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

Written2019-11Jean-Loup Huret
This article is an update of :
2008-01Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

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

Keywords Chromosome 12; Chromosome 15; ETV6; NTRK3; Chronic eosinophilic leukemia; Acute myeloid leukemia; B-Lineage Acute lymphoblastic leukemia; Secretory ductal breast carcinoma; Congenital mesoblastic nephroma; Congenital/infantile fibrosarcoma; Papillary thyroid carcinoma; Inflammatory myofibroblastic sarcoma; Secretory carcinoma of salivary glands (mammary analogue); atypical Spitz tumors.

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ICD-Topo C420,C421,C424
ICD-Morpho 9964/3 Chronic eosinophilic leukaemia, NOS
ICD-Morpho 9874/3 AML with maturation
ICD-Morpho 9872/3 AML with minimal differentiation; Myeloid sarcoma
ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
Atlas_Id 1347
Note 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.

Clinics and Pathology

Disease Myeloid leukemias and acute lymphoblastic leukemia (ALL).
Phenotype / cell stem 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).
Epidemiology 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).
Cytogenetics 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 NameETV6 (ets variant 6)
Location 12p13.2
Protein 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 ).
Gene NameNTRK3 (neurotrophic tyrosine kinase, receptor, type 3)
Location 15q25.3
Protein 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 ).

Result of the chromosomal anomaly

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

To be noted

Additional cases are needed to delineate the epidemiology of this rare entity:
you are welcome to submit a paper to our new Case Report section.


