t(12;15)(p13;q25) ETV6/NTRK3 in Hematological malignancies

2019-11-01   Jean-Loup Huret 



Review on t(12;15)(p13;q25), with data on clinics, and the genes involved.

Clinics and Pathology


Myeloid leukemias and acute lymphoblastic leukemia (ALL).

Phenotype stem cell origin

Chronic eosinophilic leukemia (one case), acute myeloblastic leukemia with maturation (FAB type M2) (one case), acute myeloblastic leukemia with minimal differentiation (FAB type M0) (one case), and B-lineage acute lymphoblastic leukemia (three cases).


A chronic eosinophilic leukemia was diagnosed in a 82-year old female patient with a previous history of breast and pancreatic carcinomas (Forghieri et al., 2011). A M2-AML was diagnosed in a 52-yr old female patient. The patient died 5 months after the onset of the leukaemia (Eguchi et al., 1999). A M0-AML was found in a 55-yr old male patient who died after a short period of supportive care (Kralik et al., 2011). Three cases of B-cell ALL were diagnosed. There was an adolescent boy and a 26-yr old male patient (Roberts et al., 2014; Gu et al., 2016; Reshmi et al., 2017).


There was a monosomy 7 in two of the three documented cases (Forghieri et al., 2011; Kralik et al., 2011), and a trisomy 8 in 2 cases as well (Eguchi et al., 1999; Forghieri et al., 2011). The lymphoid cases were not documented.

Genes Involved and Proteins

Gene name
ETV6 (ets variant 6)
Protein description
ETV6 is a strong transcriptional repressor. ETV6 is a 452 amino acid member of the ETS family (signal-dependent transcriptional regulators, mediating cell proliferation, differentiation and tumorigenesis. The ETV6 protein contains two major domains, the HLH (helix-loop-helix) and ETS domains. The N-term HLH domain, also referred to as the pointed or sterile alpha motif domain, is responsible for hetero- and homodimerization. The C-term ETS domain is responsible for sequence specific DNA-binding and protein-protein interaction. A central domain, called internal domain, is involved in the recruitment of a repression complex includingNCOR1, NCOR2, and SIN3A (Braekeleer et al., 2014 http://atlasgeneticsoncology.org//Genes/ETV6ID38.html ).
Gene name
NTRK3 (neurotrophic tyrosine kinase, receptor, type 3)
Protein description
NTRK3 is a transmembrane receptor tyrosine kinase which triggers PI3K/AKT, RAS/RAF/MAPK, and PLCG pathways. NTRK3 is a 839 amino acid protein with a N-term extra-cellular ligand binding domain, a transmembrane domain, and a C-term intracellular tyrosine kinase domain. Ligand for NTRK3 is NTF3 (neurotrophin 3) (Knezevich 2004 http://atlasgeneticsoncology.org/Genes/NTRK3ID433.html ).

Result of the Chromosomal Anomaly


In most cases, ETV6 exon 5 was fused to NTRK3 exon 15 (Forghieri et al., 2011; Roberts et al., 2014). In one case ETV6 exon 4 was fused to NTRK3 exon 15 (Eguchi: et al., 1999), and in another case, fusion transcripts contain ETV6 exons 1 through 5 fused to NTRK3 exons 13b and 14b or NTRK3 exons 13 through 18 (Kralik et al., 2011).
In solid tumors, ETV6 exon 5 - NTRK3 exon 15 fusion is the most frequent:
The fusion was exon 4 - exon 14 in most papillary thyroid carcinoma ceases, but one exon 5 - exon 14 fusion case (Leeman-Neill et al., 2014), and exon 5 - exon 15 in: secretory ductal breast carcinoma (Tognon et al., 2002), congenital mesoblastic nephroma (Knezevich et al., 1998; Rubin et al., 1998; Argani et al., 2000; Ramachandran et al., 2001; Watanabe et al., 2002; Henno et al., 2003; Anderson et al., 2006; Bayindir et al., 2009), secretory carcinoma of salivary glands (mammary analogue) (Skálová et al., 2010; Skálová et al., 2014), atypical Spitz tumors (Yeh et al., 2016), and also in a case of colon adenocarcinoma (Seshagiri et al., 2012). The classical exon 5 - exon 15 fusion is also found in congenital/infantile fibrosarcoma (Knezevich et al., 1998; Rubin et al., 1998; Bourgeois et al., 2000; Punnett et al., 2000; Argani et al., 2001; Dubus et al., 2001; Sheng et al., 2001; Miura et al., 2002; McCahon et al., 2003; Ramphal et al., 2003; Nonaka and Sun, 2004; Himori et al., 2005), but, also, a fusion NTRK3 exon 14 - ETV6 exon 6 was found in one case (Dubus et al., 2001).
Atlas Image


The SAM-PNT (sterile alpha motif- pointed) domain of ETV6 is fused to the PTK (Protein Tyrosine Kinase domain) of NTRK3.


