Myeloid Neoplasms with Germline ETV6 Mutation

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This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.

Primary Author(s)*

Jialing Huang, MD, PhD; Ying Zou, MD, PHD, FACMG

Johns Hopkins University, Baltimore, MD

Cancer Category/Type

HAEM4:Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms

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[1]. 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[2][3]. 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[4][5].

Synonyms / Terminology

ETV6-related thrombocytopenia and leukemia predisposition disorder

ETV6-related thrombocytopenia

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

Clinical Features

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[4]. Two-thirds of the predisposed hematopoietic malignancies are B -cell acute lymphoblastic leukemia (B-ALL)[6][7], 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[5][8][9][10].

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[7][11][12].

Sites of Involvement

Peripheral blood and bone marrow

Morphologic Features

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[5][8].

Bone marrow: mild dyserythropoiesis, megakaryocyte hyperplasia, hypolobulated small megakaryocytes, and mild myeloid dyspoiesis with nuclear hypolobulation and hypogranulation of myeloid cells[5][8].

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.  

Genomic Gain/Loss/LOH

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[8][13][14].

Other Mutations

Myeloid neoplasms with germline ETV6 mutation occasionally have L349P, R396G, I358M, A377T, R418G, W380R, W72Ter mutations in the ETV6 gene[8][13].

Epigenomics (Methylation)


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 Forms

Familial thrombocytopenia and leukemia predisposition syndrome.

Other Information

Next generation sequencing of the coding and non-coding regions of ETV6 gene are suggested[15].





  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, p126.
  2. Kirkpatrick, Gregory; et al. (2015). "ETV6 mutations define a new cancer predisposition syndrome". Oncotarget. 6 (19): 16830–16831. doi:10.18632/oncotarget.4842. ISSN 1949-2553. PMC 4627276. PMID 26219557.
  3. Churpek, Jane E.; et al. (2019). "Transcription factor mutations as a cause of familial myeloid neoplasms". The Journal of Clinical Investigation. 129 (2): 476–488. doi:10.1172/JCI120854. ISSN 1558-8238. PMC 6355228. PMID 30707109.
  4. 4.0 4.1 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.
  5. 5.0 5.1 5.2 5.3 Di Paola, Jorge; et al. (2019). "ETV6-related thrombocytopenia and leukemia predisposition". Blood. 134 (8): 663–667. doi:10.1182/blood.2019852418. ISSN 1528-0020. PMC 6706811. PMID 31248877.
  6. Moriyama, Takaya; et al. (2015). "Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study". The Lancet. Oncology. 16 (16): 1659–1666. doi:10.1016/S1470-2045(15)00369-1. ISSN 1474-5488. PMC 4684709. PMID 26522332.
  7. 7.0 7.1 Topka, Sabine; et al. (2015). "Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia". PLoS genetics. 11 (6): e1005262. doi:10.1371/journal.pgen.1005262. ISSN 1553-7404. PMC 4477877. PMID 26102509.
  8. 8.0 8.1 8.2 8.3 8.4 Rampersaud, Evadnie; et al. (2019). "Germline deletion of ETV6 in familial acute lymphoblastic leukemia". Blood Advances. 3 (7): 1039–1046. doi:10.1182/bloodadvances.2018030635. ISSN 2473-9537. PMC 6457220. PMID 30940639.
  9. Karastaneva, Anna; et al. (2020). "Novel phenotypes observed in patients with ETV6-linked leukaemia/familial thrombocytopenia syndrome and a biallelic ARID5B risk allele as leukaemogenic cofactor". Journal of Medical Genetics. 57 (6): 427–433. doi:10.1136/jmedgenet-2019-106339. ISSN 1468-6244. PMID 31704777.
  10. Duployez, Nicolas; et al. (2018). "Detection of a new heterozygous germline ETV6 mutation in a case with hyperdiploid acute lymphoblastic leukemia". European Journal of Haematology. 100 (1): 104–107. doi:10.1111/ejh.12981. ISSN 1600-0609. PMID 29034503.
  11. Wang, Meilin; et al. (2016). "Common genetic variation in ETV6 is associated with colorectal cancer susceptibility". Nature Communications. 7: 11478. doi:10.1038/ncomms11478. ISSN 2041-1723. PMC 4858728. PMID 27145994.
  12. Zhang, Michael Y.; et al. (2015). "Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy". Nature Genetics. 47 (2): 180–185. doi:10.1038/ng.3177. ISSN 1546-1718. PMC 4540357. PMID 25581430.
  13. 13.0 13.1 Feurstein, Simone; et al. (2017). "Germline ETV6 mutations and predisposition to hematological malignancies". International Journal of Hematology. 106 (2): 189–195. doi:10.1007/s12185-017-2259-4. ISSN 1865-3774. PMID 28555414.
  14. Noetzli, Leila; et al. (2015). "Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia". Nature Genetics. 47 (5): 535–538. doi:10.1038/ng.3253. ISSN 1546-1718. PMC 4631613. PMID 25807284.
  15. Bernardi, Simona; et al. (2020). "ETV6: A Candidate Gene for Predisposition to "Blend Pedigrees"? A Case Report from the NEXT-Famly Clinical Trial". Case Reports in Hematology. 2020: 2795656. doi:10.1155/2020/2795656. ISSN 2090-6560. PMC 7057007 Check |pmc= value (help). PMID 32148977 Check |pmid= value (help).


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