MPL and MAPK/ERK pathways and is required for appropriate platelet formation and adipogenesis[9]. The ANKRD26 protein contains N-terminal ankyrin repeat domains and C-terminal spectrin helices. The exact cellular function of ANKRD26 and the molecular basis for the predisposition to myeloid malignancies is currently unknown. It is thought that gain-of-function mutations in ANKRD26 result in increased gene transcription and signaling through the MPL pathway and impaired pro-platelet formation by megakaryocytes[5][9].
Diagnostic Testing Methods
Myeloid gene panel testing by Next generation sequencing, PCR, Sanger sequencing
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
The prognosis of myeloid neoplasms with germline ANKRD26 mutation is currently not well established.
Familial Forms
ANKRD26-related thrombocytopenia (thrombocytopenia 2) is a rare autosomal dominant disorder characterized by lifelong mild-to-moderate thrombocytopenia with a normal platelet size, mild bleeding, no syndromic associations, and an increased risk of developing MDS/AML[1][10]. The penetrance for thrombocytopenia is complete[10].
Other Information
Not applicable.
Links
References
- ↑ 1.0 1.1 Peterson LC, et al., (2017). Myeloid neoplasms with germline predisposition, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p125-126.
- ↑ 2.0 2.1 Noris, Patrizia; et al. (2011). "Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families". Blood. 117 (24): 6673–6680. doi:10.1182/blood-2011-02-336537. ISSN 1528-0020. PMID 21467542.
- ↑ Galera, Pallavi; et al. (2019). "Inherited thrombocytopenia and platelet disorders with germline predisposition to myeloid neoplasia". International Journal of Laboratory Hematology. 41 Suppl 1: 131–141. doi:10.1111/ijlh.12999. ISSN 1751-553X. PMID 31069978.
- ↑ Geyer, Julia T. (2019). "Myeloid Neoplasms with Germline Predisposition". Pathobiology: Journal of Immunopathology, Molecular and Cellular Biology. 86 (1): 53–61. doi:10.1159/000490311. ISSN 1423-0291. PMID 30048985.
- ↑ 5.0 5.1 Pippucci, Tommaso; et al. (2011). "Mutations in the 5' UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2". American Journal of Human Genetics. 88 (1): 115–120. doi:10.1016/j.ajhg.2010.12.006. ISSN 1537-6605. PMC 3014357. PMID 21211618.
- ↑ Marquez, Rafael; et al. (2014). "A new family with a germline ANKRD26 mutation and predisposition to myeloid malignancies". Leukemia & Lymphoma. 55 (12): 2945–2946. doi:10.3109/10428194.2014.903476. ISSN 1029-2403. PMC 4206674. PMID 24628296.
- ↑ Marconi, Caterina; et al. (2017). "5'UTR point substitutions and N-terminal truncating mutations of ANKRD26 in acute myeloid leukemia". Journal of Hematology & Oncology. 10 (1): 18. doi:10.1186/s13045-016-0382-y. ISSN 1756-8722. PMC 5242010. PMID 28100250.
- ↑ Perez Botero, J.; et al. (2015). "ASXL1 mutated chronic myelomonocytic leukemia in a patient with familial thrombocytopenia secondary to germline mutation in ANKRD26". Blood Cancer Journal. 5: e315. doi:10.1038/bcj.2015.41. ISSN 2044-5385. PMC 4476020. PMID 26001113.
- ↑ 9.0 9.1 Bluteau, Dominique; et al. (2014). "Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation". The Journal of Clinical Investigation. 124 (2): 580–591. doi:10.1172/JCI71861. ISSN 1558-8238. PMC 3904625. PMID 24430186.
- ↑ 10.0 10.1 Perez Botero J. et al. (2018). "ANKRD26-Related Thrombocytopenia" In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507664/.
Notes
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