It leads to dimerization, and induction of CCND1 (cyclin D1) and increased cell cycle progression. ETV6/NTRK3 also leads to constitutive activation of the PI3K/AKT, RAS/RAF/MAPK, and PLCG pathways (Lannon and Sorensen, 2005).

Highly cited references

Pubmed IDYearTitleCitations
327374492020Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular characterization.24
339237282021NTRK Fusion Genes in Thyroid Carcinomas: Clinicopathological Characteristics and Their Impacts on Prognosis.10
330243042021Problematic breast tumors reassessed in light of novel molecular data.10
326696122021Mesenchymal tumors of the gastrointestinal tract with NTRK rearrangements: a clinicopathological, immunophenotypic, and molecular study of eight cases, emphasizing their distinction from gastrointestinal stromal tumor (GIST).9
328600022021Broadening the spectrum of NTRK rearranged mesenchymal tumors and usefulness of pan-TRK immunohistochemistry for identification of NTRK fusions.9
340362192021NTRK Fusions Identified in Pediatric Tumors: The Frequency, Fusion Partners, and Clinical Outcome.9
326756582020Expanding the Molecular Spectrum of Secretory Carcinoma of Salivary Glands With a Novel VIM-RET Fusion.9
334054002021Molecular Pathology of Salivary Gland Neoplasms: Diagnostic, Prognostic, and Predictive Perspective.8
325562222020Genetic Alterations in Pediatric Thyroid Cancer Using a Comprehensive Childhood Cancer Gene Panel.7
337551582021Early-Onset Pancreas Cancer: Clinical Descriptors, Genomics, and Outcomes.6
329681852021Fusion partners of NTRK3 affect subcellular localization of the fusion kinase and cytomorphology of melanocytes.5
328807852020Detection of NTRK1/3 Rearrangements in Papillary Thyroid Carcinoma Using Immunohistochemistry, Fluorescent In Situ Hybridization, and Next-Generation Sequencing.5
339366132021Complete response to larotrectinib treatment in a patient with papillary thyroid cancer harboring an ETV6-NTRK3 gene fusion.4
344025292021NTRK oncogenic fusions are exclusively associated with the serrated neoplasia pathway in the colorectum and begin to occur in sessile serrated lesions.3
338997882021Pan-TRK Immunohistochemistry Is Highly Correlated With NTRK3 Gene Rearrangements in Salivary Gland Tumors.3
342313372022Diagnostic challenges and successful organ-preserving therapy in a case of secretory carcinoma of minor salivary glands.2
344293032021Mechanisms of targeted therapy resistance in a pediatric glioma driven by ETV6-NTRK3 fusion.2
339915272021Intraductal carcinoma of the salivary gland with NCOA4-RET: expanding the morphologic spectrum and an algorithmic diagnostic approach.2
338483862021High-grade salivary gland carcinoma with the ETV6-NTRK3 gene fusion: A case report and literature review of secretory carcinoma with high-grade transformation.2
340301252021Clinical Activity of Selitrectinib in a Patient With Mammary Analogue Secretory Carcinoma of the Parotid Gland With Secondary Resistance to Entrectinib.2
337384522021The experience of successful treatment of ETV6-NTRK3-positive infant glioblastoma with entrectinib.2
331837282020Pediatric Renal Tumors: Updates in the Molecular Era.2
331279542020Nanostring-based screening for tyrosine kinase fusions in inflammatory myofibroblastic tumors.2
351563432022Cytological and molecular characterization of secretory breast carcinoma.1
352956132022NTRK Fusions Detection in Paediatric Sarcomas to Expand the Morphological Spectrum and Clinical Relevance of Selected Entities.1
343782832021An unusual fusion gene EML4-ALK in a patient with congenital mesoblastic nephroma.1
330933552021Adjuvant Maintenance Larotrectinib Therapy in 2 Children With NTRK Fusion-positive High-grade Cancers.1
343730982021Molecular Pathology of Thyroid Tumors: Old Problems and New Concepts.1
336601472021Secretory Carcinoma of the Oral Cavity: A Retrospective Case Series with Review of Literature.1
341762002021Locally Recurrent Secretory Carcinoma of the Breast with NTRK3 Gene Fusion.1
338852002021Utility of an immunocytochemical analysis for pan-Trk in the cytodiagnosis of secretory carcinoma of the salivary gland.1
338503022021Novel BRAF gene fusions and activating point mutations in spindle cell sarcomas with histologic overlap with infantile fibrosarcoma.1