Expression of ETV6-NTRK in classical, cellular and mixed subtypes of congenital mesoblastic nephroma
Anderson J, Gibson S, Sebire NJ
Histopathology 2006 May;48(6):748-53
PMID 16681692
Reduced sensitivity of paraffin-based RT-PCR assays for ETV6-NTRK3 fusion transcripts in morphologically defined infantile fibrosarcoma
Argani P, Fritsch MK, Shuster AE, Perlman EJ, Coffin CM
Am J Surg Pathol 2001 Nov;25(11):1461-4
PMID 11684968
Cellular mesoblastic nephroma (infantile renal fibrosarcoma): institutional review of the clinical, diagnostic imaging, and pathologic features of a distinctive neoplasm of infancy
Bayindir P, Guillerman RP, Hicks MJ, Chintagumpala MM
Pediatr Radiol 2009 Oct;39(10):1066-74
PMID 19629465
Molecular detection of the ETV6-NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumors
Bourgeois JM, Knezevich SR, Mathers JA, Sorensen PH
Am J Surg Pathol 2000 Jul;24(7):937-46
PMID 10895816
Secretory carcinoma of the breast: a genetically defined carcinoma entity
Diallo R, Tognon C, Knezevich SR, Sorensen P, Poremba C
Verh Dtsch Ges Pathol 2003;87:193-203
PMID 16888913
The detection of Tel-TrkC chimeric transcripts is more specific than TrkC immunoreactivity for the diagnosis of congenital fibrosarcoma
Dubus P, Coindre JM, Groppi A, Jouan H, Ferrer J, Cohen C, Rivel J, Copin MC, Leroy JP, de Muret A, Merlio JP
J Pathol 2001 Jan;193(1):88-94
PMID 11169520
Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25)
Eguchi M, Eguchi-Ishimae M, Tojo A, Morishita K, Suzuki K, Sato Y, Kudoh S, Tanaka K, Setoyama M, Nagamura F, Asano S, Kamada N
Blood 1999 Feb 15;93(4):1355-63
PMID 9949179
Chronic eosinophilic leukaemia with ETV6-NTRK3 fusion transcript in an elderly patient affected with pancreatic carcinoma
Forghieri F, Morselli M, Potenza L, Maccaferri M, Pedrazzi L, Paolini A, Bonacorsi G, Artusi T, Giacobbi F, Corradini G, Barozzi P, Zucchini P, Marasca R, Narni F, Crescenzi B, Mecucci C, Falini B, Torelli G, Luppi M
Eur J Haematol 2011 Apr;86(4):352-5
PMID 21226763
Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia
Gu Z, Churchman M, Roberts K, Li Y, Liu Y, Harvey RC, McCastlain K, Reshmi SC, Payne-Turner D, Iacobucci I, Shao Y, Chen IM, Valentine M, Pei D, Mungall KL, Mungall AJ, Ma Y, Moore R, Marra M, Stonerock E, Gastier-Foster JM, Devidas M, Dai Y, Wood B, Borowitz M, Larsen EE, Maloney K, Mattano LA Jr, Angiolillo A, Salzer WL, Burke MJ, Gianni F, Spinelli O, Radich JP, Minden MD, Moorman AV, Patel B, Fielding AK, Rowe JM, Luger SM, Bhatia R, Aldoss I, Forman SJ, Kohlschmidt J, Mrózek K, Marcucci G, Bloomfield CD, Stock W, Kornblau S, Kantarjian HM, Konopleva M, Paietta E, Willman CL, Loh ML, Hunger SP, Mullighan CG
Nat Commun 2016 Nov 8;7:13331
PMID 27824051
Cellular mesoblastic nephroma: morphologic, cytogenetic and molecular links with congenital fibrosarcoma
Henno S, Loeuillet L, Henry C, D'Hervé D, Azzis O, Ferrer J, Poulain P, Babut JM, Merlio JP, Jouan H, Dubus P
Pathol Res Pract 2003;199(1):35-40
PMID 12650516
Infantile fibrosarcoma of thigh--a case report
Himori K, Hatori M, Watanabe M, Moriya T, Ogose A, Hashimoto H, Kokubun S
Ups J Med Sci 2005;110(1):85-93
PMID 15801689
A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma
Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH
Nat Genet 1998 Feb;18(2):184-7
Characterization of a newly identified ETV6-NTRK3 fusion transcript in acute myeloid leukemia
Kralik JM, Kranewitter W, Boesmueller H, Marschon R, Tschurtschenthaler G, Rumpold H, Wiesinger K, Erdel M, Petzer AL, Webersinke G
Diagn Pathol 2011 Mar 15;6:19
PMID 21401966
ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer
Leeman-Neill RJ, Kelly LM, Liu P, Brenner AV, Little MP, Bogdanova TI, Evdokimova VN, Hatch M, Zurnadzy LY, Nikiforova MN, Yue NJ, Zhang M, Mabuchi K, Tronko MD, Nikiforov YE
Cancer 2014 Mar 15;120(6):799-807
PMID 24327398
Non-resectable congenital tumors with the ETV6-NTRK3 gene fusion are highly responsive to chemotherapy
McCahon E, Sorensen PH, Davis JH, Rogers PC, Schultz KR
Med Pediatr Oncol 2003 May;40(5):288-92
PMID 12652616
Regression of congenital fibrosarcoma to hemangiomatous remnant with histological and genetic findings
Miura K, Han G, Sano M, Tsutsui Y
Pathol Int 2002 Sep;52(9):612-8
PMID 12406191
Congenital fibrosarcoma with metastasis in a fetus
Nonaka D, Sun CC
