Myeloid Neoplasms with Germline ETV6 Mutation

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Primary Author(s)*

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

Johns Hopkins University, Baltimore, MD

Cancer Category/Type

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 leukaemia (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, R369G, I358M, A337T, 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 G, Noetzli L, Di Paola J, Porter CC. ETV6 mutations define a new cancer predisposition syndrome. Oncotarget. 2015;6(19):16830-16831.
  3. Churpek JE, Bresnick EH. Transcription factor mutations as a cause of familial myeloid neoplasms. J Clin Invest. 2019;129(2):476-488.
  4. 4.0 4.1 Galera P, Dulau-Florea A, Calvo KR. Inherited thrombocytopenia and platelet disorders with germline predisposition to myeloid neoplasia. Int J Lab Hematol. 2019;41 Suppl 1:131-141.
  5. 5.0 5.1 5.2 5.3 Di Paola J, Porter CC. ETV6-related thrombocytopenia and leukemia predisposition. Blood. 2019;134(8):663-667.
  6. Moriyama T, Metzger ML, Wu G, et al. Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study. Lancet Oncol. 2015;16(16):1659-1666.
  7. 7.0 7.1 Topka S, Vijai J, Walsh MF, et al. Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia. PLoS Genet. 2015;11(6):e1005262.
  8. 8.0 8.1 8.2 8.3 8.4 Rampersaud E, Ziegler DS, Iacobucci I, et al. Germline deletion of ETV6 in familial acute lymphoblastic leukemia. Blood Adv. 2019;3(7):1039-1046.
  9. Karastaneva A, Nebral K, Schlagenhauf A, et al. Novel phenotypes observed in patients with ETV6-linked leukaemia/familial thrombocytopenia syndrome and a biallelic ARID5B risk allele as leukaemogenic cofactor. J Med Genet. 2019.
  10. Duployez N, Abou Chahla W, Lejeune S, et al. Detection of a new heterozygous germline ETV6 mutation in a case with hyperdiploid acute lymphoblastic leukemia. Eur J Haematol. 2018;100(1):104-107.
  11. Wang M, Gu D, Du M, et al. Common genetic variation in ETV6 is associated with colorectal cancer susceptibility. Nat Commun. 2016;7:11478.
  12. Zhang MY, Churpek JE, Keel SB, et al. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nat Genet. 2015;47(2):180-185.
  13. 13.0 13.1 Feurstein S, Godley LA. Germline ETV6 mutations and predisposition to hematological malignancies. Int J Hematol. 2017;106(2):189-195.
  14. Noetzli L, Lo RW, Lee-Sherick AB, et al. Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. Nat Genet. 2015;47(5):535-538.
  15. Bernardi S, Farina M, Zanaglio C, et al. ETV6: A Candidate Gene for Predisposition to "Blend Pedigrees"? A Case Report from the NEXT-Famly Clinical Trial. Case Rep Hematol. 2020;2020:2795656.


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