340983862021Targeted DNA profiling and the prevalence of NTRK aberrations in Chinese patients with head and neck cancer.1
338821522021Secretory carcinoma of the skin with lymph node metastases and recurrence in both lungs: A case report.1
336221652021Treatment of infantile fibrosarcoma associated to an abdominal aortic aneurysm with larotrectinib: a case report.1
333420112021Dedifferentiated secretory breast carcinoma with fibrosarcomatous features harboring an ETV6-NTRK3 fusion in both components.1
331287802021Chromosomal imbalances detected in NTRK-rearranged sarcomas by the use of comparative genomic hybridisation.1
341624062021Secretory carcinoma of the breast with multiple distant metastases in the brain and unfavorable prognosis: a case report and literature review.1
338956802021ETV6-NTRK3 translocation-associated low-grade mucinous bronchial adenocarcinoma: A novel bronchial salivary gland-type non-small cell lung cancer subtype.1
331895782021Mammary analog secretory carcinoma of the thyroid gland: A rare cancer harboring TRK fusion.1
333017512021Pan-tropomyosin receptor kinase immunoreactivity, ETV6-NTRK3 fusion subtypes, and RET rearrangement in salivary secretory carcinoma.1
324884122021Usefulness of immunohistochemistry to distinguish between secretory carcinoma and acinic cell carcinoma in the salivary gland.1
359775942022Pan-tropomyosin receptor kinase immunohistochemistry is a feasible routine screening strategy for NTRK fusions in mismatch repair-deficient colorectal carcinomas.0
359744312022Secretory carcinoma of the salivary gland: a multi-institutional clinicopathologic study of 90 cases with emphasis on grading and prognostic factors.0
357879222022Therapeutic targeting of RBPJ, an upstream regulator of ETV6 gene, abrogates ETV6-NTRK3 fusion gene transformations in glioblastoma.0
358563622022A novel ETV6-NTRK3 gene fusion in primary renal fibrosarcoma.0
359825912022Secretory Carcinoma of the Breast Mimicking Invasive Ductal Carcinoma: A Case Report.0
358105662022The genomic profile of double primary secretory breast carcinoma in one patient provides evidence for the treatment of such carcinoma: A case report.0
355430762022Histologic characterization of paediatric mesenchymal neoplasms treated with kinase-targeted therapy.0
352670842022The evolving role of molecular pathology in the diagnosis of salivary gland tumours with potential pitfalls.0
357619042022Larotrectinib as an Effective Therapy in Congenital Infantile Fibrosarcoma: Report of Two Cases.0
356708542022Low-grade tracheal adenocarcinoma with ETV6::NTRK3 fusion: unique morphology akin to subsets of sinonasal low-grade non-intestinal-type adenocarcinoma.0
346554082022Secretory Carcinoma of the Thyroid in a 49-Year-Old Man Treated with Larotrectinib: Protracted Clinical Course of Disease Despite the High-Grade Histologic Features.0
342552772022An Underappreciated Cytomorphological Feature of Secretory Carcinoma of Salivary Gland on Fine Needle Aspiration Biopsy: Case Report with Literature Review.0
358064722022Limited Accuracy of Pan-Trk Immunohistochemistry Screening for NTRK Rearrangements in Follicular-Derived Thyroid Carcinoma.0
357354232022TRK Inhibition with Entrectinib in Metastatic Salivary Secretory Carcinoma (SC): A Case Report.0
357204852022A unique case of inflammatory myofibroblastic tumor of the liver manifesting with biloma: A case report.0
355367332022Larotrectinib Treatment for Patients With TRK Fusion-Positive Salivary Gland Cancers.0
357371552022Prediction of EVT6-NTRK3-Dependent Papillary Thyroid Cancer Using Minor Expression Profile.0
356722772022Identification of a novel PHIP::BRAF gene fusion in infantile fibrosarcoma.0
328355762022The Giant Infantile Fibrosarcoma of Fetal Oropharynx and Anterior Neck.0
359150422022Molecular identification of an ETV6-RET fusion in a secretory carcinoma associated with a pleomorphic adenoma.0
353856042022Secretory carcinoma of the salivary gland, a rare entity: An international multi-institutional study.0
353848762022Using pan-TRK and RET Immunohistochemistry for the Detection of Fusion Types of Salivary Gland Secretory Carcinoma.0
350328962022Infantile fibrosarcoma with an EGFR kinase domain duplication: Underlining a close relationship with congenital mesoblastic nephroma and highlighting a similar morphological spectrum.0
