Myeloid Neoplasms with Germline ANKRD26 Mutation
Fei Yang, MD, FACMG
Oregon Health & Science University, Portland, OR
Myeloid Neoplasms with Germline Predisposition
Cancer Sub-Classification / Subtype
Myeloid Neoplasms with Germline ANKRD26 Mutation
Definition / Description of Disease
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.
Patients with germline ANKRD26 mutation initially present with mild bleeding and thrombocytopenia at very variable age of onset. The common bleeding symptoms include petechiae, ecchymosis, gum bleeding, epistaxis, and menorrhagia. The risk of developing myeloid neoplasms is estimated 30 times higher than that in the general population.
Sites of Involvement
Blood and bone marrow.
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.
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.
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. Truncating mutation in the N-terminus has also been reported.
Co-occurring somatic mutation in ASXL1 has been reported in a patient with germline ANKRD26-related thrombocytopenia and CMML.
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. 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.
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.
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. The penetrance for thrombocytopenia is complete.
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*Citation of this Page: Yang F. “Myeloid Neoplasms with Germline ANKRD26 Mutation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/2/2021, https://ccga.io/index.php/Myeloid Neoplasms with Germline ANKRD26 Mutation.