Myeloid Neoplasms with Germline ETV6 Mutation
Jialing Huang, MD, PhD; Ying Zou, MD, PHD, FACMG
Johns Hopkins University, Baltimore, MD
Cancer Sub-Classification / Subtype
Myeloid neoplasms with germline ETV6 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. Myeloid neoplasms with germline ETV6 mutation is a familial platelet disorder inherited in an autosomal dominant pattern with dysfunction of thrombocytopenia 5 (THC5, OMIM 616216) protein. It accounts for 5% of inherited thrombocytopenia. The clinical presentation include variable degrees of thrombocytopenia, and mild to moderate bleeding tendencies. Some patients have erythroid macrocytosis but no anemia. Platelet size is normal but aggregation or activation is variably decreased. Occasional elongated platelet α granules can be seen on electric microscopy. Macrocytosis is often present. Most importantly, patients have increased risks for lymphocytic and myeloid malignancies, including AML, MDS, B-lymphoblastic leukemia, chronic myelomonocytic leukemia, and plasma cell myeloma.
Synonyms / Terminology
ETV6-related thrombocytopenia and leukemia predisposition disorder
Familial thrombocytopenia and leukemia predisposition syndrome
Epidemiology / Prevalence
Approximately 5% of inherited thrombocytopenia and 3% of all familial thrombocytopenia.
- Occur mostly in children and occasionally in adults.
- Median patient age is 3 years old
- Both males and females are equally affected
ETV6-related thrombocytopenia and leukemia predisposition is an autosomal dominant disorder of thrombocytopenia with near-complete penetrance of phenotype. Patients usually present with mild to moderate bleeding tendencies and mild to moderate thrombocytopenia. Some carriers have normal platelet counts. Although platelet aggregation ability is usually normal with high dose agonists, aggregation with ADP and arachidonic acid can be decreased; spread on fibrinogen and clot retraction is impaired.
ETV6 germline mutations predispose to both lymphoid and myeloid hematological malignancies. Two-thirds of the predisposed hematopoietic malignancies are B -cell acute lymphoblastic leukemia (B-ALL), and the remaining include MDS, AML, high-hyperdiploid acute lymphoblastic leukemia (HD-ALL), mixed-phenotype acute leukemia, diffuse large B-cell lymphoma, polycythemia vera, and multiple myeloma. About 30% of all carriers have certain type of hematologic malignancy.
Increased risk in solid malignancies such as colorectal adenocarcinoma, duodenal adenocarcinoma, breast cancer, breast fibroadenoma, meningioma, renal cell cancer, and skin cancers, is also noted.
Sites of Involvement
Peripheral blood and bone marrow
Peripheral blood: mild to moderate thrombocytopenia, with platelet counts >75 × 109/L (range 32-118× 109/L). Mean platelet volume is sometimes slightly reduced. An increase in platelet diameter distribution width may indicate platelet anisocytosis. Some carriers have normal platelet counts. Occasional low mean platelet volume is present. White blood cell counts and hemoglobin concentrations are normal, and mean corpuscular volumes are variably high. Macrocytosis is often present.
Predisposed hematopoietic malignancies have characteristic morphologies for individual types.
Non-neoplastic hematopoietic cells are immunophenotypically normal.
Neoplastic hematopoietic cells are immunophenotypically identical to those seen in the same type of neoplasm without ETV6 germline mutation.
Chromosomal Rearrangements (Gene Fusions)
No known recurring or common cytogenetic abnormality associated with ETV6 gene mutations.
Characteristic Chromosomal Aberrations / Patterns
No known chromosomal abnormalities associated with ETV6 gene mutations.
No known chromosomal abnormalities associated with ETV6 gene mutations.
Gene Mutations (SNV/INDEL)
The common pathogenic germline mutations of ETV6 gene are single nucleotide substitutions and deletions leading to frameshift, missense, nonsense and splice site mutations. These mutations mainly affect the DNA-binding domain of the THC-5 protein. P214L mutation is located in the central domain. Mutations N385Vfs, Y401N, R369W, and R369Q are located within the ETS domain.
Genes and Main Pathways Involved
Diagnostic Testing Methods
Somatic DNA mutation analysis
Germline mutation testing
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
Due to the high risk of malignancies, the families with thrombocytopenia and a predisposition to hematological malignancies should be screened for germline ETV6 mutations and segregating mutations. The germline testing should be done on cultured skin fibroblasts or cultured bone marrow-derived stromal cells.
Patients with pathogenic ETV6 germline mutation(s) should be closely followed up for clinical examination, complete blood counts, white blood cell differentials, bone marrow biopsy and regular cancer screening. Genetic counseling should be offered to at-risk family member.
Familial thrombocytopenia and leukemia predisposition syndrome.
Next generation sequencing of the coding and non-coding regions of ETV6 gene are suggested.
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*Citation of this Page: Huang J, Zou Y. “Myeloid Neoplasms with Germline ETV6 Mutation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/2/2021, https://ccga.io/index.php/Myeloid Neoplasms with Germline ETV6 Mutation.