351068562022Fusion-associated carcinomas of the breast: Diagnostic, prognostic, and therapeutic significance.0
344865432022Secretory Carcinoma of the Salivary Gland: A Rarity in Children.0
353221952022Low-grade non-intestinal-type sinonasal adenocarcinoma: a histologically distinctive but molecularly heterogeneous entity.0
351026302022NTRK gene fusions are detected in both secretory and non-secretory breast cancers.0
349157532022Unique Molecular Signatures Are Associated with Aggressive Histology in Pediatric Differentiated Thyroid Cancer.0
346063892022Secretory Carcinoma in Children and Young Adults: A Case Series.0
355740462022Fibrous hamartoma of infancy with sarcomatous transformation: an unusual morphology.0
349534442022Mammary analogue secretory carcinoma: A challenging case arising in a young man with radiation exposure.0
351581212022Genomic landscape of secretory carcinoma of the breast with axillary lymph node metastasis.0
349435212021Cytopathological Findings of Secretory Carcinoma of the Salivary Gland and the Diagnostic Utility of Giemsa Staining.0
349915632022Clinicopathological investigation of secretory carcinoma cases including a successful treatment outcome using entrectinib for high-grade transformation: a case report.0
349585032022Mesenchymal neoplasms with NTRK and other kinase gene alterations.0
347940692022NTRK-Rearranged soft tissue neoplasms: A review of evolving diagnostic entities and algorithmic detection methods.0
346507982021Mammary analogue secretory carcinoma of a salivary gland of the hard palate with contralateral cervical lymph node metastases: A case report.0
340892032021Secretory carcinoma of the breast limited to the dermis: Cutaneous or breast primary?0
341205112021Second Report of PDE10A-BRAF Fusion in Pediatric Spindle Cell Sarcoma With Infantile Fibrosarcoma-Like Morphology Suggesting PDE10A-BRAF Fusion Is a Recurrent Event.0
346036392021Hypofractionated radiation in secretory breast cancer: A case report.0
335443812021High-grade Salivary Gland Adenocarcinoma Harboring ETV6-NTRK3 Fusion: Defined by Morphology or Molecular Aberration?0
334599932021Clinicopathologic and Molecular Characterization of Four Cases of Pediatric Salivary Secretory Carcinoma (SSC), One with ETV6-RET Fusion.0
346290792021Secretory breast carcinoma in a female adult with liver metastsis: a case report and literature review.0
346227262021Fetal Mediastinal Fibrosarcoma. Report of Two Cases.0
346509242021Profiling Receptor Tyrosine Kinase Fusions in Chinese Breast Cancers.0
334529132021A case of "ETV6-FISH-negative" secretory carcinoma of the parotid gland: immunohistochemical study.0
343890352021Development of metastatic poorly differentiated thyroid cancer from a sub-centimeter papillary thyroid carcinoma in a young patient with a germline MET mutation - association or random chance?0
343728732021Characterization of an ETV6-NTRK3 rearrangement with unusual, but highly significant FISH signal pattern in a secretory carcinoma of the salivary gland: a case report.0
343440732021[Secretory carcinoma of salivary gland: a clinicopathological and prognostic analysis of twelve cases].0
335738742021Secretory carcinoma of salivary glands at the National Cancer Institute: A 20-year retrospective clinical, pathological, immunohistochemical and molecular study.0
341417662021Parotid mammary analogue secretory carcinoma: A case report and review of literature.0
342504012021Response to Cabozantinib Following Acquired Entrectinib Resistance in a Patient With ETV6-NTRK3 Fusion-Positive Carcinoma Harboring the NTRK3 G623R Solvent-Front Mutation.0
341004142021Secretory carcinoma of salivary gland origin: A recently established masquerader.0
345145742021What Would Next Generation Sequencing Bring to the Diagnosis and Treatment of Sarcomas? A Series of 20 Cases, a Single Institution's Experience.0
326876872021Secretory carcinoma of salivary type in a lymph node presenting as a neck cyst diagnosed by cytology: A case report.0
330690822020von Ebner's glands intercalated duct adenocarcinoma with PALB2 gene mutation.0
346094372021ETV6-NTRK3-positive parotid mammary analogue secretory carcinoma: a case report.0
332310592020[Infantile intestinal fibrosarcoma. Case report with digestive bleeding in an infant].0