Pediatr Dev Pathol 2004 Mar-Apr;7(2):187-91
PMID 15022058
Retroperitoneal infantile fibrosarcoma: clinical, molecular, and therapeutic aspects of an unusual tumor
Ramphal R, Manson D, Viero S, Zielenska M, Gerstle T, Pappo A
Pediatr Hematol Oncol 2003 Dec;20(8):635-42
PMID 14578034
Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group
Reshmi SC, Harvey RC, Roberts KG, Stonerock E, Smith A, Jenkins H, Chen IM, Valentine M, Liu Y, Li Y, Shao Y, Easton J, Payne-Turner D, Gu Z, Tran TH, Nguyen JV, Devidas M, Dai Y, Heerema NA, Carroll AJ 3rd, Raetz EA, Borowitz MJ, Wood BL, Angiolillo AL, Burke MJ, Salzer WL, Zweidler-McKay PA, Rabin KR, Carroll WL, Zhang J, Loh ML, Mullighan CG, Willman CL, Gastier-Foster JM, Hunger SP
Blood 2017 Jun 22;129(25):3352-3361
PMID 28408464
Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia
Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, Pei D, McCastlain K, Ding L, Lu C, Song G, Ma J, Becksfort J, Rusch M, Chen SC, Easton J, Cheng J, Boggs K, Santiago-Morales N, Iacobucci I, Fulton RS, Wen J, Valentine M, Cheng C, Paugh SW, Devidas M, Chen IM, Reshmi S, Smith A, Hedlund E, Gupta P, Nagahawatte P, Wu G, Chen X, Yergeau D, Vadodaria B, Mulder H, Winick NJ, Larsen EC, Carroll WL, Heerema NA, Carroll AJ, Grayson G, Tasian SK, Moore AS, Keller F, Frei-Jones M, Whitlock JA, Raetz EA, White DL, Hughes TP, Guidry Auvil JM, Smith MA, Marcucci G, Bloomfield CD, Mrózek K, Kohlschmidt J, Stock W, Kornblau SM, Konopleva M, Paietta E, Pui CH, Jeha S, Relling MV, Evans WE, Gerhard DS, Gastier-Foster JM, Mardis E, Wilson RK, Loh ML, Downing JR, Hunger SP, Willman CL, Zhang J, Mullighan CG
N Engl J Med 2014 Sep 11;371(11):1005-15
PMID 25207766
Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma
Rubin BP, Chen CJ, Morgan TW, Xiao S, Grier HE, Kozakewich HP, Perez-Atayde AR, Fletcher JA
Am J Pathol 1998 Nov;153(5):1451-8
PMID 9811336
Recurrent R-spondin fusions in colon cancer
Seshagiri S, Stawiski EW, Durinck S, Modrusan Z, Storm EE, Conboy CB, Chaudhuri S, Guan Y, Janakiraman V, Jaiswal BS, Guillory J, Ha C, Dijkgraaf GJ, Stinson J, Gnad F, Huntley MA, Degenhardt JD, Haverty PM, Bourgon R, Wang W, Koeppen H, Gentleman R, Starr TK, Zhang Z, Largaespada DA, Wu TD, de Sauvage FJ
Nature 2012 Aug 30;488(7413):660-4
PMID 22895193
Congenital-infantile fibrosarcoma
Sheng WQ, Hisaoka M, Okamoto S, Tanaka A, Meis-Kindblom JM, Kindblom LG, Ishida T, Nojima T, Hashimoto H
A clinicopathologic study of 10 cases and molecular detection of the ETV6-NTRK3 fusion transcripts using paraffin-embedded tissues Am J Clin Pathol
PMID 11242790
Mammary 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, Vanecek T, Majewska H, Laco J, Grossmann P, Simpson RH, Hauer L, Andrle P, Hosticka L, Branžovský J, Michal M
Am J Surg Pathol 2014 Jan;38(1):23-33
PMID 24145651
Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma
Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, Becker L, Carneiro F, MacPherson N, Horsman D, Poremba C, Sorensen PH
Cancer Cell 2002 Nov;2(5):367-76
PMID 12450792
Cryptic 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, Kobayashi H, Hirama T, Kikuta A, Koizumi S, Tsuru T, Kaneko Y
Cancer Genet Cytogenet 2002 Jul 1;136(1):10-6
PMID 12165445
NTRK3 kinase fusions in Spitz tumours
Yeh I, Tee MK, Botton T, Shain AH, Sparatta AJ, Gagnon A, Vemula SS, Garrido MC, Nakamaru K, Isoyama T, McCalmont TH, LeBoit PE, Bastian BC
J Pathol 2016 Nov;240(3):282-290
PMID 27477320


This paper should be referenced as such :
Jean-Loup Huret
t(12;15)(p13;q25) ETV6/NTRK3 in Hematological malignancies
Atlas Genet Cytogenet Oncol Haematol. 2020;24(9):346-349.
Free journal version : [ pdf ]   [ DOI ]
On line version :
History of this paper:
Huret, JL. t(12;15)(p13;q25). Atlas Genet Cytogenet Oncol Haematol. 2009;13(2):130-131.

Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes ETV6

Translocations implicated (Data extracted from papers in the Atlas)

 t(12;15)(p13;q25) ETV6/NTRK3

External links

Mitelman databaset(12;15)(p13;q25)
arrayMap (UZH-SIB Zurich)Morph ( 9964/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9874/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9872/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9811/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
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