Pubmed IDLast YearTitleAuthors
166816922006Expression of ETV6-NTRK in classical, cellular and mixed subtypes of congenital mesoblastic nephroma.Anderson J et al
116849682001Reduced sensitivity of paraffin-based RT-PCR assays for ETV6-NTRK3 fusion transcripts in morphologically defined infantile fibrosarcoma.Argani P et al
196294652009Cellular mesoblastic nephroma (infantile renal fibrosarcoma): institutional review of the clinical, diagnostic imaging, and pathologic features of a distinctive neoplasm of infancy.Bayindir P et al
108958162000Molecular detection of the ETV6-NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumors.Bourgeois JM et al
168889132003Secretory carcinoma of the breast: a genetically defined carcinoma entity.Diallo R et al
111695202001The detection of Tel-TrkC chimeric transcripts is more specific than TrkC immunoreactivity for the diagnosis of congenital fibrosarcoma.Dubus P et al
99491791999Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25).Eguchi M et al
212267632011Chronic eosinophilic leukaemia with ETV6-NTRK3 fusion transcript in an elderly patient affected with pancreatic carcinoma.Forghieri F et al
278240512016Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia.Gu Z et al
126505162003Cellular mesoblastic nephroma: morphologic, cytogenetic and molecular links with congenital fibrosarcoma.Henno S et al
158016892005Infantile fibrosarcoma of thigh--a case report.Himori K et al
214019662011Characterization of a newly identified ETV6-NTRK3 fusion transcript in acute myeloid leukemia.Kralik JM et al
243273982014ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer.Leeman-Neill RJ et al
126526162003Non-resectable congenital tumors with the ETV6-NTRK3 gene fusion are highly responsive to chemotherapy.McCahon E et al
124061912002Regression of congenital fibrosarcoma to hemangiomatous remnant with histological and genetic findings.Miura K et al
150220582004Congenital fibrosarcoma with metastasis in a fetus.Nonaka D et al
145780342003Retroperitoneal infantile fibrosarcoma: clinical, molecular, and therapeutic aspects of an unusual tumor.Ramphal R et al
284084642017Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group.Reshmi SC et al
252077662014Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.Roberts KG et al
98113361998Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma.Rubin BP et al
228951932012Recurrent R-spondin fusions in colon cancer.Seshagiri S et al
112427902001Congenital-infantile fibrosarcoma. A clinicopathologic study of 10 cases and molecular detection of the ETV6-NTRK3 fusion transcripts using paraffin-embedded tissues.Sheng WQ et al
241456512014Mammary analogue secretory carcinoma of salivary glands with high-grade transformation: report of 3 cases with the ETV6-NTRK3 gene fusion and analysis of TP53, β-catenin, EGFR, and CCND1 genes.Skálová A et al
124507922002Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma.Tognon C et al
121654452002Cryptic t(12;15)(p13;q26) producing the ETV6-NTRK3 fusion gene and no loss of IGF2 imprinting in congenital mesoblastic nephroma with trisomy 11: fluorescence in situ hybridization and IGF2 allelic expression analysis.Watanabe N et al
274773202016NTRK3 kinase fusions in Spitz tumours.Yeh I et al


Fusion gene



The t(12;15)(p13;q25) ETV6/NTRK3 is also found in: Secretory ductal breast carcinoma; Congenital mesoblastic nephroma; Congenital/infantile fibrosarcoma; Papillary thyroid carcinoma (PTC), especially so in radiation-associated PTCs; ALK-negative inflammatory myofibroblastic sarcoma; Secretory carcinoma of salivary glands (mammary analogue); atypical Spitz tumors, and rare other conditions.


Jean-Loup Huret

t(12;15)(p13;q25) ETV6/NTRK3 in Hematological malignancies

Atlas Genet Cytogenet Oncol Haematol. 2019-11-01

Online version: http://atlasgeneticsoncology.org/haematological/1347/t(12;15)(p13;q25)-etv6-ntrk3-in-hematological-malignancies

Historical Card

2008-01-01 t(12;15)(p13;q25) ETV6/NTRK3 in Hematological malignancies by  Jean-Loup Huret 


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